Genetic Investigations of Juvenile Idiopathic Arthritis

Genetic investigations of juvenile idiopathic

arthritis

A dissertation submitted to the

Graduate School

of the University of Cincinnati

in partial fulfillment of the

requirements for the degree of

Doctor of Philosophy

in the Immunology Graduate Program

of the College of Medicine

Laura A. McIntosh

B.A. Thomas More College, 2011

Committee Chair: Susan D. Thompson, Ph.D.

Abstract

Juvenile idiopathic arthritis (JIA) is a complex disease characterized by inflammation of the joints and surrounding tissues that manifests before the age of 16 and persists for at least six weeks. It is a heterogeneous disease categorized into seven subtypes and has a prevalence of approximately 1 in 1,000 children. Two subtypes, oligoarticular and rheumatoid factor-negative (RF-) polyarticular

JIA (poly RF-), are the most common and are primarily differentiated by the number of involved joints during the first six months of disease. JIA has a strong genetic component, which has been elucidated by association studies that interrogate common variation in case-control populations.

These studies have identified more than 30 JIA susceptibility loci. Yet, a significant proportion of the genetic heritability for JIA remains unaccounted for, as such studies have included limited sample sizes, heterogeneous patient cohorts, only interrogated candidate regions or common variants, or have not adequately considered additive or epigenetic effects. The overarching hypothesis for the work described in this dissertation is that both common variants and de novo mutations (DNMs) associated with oligoarticular and poly RF- JIA contribute to disease pathogenesis. This hypothesis was tested using genome-wide arrays and whole exome sequencing

(WES), followed by bioinformatic analyses. Common variants and DNMs among oligoarticular and poly RF- JIA patients identified novel susceptibility loci and highlighted biological pathways of potential significance to disease pathogenesis. First, evidence of common variation association was found for nine loci (P < 1x10-6): PRR9_LOR, ILDR1_CD86, WDFY4, PTH1R, RNF215,

AHI1_LINC00271, JAK1, LINC00951, and HBP1. Of these, PRR9_LOR, ILDR1_CD86, RNF215,

LINC00951, and HBP1 are reported as autoimmune disease susceptibility loci for the first time, while WDFY4, PTH1R, AHI1_LINC00271, and JAK1 have been associated in other autoimmune diseases. Single nucleotide polymorphisms (SNPs) located in these novel oligoarticular and poly

RF- JIA loci were evaluated, and all but the PRR9_LOR and LINC00951 loci were found to be functionally relevant. Associated SNPs included cis expression quantitative trait loci that impact gene transcription of WDFY4, CCDC12, MTP18, SF3A1, COG5, HBP1, and GPR22. Furthermore, several SNPs were located in regions with enriched histone marks, indicating that these variants are likely located in functionally active chromatin regions. Additionally, WES and Sanger sequencing identified and validated 15 nonsynonymous, coding region DNMs among 10 JIA patient-parent trios. One DNM was located in DOCK2, whose gene product complexes with the gene product of two JIA-associated loci. Further studies utilized the K/BxN serum-transfer murine model of arthritis to determine the role of DOCK2 in the pathogenesis of disease using DOCK2 deficient mice. These studies demonstrated that DOCK2 is a molecular determinant of autoantibody-induced arthritis that augments disease severity and joint pathology, potentially by driving neutrophil infiltration. In conclusion, this work demonstrates that investigations elucidating the genetic architecture of JIA are valuable for identifying genes or pathways that influence disease pathogenesis. Future work defining the functional implications of these associated SNPs and DNMs, as they relate to JIA disease risk, is necessary to appreciate their contribution to immune regulation and identify potential therapeutic targets for clinical care.

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Acknowledgements

First, I would like to thank my advisor, Dr. Susan Thompson, for her support and insight during the past six years. It has been a pleasure to be her first graduate student. Sue has taught me how to think critically, design thoughtful experiments, and be an independent scientist. I appreciate the time, energy, and contributions she has made to my projects over the years.

I could not have completed this thesis without the help of the Thompson Lab – Lorie Luyrink,

Marc Sudman, Monica Tsoras, Mimi Ryan, and Kenzie Gauck. I am forever indebted to each of you for your constant support and assistance.

Additionally, I thank Dr. Halima Moncrieffe and Dr. Sherry Thornton for their mentorship, guidance, and expertise. Their insight was critical to my success, and I am grateful for the time, effort, and assistance they gave to my thesis work. I thank collaborators at Wake Forest University,

Dr. Carl Langefeld, Dr. Timothy Howard, Miranda Marion, and Mary Comeau, for their support and proficiency.

I would also like to thank the members of my thesis committee, Dr. Alexei Grom, Dr. John Harley,

Dr. Jonathan Katz, Dr. William Nichols, and Dr. William Ridgway, for their scientific input and project suggestions.

To my parents, thank you for being my biggest fans. Your unconditional love and support has driven me to this point, and I could not have done this without you. I also thank the rest of my family and friends for their encouragement, humor, and love over the years.

Lastly, I thank my husband. You have loved and motivated me every minute of this journey, and

I cannot tell you enough how much that has meant to me. On my worst days, you made me believe in myself and continually reminded me that I could overcome any obstacle that stood in my way.

Your inspiration and reassurance have made this possible. I love you, always.

Table of Contents Abstract………………………………………………………………………………..…. ii Acknowledgements……………………………………………………………………..... v Table of Contents………………………………………………………..……………….. vii List of Abbreviations……………………………………………………………..……… viii List of Figures/Tables……………………………………………………………………. xii CHAPTER 1: Introduction………………….………………………………...………… 1 1.1 Juvenile Idiopathic Arthritis Overview…………………………………………….. 2 1.2 Etiology of JIA…………………………………………………………………...…... 4 1.3 Genetics of JIA……………………………………………………………………...... 5 1.3.1 Common variation in JIA.………………………………………………………... 6 1.3.2 Disease impact of rare and low frequency variants…………………………...… 10 1.4 Pathophysiology of JIA…………………………………………………………….... 13 1.4.1 Innate immune system in JIA………….…………………………………………. 14 1.4.2 Adaptive immune system in JIA………….………………………………………. 21 1.4.3 Resident joint cells in JIA………………………………………………………... 27 1.4.4 Cartilage and bone destruction in JIA…………………………………………… 27 1.5 Mouse Models of Arthritis……………………………………………………….….. 29 1.5.1 K/BxN serum-transfer model of arthritis………………………………………… 30 1.6 Hypothesis and Specific Aims………………………………..……………………… 32 References……………………………………………………………………………….... 34 CHAPTER 2: Genome-wide association meta-analysis reveals novel juvenile idiopathic arthritis susceptibility loci…………………………………...………………. 50 Abstract……………………………………………………………………………….. 53 Introduction…………………………………………………………………………… 55 Patients and Methods……………………………………………………………….... 57 Results…………………………………………………………………………………. 62 Discussion……………………………………………………………………………... 67 Acknowledgements…………………………………………………………………… 73 References…………………………………………………………………………….. 74 Appendix A………………………………………………………………………….... 77 Figures/Tables………………………………………………………………………… 79 CHAPTER 3: Whole exome trio sequencing implicated DOCK2 in juvenile idiopathic arthritis…………………..…………………………………………………… 286 Abstract……………………………………………………………………………….. 287 Introduction…………………………………………………………………………… 288 Materials and Methods……………………………………………………………….. 290 Results…………………………………………………………………………………. 294 Discussion……………………………………………………………………………... 299 Acknowledgements…………………………………………………………………… 305 References……………………………………………………………………………... 306 Figures/Tables………………………………………………………………………… 309 CHAPTER 4: Summary, discussion, and future directions…………………………. 322 Overall Summary……………………………………………………………………... 323 Discussion and Future Work………………………………………………………… 326 References……………………………………………………………………………... 335

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List of Abbreviations

AID: Autoimmune disease

ANA: Anti-nuclear antibody

ASD: Autism spectrum disorder

APC: Antigen presenting cell

APCA: Anti-citrullinated protein antibody

ASD: Autism spectrum disorder

BIM: Bcl-2 like protein 11

BLyS: B lymphocyte stimulator bp: Base pair

CAP37: Cationic antimicrobial protein of 37kd

CD: Cluster of differentiation

CeD: Celiac disease

CIA: Collagen induced arthritis

CNV: Copy number variant

CTLA-4: Cytotoxic T lymphocyte associated protein-4

DC: Dendritic cell

DC-SIGN: Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin

DMARD: Disease-modifying anti-rheumatic drug

DKK-1: Dickkopf 1

DNA: Deoxyribonucleic acid

DNM: de novo mutation

EBV: Epstein-Barr virus

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FAS: Fas cell surface death receptor

FDA: Food and Drug Administration fMLP: N-formylmethionine-leucyl-phenylalanine

FLS: Fibroblast-like synoviocytes

G6PI: Glucose-6-phosphate isomerase

GM-CSF: Granulocyte-macrophage colony-stimulating factor

GWAS: Genome-wide association study

HLA: Human leukocyte antigen

IBD: Inflammatory bowel disease

IC: Immune complex

ID: Intellectual disability

IFN: Interferon

IL: Interleukin

ILAR: International League of Associations for Rheumatology

Indel: Insertion-deletion iNOS: Inducible nitric oxide synthase

IRF1: Interferon regulatory factor 1

JACI: Juvenile Arthritis Consortium for Immunochip

Jak: Janus

JIA: Juvenile idiopathic arthritis

LCK: Lymphocyte specific protein tyrosine kinase

MAF: Minor allele frequency

MHC: Major histocompatibility complex

MMP: Matrix metalloproteinases

MS: Multiple sclerosis

MTX: Methotrexate

NET: Neutrophil extracellular trap

NF-κB: Nuclear factor kappa-light-chain-enhancer of active B cells

NGS: Next generation sequencing

NK: Natural killer

NKT: Natural killer T

NOD: Non-obese diabetic

NSAID: Nonsteroidal anti-inflammatory drug

OPG: Osteoprotegerin

PAD4: Peptidyl arginine deiminase 4

PBC: Primary biliary cirrhosis

PBMC: Peripheral blood mononuclear cell

Poly RF-: Rheumatoid factor-negative polyarthritis

PTPN2: Protein tyrosine phosphatase non-receptor type 2

PTPN22: Protein tyrosine phosphatase non-receptor type 22

RA: Rheumatoid arthritis

RANK: Receptor activator of NF-κB

RANKL: Receptor activator of NF-κB ligand

RF: Rheumatoid factor

ROS: Reactive oxygen species

SF: Synovial fluid

SFMC: Synovial fluid mononuclear cell

SH2B3: SH2B adaptor protein 3

SLE: Systemic lupus erythematosus

SNP: Single nucleotide polymorphism

SNV: Single nucleotide variant

STAT: Signal transducer and activator of transcription

T1DM: Type 1 diabetes mellitus

Th: T helper

TCR: T cell receptor

TGF: Transforming growth factor

TLR4: Toll-like receptor 4

TNF-α: Tumor necrosis factor alpha

Treg: Regulatory T cell

TREX1: 3’ repair exonuclease 1

TYK2: Tyrosine kinase 2

UBE2L3: Ubiquitin conjugating enzyme E2 L3

WES: Whole exome sequencing

WGS: Whole genome sequencing

Zap-70: Zeta chain-associated protein kinase 70

List of Figures/Tables Chapter 2: Genome-wide association meta-analysis reveals novel juvenile idiopathic arthritis susceptibility loci Figure 1. Manhattan plot of genome-wide genetic association statistics for oligoarticular 79 and rheumatoid factor-negative polyarticular juvenile idiopathic arthritis (JIA) risk loci Figure 2. IPA showing interactions between products of genes located in juvenile idiopathic arthritis-associated regions from the current study and previous Immunochip 80 studies Table 1. SNPs representing top statistical associations (P < 1x10-6) with oligoarticular 81 JIA and RF-negative polyarticular JIA Table 2. Overlapping regions of association between oligoarticular and RF-negative 82 polyarticular JIA and other autoimmune diseases Table 3. Expression of quantitative trait locus (eQTL) genes in novel oligoarticular- and 83 RF-negative polyarticular JIA-associated regions Supp Figure 1. Power analysis over range of minor allele frequencies (MAF) for meta- 84 analysis with type I error rate of 1x10-6 Supp Figure 2. LocusZoom plots for the nine novel regions associated with JIA (P < 85 1x10-6) Supp Table 1. Sample collection breakdown by gender and ILAR subtype post-QC 95 Supp Table 2. Second tier findings of genetic association with oligoarticular and 96 polyarticular RF negative JIA 1.0x10-6 < P < 1.0x10-5 Supp Table 3. Association findings for all SNPs showing evidence of association with 100 oligoarticular and RF negative polyarticular JIA (FDR < 0.05) Supp Table 4. Histone modifications at SNP positions in the nine regions with genetic 273 association with oligoarticular and polyarticular RF negative JIA (P < 1x10-6) Supp Table 5. Oligoarticular and RF negative polyarticular JIA association results for 275 genome-wide significant SNPs associated with rheumatoid arthritis (RA) Supp Table 6. Oligoarticular and RF negative polyarticular JIA association results for genome-wide significant SNPs associated with type 1 diabetes (T1D) 282

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Chapter 3: Whole exome trio sequencing implicated DOCK2 in juvenile idiopathic arthritis Figure 1. DOCK2 deficiency decreases measures of joint inflammation in the K/BxN 309 serum-transfer model of arthritis Figure 2. DOCK2 deficiency diminishes K/BxN serum-transfer arthritis in the forepaws 310 of C57/BL6 mice Figure 3. DOCK2 deficiency ameliorates K/BxN serum-transfer arthritis in the knees of 312 C57/BL6 mice Figure 4. DOCK2 deficiency decreases hindpaw neutrophil infiltration in K/BxN serum- 313 transfer arthritis. Table 1. Validated DNMs among 10 trio probands with oligoarticular or RF-negative 314 polyarticular JIA Supp Figure 1. Depiction of hindpaw and ankle thickness measurements 317 Supp Figure 2. Cellular homing of T and B cells to the spleen is impaired with genetic 318 loss of DOCK2 Supp Table 1. Demographic and allele-specific genotypes of trio probands 320 CHAPTER 4: Summary, discussion, and future directions Table 1. Top statistical associations from genome-wide meta-analysis for oligoarticular and poly RF- juvenile idiopathic arthritis (JIA) with P < 1.0x10-6 for loci originally 327 reported in the Immunochip study

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Chapter 1: Introduction

1.1 Juvenile Idiopathic Arthritis Overview

Juvenile idiopathic arthritis (JIA) describes a group of clinically heterogeneous, chronic arthritides with unknown cause that begins prior to the age of 16 and lasts a minimum of 6 weeks [1]. It is the most common childhood rheumatic disease with a prevalence of 1 in 1,000 children in the

United States [2, 3] and exhibits a gender bias towards females (F:M = 3-6.6:1) that appears to be unrelated to hormones, as disease is affecting prepubescent individuals [4]. The International

League of Associations for Rheumatology (ILAR) has defined criteria for JIA diagnosis, dividing the disease into 7 subtypes that present with different clinical features [5]. These include oligoarticular JIA, rheumatoid factor (RF)-negative polyarticular JIA, RF-positive polyarticular

JIA, systemic JIA, enthesitis-related arthritis, psoriatic JIA, and undifferentiated JIA. Despite this heterogeneity, all disease subtypes exhibit a persistent inflammation of the joint(s), due to the accrual of synovial fluid (SF) and a thickened lining of the synovium [6]. If left untreated, patients with this debilitating disease face the possibility of irreversible damage to the joint that could lead to total loss of function and potential disability.

Significant advances have been made in understanding JIA immunopathology, leading to the use of therapies that have had a transformative effect on the health of many patients. Nonsteroidal anti- inflammatory drugs (NSAIDs), such as ibuprofen and naproxen, remain a staple in the treatment of all JIA subtypes. However, these medications treat symptoms and are therefore not recommended to be the only form of pharmacologic therapy for more than 2 months if disease is still active [7]. Corticosteroids, typically given as intra-articular injections, also help to alleviate inflammation and restore the functional mobility of the joint [8]. While NSAIDs and corticosteroids are traditional methods of managing JIA, disease-modifying anti-rheumatic drugs

(DMARDs), such as methotrexate (MTX), remain the gold standard. However, nearly 30-40% of patients fail to respond to MTX treatment based on clinical outcome measures [9]. While the quality of life for JIA patients who do respond has been shown to improve while taking MTX [10], it can be accompanied by side effects that make tolerance and compliance difficult [11-13].

Patients that fail to respond or have a sub-optimal response to conventional DMARDs are subsequently placed on biologic agents. These immunomodulatory drugs may be given in combination with MTX therapy [14]. Currently, the U.S. Food and Drug Administration (FDA) has approved five biological agents to be used in the treatment of JIA. These include two agents that target tumor necrosis factor alpha or TNF-α (Etanercept and Adalimumab), one that interferes with T cell activation (Abatacept), one that antagonizes the interleukin (IL)-6 receptor

(Tocilizumab), and one that antagonizes IL-1β (Canakinumab) [15]. Each of these biologics target different molecules that play critical roles in the JIA disease process. TNF-α, IL-6, and IL-1β drive synovial inflammation, which leads to joint destruction [16]. Additionally, IL-6 drives T cell differentiation into the pro-arthritic T helper (Th) Th17 cell subtype and away from the immune- dampening regulatory T cell (Treg) subtype [17]. TNF inhibitors have been shown to decrease the concentration of certain pro-inflammatory cytokines in the serum, the number of joints with active disease, and progressive joint damage [18-20], while improving quality of life, growth, and bone mass [21, 22]. The IL-6 receptor antagonist, Tocilizumab, has been shown to significantly improve disease while decreasing the rate of flare occurrence [23]. The use of Canakinumab, the IL-1β antagonist, has only been approved for use in systemic JIA patients, but has shown improvement in time to response and tolerance measures [24]. Abatacept is a human fusion protein that contains the extracellular portion of cytotoxic T lymphocyte associated protein-4 (CTLA-4), which binds

to CD80/CD86 (CD, cluster of differentiation) to prevent the secondary signal needed for T cell activation [25]. Its usage has also been shown to improve disease and decrease the risk of flares in

JIA patients [26].

While the benefit of pharmaceutical intervention in the treatment of JIA is undeniable, the goal of clinical remission off medication for all children still remains. There is an unmet need to understand mechanisms of disease initiation and progression in order to target these, as yet undefined, pathways in future therapies that will translate to better clinical outcomes in JIA patients.

1.2 The Etiology of JIA

The etiology of JIA has yet to be fully elucidated, but the most widely accepted working model involves a complex interaction between environmental factors and genetics. Disease incidence varies significantly across ethnicities [27-30], and individuals of European descent appear to have an increased risk of developing JIA [31, 32]. Moreover, JIA subtype frequency varies by ethnicity as well [33]. These ethnic differences further support a JIA etiology model involving interactions between environmental factors and various genes.

As a whole, the influence of environmental factors to JIA etiology is largely undefined. Such studies are constrained by the need to evaluate each subtype individually due to disease heterogeneity, which is confounded by a limited number of new onset cases and lack of properly controlled prospective studies [34]. Published studies have implicated viral (e.g. Parvovirus B19 and Epstein-Barr virus (EBV)) and bacterial pathogens (e.g. enteric bacteria, Chlamydophila

pneumoniae, and Streptococcus pyogenes), as well as antibiotic usage in the development of JIA

[35-40]. Emerging studies on the role of the microbiome in JIA have found that microbial diversity is disrupted during disease [41, 42], but it is unclear at this time if this dysbiosis is caused by, an effect of, or unrelated to disease manifestation. Breastfeeding [43] and maternal smoking [44] have also been linked to JIA etiology, but results from replication studies have been inconsistent [45-

48]. Vitamin D/sun exposure has been suggested to influence disease risk among other autoimmune diseases (AIDs), but there is no clear evidence supporting this hypothesis in JIA [34,

49]. These environmental studies were underpowered and/or included heterogeneous patient populations, which makes drawing accurate conclusions applicable to the greater population difficult.

Compelling evidence for the role of genetics in JIA susceptibility includes twin and family studies.

Studies involving monozygotic twins have led to an estimated JIA concordance rate between 25% and 40% [50], which is significantly greater than prevalence rates reported for the general population of various ethnicities [27-30]. Furthermore, the sibling and first cousin relative risk ratios have been calculated at 11.6 and 5.8, respectively [27]. These values corroborate a genetic predisposition to JIA disease risk, which has led to the employment of numerous genetic studies to further dissect the complex genetic etiology of JIA.

1.3 Genetics of JIA

JIA is a complex genetic disease with multiple gene loci contributing to disease risk. Over the last couple decades, dissecting the genetic basis of complex diseases has been accomplished by the use of genome-wide association studies (GWAS). Such studies are based on the “common disease-

common variant” hypothesis (minor allele frequency, MAF > 5%), which reasons that genetic polymorphisms with appreciable frequency in case populations are the primary contributors to disease susceptibility [51]. Common variant studies have identified a number of JIA susceptibility loci and are discussed in detail below.

1.3.1 Common variation in JIA

Genetic studies identifying common JIA risk loci have proven challenging given the relative rarity and heterogeneity of the disease. To overcome such hurdles, the oligoarticular and

RF- polyarticular (poly RF-) subtypes are often studied together. These two subtypes comprise approximately 70% of all JIA cases and are phenotypically similar to another, differing primarily in the number of affected joints at diagnosis [52]. Oligoarthritis is defined to include patients with up to four affected joints in the first six months following disease onset, whereas polyarthritis affects five or more joints during the same time frame [5]. Additionally, the age at disease onset is similar for these two subtypes, peaking at 1-4 years, with the polyarticular subtype exhibiting a biphasic pattern and also peaking at 6-12 years of age [53]. Investigating these two subtypes together has limited heterogeneity (when compared to studying all JIA subtypes together), while maintaining the ability to execute a well-powered genetic study capable of detecting variants with

MAF > 5%. Many reports have centered on oligoarticular and poly RF- JIA [54-57], and these subtypes in patients of European ancestry are the focus of this thesis.

The locus with the greatest effect size is the human leukocyte antigen (HLA) region on chromosome 6 (rs7775055, P = 3.1x10-174) [55], and this region was first discovered for association with JIA in the 1980s/early 1990s [58-62]. HLA molecules are responsible for

presenting antigens to T cells. Specifically, the class I HLA allele A2 and the class II HLA alleles

DRB1:0801, DRB1:1103/1104 and DRB1:1301 are associated with both oligoarticular and poly

RF- JIA [58, 62-64]. However, the HLA DRB1:1103/1104 susceptibility alleles are limited to patients with oligoarticular JIA and younger onset (< 6 years) poly RF- JIA [63, 64]. Interestingly,

HLA DRB1:0401, DRB1:0701, and DRB1:1501 do not appear frequently in oligoarticular and poly

RF- JIA patients, suggesting that these alleles are protective [61, 63]. These risk and protective alleles have the opposite effect in adult-onset rheumatoid arthritis (RA), with DRB1:08, DRB1:11, and DRB1:13 being protective alleles and DRB1:04 being a susceptibility allele [65]. Fine- mapping of the HLA locus in oligoarticular and poly RF- JIA patients revealed that the strongest association was with HLA-DRB1 amino acid position 13, with glycine13 conferring the strongest risk and histidine13 being protective [66]. Conversely, glycine13 is protective in seropositive RA and histidine13 confers risk [65]. Thus, despite being clinically similar, the two diseases are genetically different at the HLA locus.

Following HLA, the PTPN22 (protein tyrosine phosphatase non-receptor type 22) and PTPN2

(protein tyrosine phosphatase non-receptor type 2) loci, found on chromosomes 1 and 18, respectively, were next reported and reach genome-wide levels of significance (P < 5x10-8) [57].

Associations with these loci are not unique to JIA, but are also associated with other AIDs such as

RA, type 1 diabetes mellitus (T1DM), and celiac disease (CeD) [67-69]. PTPN22 and PTPN2 dephosphorylate T cell receptor (TCR)-associated LCK (lymphocyte specific protein tyrosine kinase) and Zap-70 (zeta chain-associated protein kinase 70), which downregulates TCR activation

[70, 71]. Furthermore, PTPN2 has also been described to reduce chemokine production via

dephosphorylation of STAT1 (signal transducer and activator of transcription 1) dimers and apoptosis by dephosphorylation of BIM (Bcl-2 like protein 11) proteins [70, 71].

Perhaps the genotyping array that has had the greatest impact on the field of JIA genetics was established by the Immunochip Consortium. The Immunochip cost-effectively interrogates roughly 196,000 SNPs across 186 loci, including dense coverage in the HLA region [72]. These loci were selected based on their known association with a number of diseases, including: RA, ankylosing spondylitis, systemic lupus erythematosus (SLE), T1DM, autoimmune thyroid disease,

CeD, multiple sclerosis (MS), ulcerative colitis, Crohn’s disease, and psoriasis from published

GWAS [72].

Following the advent of the Immunochip, the Juvenile Arthritis Consortium for Immunochip

(JACI) assembled the largest cohort of oligoarticular and poly RF- JIA patients (n = 2,816) used to date. This well-powered study identified 14 susceptibility loci that reach genome-wide levels of association [55]. The risk loci included: STAT4, ANKRD55, IL2-IL21, TYK2, IL2RA, SH2B3-

ATXN2, ERAP2-LNPEP, UBE2L3, C5orf56-IRF1, RUNX1, IL2RB, ATP8B2-IL6R, FAS, and

ZFP36L1 [55]. Previously known JIA genome-wide associations at the HLA, PTPN22, and PTPN2 loci were also confirmed [55]. Additionally, 11 loci showed suggestive evidence of association:

LTBR, IL-6, COG6, 13q14, CCR1-CCR3, PRR5L, PRM1-RMI2, RUNX3, TIMMDC1-CD80,

JAZF1, and AFF3-LONRF2 [55]. As anticipated, many of these regions overlap with loci known to be associated with other AIDs, with the lead SNPs for each region being the same or highly correlated and with the same directional effect [55].

A number of associated loci identified in the Immunochip study also have known roles in the immune system. Of note, IL-2 and IL-21 play a role in T cell proliferation and differentiation [73,

74]. Mouse knockout studies have revealed that IL-2 downregulates the immune response to prevent autoimmunity [75, 76]. STAT4 activation via IL-12, IL-23, and type I interferons (IFNs) drives IFN-γ and IL-17 production, as well as Th1 and Th17 cell lineages [77]. TYK2 (tyrosine kinase 2) is a member of the Janus (Jak) tyrosine kinase family involved in the signaling of type I and III IFNs, IL-6, IL-10, IL-12, IL-22, IL-23, and IL-26 [78]. SH2B3 (SH2B adaptor protein 3) is a negative regulator of B and T lymphopoiesis, inflammation, and cellular adhesion/migration

[79]. UBE2L3 (ubiquitin conjugating enzyme E2 L3) is an E2 ubiquitin-conjugating enzyme that leads to the activation of NF-κB (nuclear factor kappa-light-chain-enhancer of active B cells) [80].

IRF1 (interferon regulatory factor 1) plays a multifactorial role in the immune response. It drives

IFN, IL-12, and inducible nitric oxide synthase (iNOS) expression, T cell differentiation, natural killer (NK) cell development, and apoptosis [81, 82]. Lastly, FAS (Fas cell surface death receptor) is critical to apoptosis, and if rendered mutant, spontaneous autoantibodies can result [83].

Despite attempts to reduce disease heterogeneity by focusing on two phenotypically similar disease subtypes, oligoarticular and poly RF- JIA association studies to date remain underpowered

[56, 57] or have not utilized genome-wide arrays [55]. Moreover, while these studies have identified a number of JIA risk loci, disease inheritance cannot be fully explained. In fact, it is estimated that the common variation described above only accounts for approximately one-third of the predicted JIA genetic susceptibility [55]. It is plausible then that this missing heritability can be attributed to low frequency (defined as MAF 0.5-5%) [84] and rare variants (MAF < 0.5%)

with modest to large effects that are not measured with the use of genotyping arrays and undetectable with small patient populations.

1.3.2 Disease impact of rare and low frequency variants

In contrast to the search for common variation among diseased individuals, recent studies have elucidated the role of rare and low frequency variants that are undetectable by GWAS arrays [85-

89]. Indeed, the Immunochip included approximately 23,000 rare (16% of SNP content) and

25,000 low frequency variants (18% of SNP content) on the array [90]. As opposed to array-based genotyping, the development of next generation sequencing (NGS) technology does not require predetermined probes to interrogate specific sequences, but can evaluate any variant in the genome. This has proved incredibly influential for rare and low frequency variant detection. NGS has revolutionized the field of genetic research by enabling the entire human genome to be sequenced within a single day as opposed to previous methods (e.g. Sanger sequencing) that took several years [91]. Using NGS, DNA (deoxyribonucleic acid) is fragmented into millions of pieces that are sequenced in parallel. Each base is sequenced multiple times to ensure accuracy. Following sequencing, DNA fragments are aligned to reference genomes. NGS can be utilized to sequence the entire genome (WGS, whole genome sequencing), portions of DNA that code for proteins

(WES, whole exome sequencing), or to fine map a specific target region [91].

NGS has the ability to detect rare variants called de novo mutations (DNMs). DNMs most commonly occur as single nucleotide variants (SNVs), but also refer to insertion-deletions (indels) or copy number variants (CNVs) [92]. The frequencies at which indels and CNVs occur are not well-established, but it is the general consensus that they are of lower incidence than SNVs [92].

Rough estimates place the number of small (<50 bp, base pairs) indels, large (50-5,000 bp) indels, and CNVs at 2.9-9, 0.16, and 0.015 per generation, respectively [93, 94]. It is estimated that 40-

80 SNVs occur per genome per generation [95, 96] and tend to occur most frequently at CpG sites

[97, 98]. Furthermore, a positive correlation exists between SNV total and paternal age [99]. Given the frequency of SNVs and their ease of detection using family-based sequencing approaches, a number of studies have investigated their role in human disease.

Monogenic diseases have greatly benefited from NGS technology. Using WES of patient- biological parent trios, the causal genes underpinning Schinzel-Giedion syndrome, Kabuki syndrome, and Bohring-Opitz syndrome have been identified [100-102]. In fact, it has been reported that the root causes of half of all Mendelian disorders have been identified [103]. Disease mechanisms underlying monogenic diseases have also provided valuable insights into the etiology of autoimmune diseases, specifically SLE. Aicardi-Goutières syndrome is a monogenic disease with known causal mutations in TREX1 (3’ repair exonuclease 1) [104] and clinical features that overlap with SLE (e.g. IFN-α and anti-nuclear antibody (ANA) production). In view of this similar phenotype, studies have been done to sequence TREX1 in SLE patients and reported rare, coding mutations [105, 106]. This discovery illustrates a potential role for rare variants in complex diseases.

SNV detection has proved useful in elucidating disease mechanisms for rare phenotypes. For example, a heterozygous SNV, acting in a dominant negative manner, in the thyroid receptor alpha gene explained atypical hypothyroidism in a child [107]. Moreover, a heterozygous SNV in CTLA-

4 resulted in decreased protein expression, which subsequently altered the Treg phenotype in a

patient with Evan’s syndrome (an autoimmune disease) and primary immunodeficiency [108].

Considering these successes, rare variants have received more attention in recent years.

The role that rare SNVs play in complex genetic traits was first elucidated in psychiatric disorders.

The first study performed for psychiatric disorders included WES of trios, where the probands had intellectual disability (ID) [109]. Here, nine nonsynonymous SNVs were found in patients with

ID, but neither parent. Of these, six occurred in genes with functional evidence for a role in ID based on known causal genes, model organisms, and protein-protein interaction investigations

[109]. The same experimental design was subsequently extended to other psychiatric disorders, such as autism spectrum disorders (ASDs) and schizophrenia [110-112], and have found that the rare variants detected in each respective study are associated with increased risk. These exome sequencing studies convincingly showed this approach to be a path to gene discovery or revealed the genetic basis for the disease, thus highlighting WES as a complimentary strategy to GWAS.

To further elucidate the genetic architecture of AIDs, studies have detected a number of rare variants within or near established associated-disease loci. Using a case-control candidate sequencing approach, rare, nonsynonymous variants within/near IL2RA and IL2RB (established

RA susceptibility loci) accumulated exclusively in RA patients [113]. Similar methods were used to detect rare, SNVs in NOD2 with inflammatory bowel disease (IBD) [114, 115] and in CARD14 with psoriasis [116]. The Immunochip has also been utilized to identify rare variants in IL12A associated with systemic sclerosis [117] and primary biliary cirrhosis (PBC) patients [118], and within the 16p13 region with PBC [118] and CeD [90]. Lastly, WES has identified rare frequency variants in PRDM1 in ulcerative colitis patients [119] and variants in DNMT3A, PRKCD, and

C1QTNF4 in SLE patients [89]. These studies have identified rare SNVs that may provide new clues for disease pathogenesis and require further functional studies.

In addition to the identification of rare SNVs, AID studies have also searched for low frequency variants contributing to disease risk. Low frequency variants, detected by candidate gene sequencing, the Immunochip array, and WES, have been reported within/near the following genes with the following diseases: IFIH1 with T1DM [120]; IL23R with IBD [121]; TYK2, IL23R, and

GJB2 with psoriasis [122, 123]; TYK2 with RA [124]; BLK and TREX1 with SLE [106, 125]; TYK2 with PBC [118]; CD28-CTLA4-ICOS, RGS1, and PTPN2 with CeD [90]. This prompts the need for innovative studies exploring other potential sources of variability, such as rare and other low frequency variants, in order to advance genetic discovery in JIA.

1.4 Pathophysiology of JIA

The pathology of JIA is multifaceted and entails a broad dysregulation of the immune system. JIA is predominantly distinguished by chronic inflammation of the joint(s), as a result of accruing SF and synovial thickening. Cells involved in both the innate (e.g. neutrophils, dendritic cells (DCs), and macrophages) and adaptive (e.g. T and B lymphocytes) immune systems are present in the SF and surrounding tissues [126-128], but the exact event triggering this autoinflammatory response in the joint(s) remains elusive. Some reports describe a self-reactive T cell response that drives autoantibody production by B cells and inflammatory cytokine production (e.g. IL-1β, IL-6, and

TNF-α) by macrophages [129, 130]. Others propose an innate immune response where mediators

(e.g. IFN-γ and BLyS (B lymphocyte stimulator)) are released to initiate T cell activation/expansion and B cell maturation [131]. Despite this, it is agreed upon that both the innate

and adaptive immune responses are contributors to the induction of disease pathogenesis. Cells residing within the joint, such as synoviocytes, chondrocytes, osteoclasts, and osteoblasts, also play critical roles to the disease process [132-134]. The presence of inflammatory cytokines in the joint, such as IL-1β, IL-6, and TNF-α, aid in the activation of immune cells, propagate inflammation, and damage local tissues/bones [135, 136]. Each of these mediators are critical to

JIA pathology, which is shown by the success of the biologic therapies used to target them in the treatment of JIA [18-24]. By assessing the impact of each cell type and mediator on disease, the processes underlying JIA pathophysiology can be understood in greater detail.

1.4.1 Innate immune system in JIA

The immune system requires strict regulation when responding to foreign pathogens in order to maintain self-tolerance and prevent chronic stimulation that damages the host. The innate immune system is responsible for surveying host tissues for the presence of potentially dangerous material and eliciting a rapid response in the event that such material is detected. Thus, it acts as the first line of defense against pathogenic organisms. Following activation, innate immune cells promote responses from antigen-specific cells of the adaptive immune system. Apart from the protective role that the innate immune system has in response to pathogens, it can also assist in driving autoimmune responses. Cells of the innate immune system and their role in JIA pathophysiology are discussed in more detail below.

Neutrophils. Neutrophils are the most abundant circulating leukocyte population in humans and serve as the first line of defense against bacterial and fungal pathogens. Moreover, they are the most abundant cell type found within the SF of JIA patients [126] and display a chronically

activated phenotype even when disease is in remission [137]. Despite this and the fact that they possess a plethora of antimicrobial proteins with the capacity to damage host tissues when aberrantly activated, their role in JIA and other AID pathogenesis has largely been undefined [131,

138]. This is most likely attributed to the fact that they are terminally differentiated, short-lived cells [139]. However, it is becoming more apparent that neutrophils and their effector functions bridge the innate and adaptive immune responses.

Neutrophils are recruited into the joint space by chemokines (e.g. IL-8, CXCL1, and CXCL2) and other soluble mediators (e.g. N-formylmethionine-leucyl-phenylalanine (fMLP) and C5a) [140].

Their Fcγ receptors are then engaged by immune complexes (ICs) located in the SF or deposited on the articular cartilage surface [141]. This results in the degranulation of reactive oxygen species

(ROS) and proteases (e.g. matrix metalloproteinases (MMPs)) that degrade cartilage and other joint tissues [141-144]. Neutrophils perpetuate the inflammatory cytokine milieu by expression of

TNF-α, IL-1β, IL-18, and others [138, 145, 146]. The quick formation of neutrophil extracellular traps (NETs), coined NETosis, can also contribute to the pathophysiology of JIA. NETosis releases histone-containing chromatin into the extracellular space where arginine residues can be citrullinated by neutrophil-produced peptidyl arginine deiminase 4 (PAD4) [147]. These citrullinated peptides create novel antigens recognized by anti-citrullinated protein antibodies

(APCAs), which can be detected in JIA patients [148]. Furthermore, neutrophil expression of

TLR4 (toll-like receptor 4)-induced RANKL (receptor activator of NF-κB ligand) activates osteoclasts to resorb bone [149]. Thus, there is direct evidence for a pathophysiologic role of neutrophils in JIA.

In addition to the role that neutrophils themselves play in JIA, they have also been shown to shape the adaptive immune response. Neutrophil influences on monocytes, DCs, B, and T cells have been demonstrated. For example, neutrophil degranulation of myeloperoxidase and CAP37

(cationic antimicrobial protein of 37kd) drives monocyte chemotaxis and HLA class II upregulation [150, 151]. Similarly, activated neutrophils secrete chemokines (e.g. CCL3 and

CCL4) and cytokines (e.g. TNF-α) that attract immature DCs and induce their maturation by DC upregulation of costimulatory molecules and production of TNF-α and IL-12 [152-154]. In addition to the direct effects that neutrophils have on innate immune cells, which in turn activate the adaptive immune response, they can also directly influence B and T cells. Activated neutrophils secrete large amounts of BLyS, driving B cell differentiation, apoptosis, and antibody production

[155]. Recently, it was discovered that neutrophils possess the capability to present antigen to T cells [156, 157]. These data suggest that neutrophils are more than just bystanders to the immune process.

Murine models of arthritis speak to the importance of neutrophils in the disease process as a whole.

The depletion of neutrophils protects mice from developing arthritis in the K/BxN serum-transfer

[158, 159] and collagen antibody-induced arthritis models [160, 161], indicating that these cells are essential for disease onset. Furthermore, administering neutrophil-depleting antibodies following disease onset in these models resulted in decreased disease severity. This implies that neutrophils are also important to disease progression. While it is evident that neutrophils are critical to arthritis pathogenesis in mice, their role in human arthritis is not yet fully understood.

Macrophages. Macrophages are tissue-resident cells of the innate immune system that magnify inflammation in the joint. The importance of macrophages to disease progression has been demonstrated in the K/BxN serum-transfer model, where macrophage depletion confers resistance to arthritis [162]. Macrophages express MHC (major histocompatibility complex) class II and costimulatory molecules for antigen presentation to T cells and secrete pro-inflammatory cytokines

(e.g. TNF-α, IL-1β, IL-6, IL-12, and IL-18) and chemokines (e.g. CCL15, CCL20, CXCL8,

CXCL11, and CXCL13) [163, 164]. The expression of these mediators perpetuate the immune response and mediate the destruction/remodeling of joint tissues. For example, macrophages are the main producers of TNF-α in the synovium [165], and its concentration in the SF correlates with the total macrophage population and the extent of radiologically measured bone erosion

[166]. Furthermore, IL-1β stimulates the production of MMPs and collagenase while promoting the degradation of proteoglycans [167]. Synovial macrophages produce IL-8, which promotes angiogenesis and explains the increased vascularity observed in the rheumatoid synovium [168].

Given the pro-inflammatory nature of synovial macrophages, it is generally agreed that classically activated M1 macrophages dominate the environment [169]. While the alternatively activated M2 macrophages have not been studied in much detail in AIDs, they have been shown to induce Treg signatures in naïve, CD4+ T cells [170]. Thus, altering the M1/M2 balance in the rheumatoid synovium may prove to be a beneficial therapy for JIA patients.

Dendritic cells (DCs). The presence of activated, oligoclonal T cells in the synovium of JIA patients speaks to an immunopathology that is in part dictated by a T cell response. One proposed mechanism for T cell homing to the joint is by chemokine secretion from APCs, such as DCs

[171]. Both plasmacytoid and conventional DCs are enriched within the SF of JIA patients [172].

Plasmacytoid DCs produce IFN-α and are located near lymphoid follicle-like structures in the synovium [172]. Mature, conventional DCs that express DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin) for migration into tissues from the blood and CD86 for co-stimulation for T cells [173] are found at the lining and sublining of synovial tissues [172]. Furthermore, a number of these conventional DCs were found to express RANK

(receptor activator of NF-κB) [173], and RANK signaling can promote T cell survival [174]. This suggests that DCs may promote the perpetuation/expansion of T cells in the joint.

Natural killer (NK) cells. NK cells are cytotoxic, innate lymphocytes that detect and kill tumor and virally-infected cells [175]. Studies investigating their role in non-systemic JIA pathophysiology have been limited and contradictory. One report showed decreased NK cell activity in PBMCs

(peripheral blood mononuclear cells), SFMCs (synovial fluid mononuclear cells), and synovial tissue in JIA patients [176]. Others found no statistical differences in the frequency of NK cells

(using only CD16 as a surface marker) among patients with active disease, disease in remission, or controls [177]. Considering the evidence implicating viral infections in JIA etiology [36], investigations into whether or not NK cells function aberrantly in JIA patients may prove valuable.

Natural killer T (NKT) cells. Despite being a relatively rare population, NKT cells, which possess both NK and T cell properties, can quickly direct the immune response through their vast cytokine production. While it was once suggested that NKT cells play a protective role in the generation of adult arthritis [178], mice that lack NKT cells (Jα18-/-) or CD1d (MHC class I molecule that presents antigen to NKT cells) have less severe arthritis compared to normal controls in the K/BxN serum-transfer model of arthritis [179]. To date, only one study has reported on the function of

these cells in oligoarticular and polyarticular JIA patients, which observed increased percentages and total numbers of CD3+CD56+perforin+ and CD3+CD56+granzyme B+ cells in patients with disease compared to controls [180]. Furthermore, these percentages and cell numbers decrease in patients that respond to Etanercept treatment (anti-TNF-α therapy) [180]. Thus, NKT cells may play a role in the pathophysiology of JIA.

γδ T cells. γδ T cells compose a small percentage (5-10%) of the overall T cell population found within the joint [181-183]. They possess the ability to interact with other immune cells (e.g. DCs, macrophages, and B cells), contribute to the cytokine environment, and present antigen to αβ+ T cells [184]. A subset of γδ T cells present in PBMC and SFMC populations have been shown to secrete TNF-α and IFN-γ [185], further promoting the inflammatory milieu present within the rheumatoid joint. Furthermore, a large fraction of these cells express CD69, a marker of activation

[182, 185].

Mast cells. Although typically discussed in the context of allergic diseases, mast cells comprise up to 3% of cells within the healthy synovium [186]. In active rheumatoid joints (e.g. JIA, SLE, and osteoarthritis), the mast cell population is significantly larger compared to numbers in healthy joints [187]. This is accompanied by an increased concentration of the soluble mediators that they produce, such as histamine and tryptase [188, 189]. While their function in JIA has not been specifically studied, mast cell deficient mice (KitW/W-v) have been shown to be resistant to K/BxN serum-transfer arthritis, but reconstitution with wildtype mast cells renders these mice susceptible to disease [190]. However, these mice were found to be lacking other cell lineages, such as neutrophils [191]. This lead to the development of a specific mast cell deficient mouse (Cpa3Cre/+)

that is susceptible to arthritis [191], thus confirming that mast cells are dispensable in the K/BxN serum-transfer arthritis model. Determining the role of mast cells in human childhood arthritis pathology remains to be defined.

The complement system. The presence of circulating ICs in the joint has been suggested to activate the complement system, resulting in further tissue damage. The data quantifying IC concentrations in the sera and SF have been inconsistent [192-195], but one report has stated that ICs have been detected in the sera of 79% of JIA patients [196]. Support for the role of complement and ICs in

JIA pathophysiology includes an increased presence of C3c, C3d, and/or C4d (byproducts of complement degradation) in the sera of oligoarticular and polyarticular JIA patients [194, 197,

198]. Furthermore, elevated plasma levels of factor Bb and the sC5-9 complex were detected in

JIA patients when compared to controls [199]. This suggests that the alternative complement pathway is active in these individuals, which results in the formation of the membrane attack complex. The K/BxN serum-transfer arthritis model supports a role for the alternative complement pathway in disease development. Complement factor B deficient mice are protected from arthritis, corroborating a role for the alternative pathway in K/BxN serum-transfer arthritis development

[200]. Alternatively, mice deficient in C1q, C4, and mannose-binding protein A have typical arthritis development, indicating that the classical and lectin pathways do not contribute to disease

[200].

Conclusion. Without a doubt, cells of the innate immune system have a role in the exacerbation of arthritis. This role has been highlighted in both mouse models of arthritis and JIA patients. In fact, current therapies to treat the disease are either nonspecific (e.g. MTX) or target features of the

innate immune process (e.g. TNF-α) [131]. Moreover, concentrations of S100A12, a pro- inflammatory biomarker produced by neutrophils, correlate with disease activity and response to therapeutics [201, 202]. Therefore, understanding why cells of the innate response become activated in the absence of exogenous stimuli is critical. Defects in the innate immune system could initiate and maintain the presence of autoreactive T cell responses that drive disease persistence. Thus, modifying the innate immune response may restore control to the aberrantly active adaptive immune response. By recognizing the mechanisms regulating JIA by innate cells, promising therapeutic strategies may be developed for the future.

1.4.2 Adaptive immune system in JIA

The adaptive immune response is critical to the initiation and progression of inflammatory arthritis.

This fundamental role is evidenced in JIA by a number of associated immune loci from genetic studies and the presence of circulating autoantibodies. While the antigens driving disease and the specific role that B cells have in disease pathogenesis remain elusive, it is clear that antigen-driven autoimmunity explains many features of oligoarticular and poly RF- JIA. The role of adaptive immune cells in JIA are summarized here.

CD4+ T cells. CD4+ T cells do not only directly fight off attacks from pathogenic organisms, but they also control other aspects of the immune response by enhancing B cell antibody production and CD8+ T cell responses, regulating macrophage function, as well as the determining the scale and duration of the immune response. CD4+ T cells recognize antigen presented in the context of

MHC class II molecules, which leads to their proliferation and differentiation into distinct populations of effector cells or induced Tregs. The strong association among oligoarticular and

poly RF- patients with HLA DRB1 alleles [58, 62-64] implies a role for a CD4+ T cell response in the pathogenesis of JIA. As follows, increased populations of CD4+ T cells are found in the peripheral blood and synovium of JIA patients [127, 203] and are clonal, with different clones being found in each site [204-209]. While antigens that initiate the T cell response have not been identified, studies have shown CD4+ T cells aberrantly react to a number of self-proteins, including aggrecan, fibrillin, MMP-3, transthyretin, and heat shock proteins [129, 210-212]. CD4+ T cells found in the SF express markers indicative of a proliferating, activated memory phenotype as they express Ki67, CD45RO, CD69, and HLA-DR [213, 214]. Furthermore, a subset of the CD4+ population also expresses the chemokine receptor CCR7, which dictates memory T cell migration to sites of inflammation [215]. Unsurprisingly, increased expression levels of CCL21, the ligand that binds CCR7, were reported in the SF when compared to the serum of oligoarticular and polyarticular JIA patients [215].

As stated earlier, CD4+ T cells have the potential to differentiate into a variety of effector Th cells or induced Tregs. This process is governed by the cytokine milieu at the time of CD4+ cell activation. In the presence of IFN-γ and IL-12, naïve CD4+ T cells differentiate into Th1 cells that predominately secrete IFN-γ, but can also produce IL-12 and TNF-α [216]. Th1 cells are the most enriched CD4+ T cell population in the inflamed joint of JIA patients, which is driven by the presence of IL-12 in the SF [53, 217]. These classical Th1 cells upregulate the expression of

CD106 (VCAM-1) on synovial fibroblasts, allowing leukocytes to adhere and be retained in the joint [217]. This process can further exacerbate tissue pathology. CD4+ T cells differentiate into

Th2 cells in the presence of IL-4 and IL-2. Th2 cells, involved in allergic diseases and defense from helminth infections, primarily produce IL-4, IL-5 and IL-13 [216]. This effector cell type

represents only a minor component of the cell population within the joint, as shown by high concentration ratios of IFN-γ:IL-4 in JIA patients [218]. However, shifting toward a Th2 phenotype within the inflamed joint may prove to be beneficial, as IL-4 is expressed in higher concentrations within the joints of patients with oligoarticular JIA as opposed to those with polyarticular JIA [219]. Thus, insinuating a divergence from the Th1 phenotype in patients where disease is limited to fewer joints.

CD4+ T cells differentiate into IL-17 secreting cells, known as Th17 cells, in the context of IL-6 and transforming growth factor (TGF)-β [216]. A large population of Th17 cells can be found in the affected joints of JIA patients, as well as increased levels of IL-17 in the serum and SF [220,

221]. IL-17 contributes to joint pathology by stimulating synoviocyte expression of IL-6, MMP-

1, and the neutrophil chemoattractant, IL-8 [220]. Interestingly, Th17 cells are not terminally differentiated. Rather, in an IL-12-dependent mechanism, Th17 cells become plastic and can transition into nonclassic Th1 cells that express IFN-γ and markers characterizing Th17 cells (e.g.

CD161 and RORC2) [206, 217, 222]. Nonclassic Th1 cells are enriched in the SF of JIA patients, express granulocyte-macrophage colony-stimulating factor (GM-CSF, a chemokine for innate immune cells), and are capable of inducing CD106 (VCAM-1) expression on synovial fibroblasts that contribute to tissue pathology [217, 222]. Th17 cell plasticity to a nonclassic Th1 phenotype can be hindered by treatment with Etanercept [223].

Lastly, naïve CD4+ T cells can be funneled into an induced Treg phenotype in the presence of

TGF-β. These induced Tregs, along with the naturally occurring Treg population, are tasked with maintaining the balance of the immune system between tolerance to self and protection from

pathogens. While the frequency of Tregs in the peripheral blood of JIA patients is normal, there is an inverse correlation between the frequency of Th17 cells and Tregs in joints with active disease

[221, 224]. Furthermore, Tregs found in the inflamed joints are unable to suppress the proliferation of effector CD4+ T cells [214, 225]. It has been suggested that this is due to high SF concentrations of IL-7 and IL-15, which drive population expansion and decrease susceptibility to Tregs [226,

227]. This hypothesis is consistent with studies that have confirmed that there is no inherent defect in JIA-derived SF Tregs, but rather an insensitivity of effector cells to Treg-mediated suppression

[214]. Treatment of JIA patients with Etanercept does not appear to have any impact on Treg numbers or function, as previously described in RA [228, 229]. However, Etanercept therapy may allow Tregs to be more efficient suppressors by decreasing phosphorylated protein kinase B levels in effector T cells, which is associated with insensitivity to suppression [230].

CD8+ T cells. CD8+ T cells recognize antigens presented in the context of MHC class I molecules, leading to their proliferation and differentiation into cytotoxic T lymphocytes that produce cytokines, such as TNF-α and IFN-γ. The influence of CD8+ T cells on JIA pathophysiology has not been extensively studied, but the association of the class I HLA allele A2 with disease risk [55,

63] supports the notion that CD8+ T cells play some role. One study has identified self-HLA peptides from HLA DRB1*1101, DRB1*0801, and DRP1*0201 that elicit CD8+ T cell cytotoxicity and IFN-γ production; these self-peptides molecularly mimic peptides of EBV, a viral pathogen implicated in JIA etiology [36]. Furthermore, there is an expanded and persisting oligoclonal population of CD8+ T cells that are resistant to Treg suppression present in JIA patients

[231, 232]. Interestingly, while the clonal repertoire differs between blood and SF, overlapping

Vβ chains can be found from different active joints within the same individual [204, 205, 209].

Furthermore, there is a positive correlation between the CD8:CD4 cell ratio and disease severity in oligoarticular patients that progress to the extended phenotype with more joint involvement

[231]. A population of CD8+CD28- cells have also been described in JIA patients, which is most likely due to the chronically stimulated, inflammatory environment [209, 233]. Loss of CD28 appears to result in a mixed population of effector, senescent, and regulatory cells [234-237]. This heterogeneity was also seen in JIA patients, as these CD8+CD28- cells expressed markers of senescence (e.g. γH2AX and p16) and were capable of secreting IFN-γ and IL-10 [233]. Studies have also explored the effect that MTX and Etanercept therapy has on CD8+ T cells. Six months of MTX treatment enhanced CD8+ T cell proliferation and failed to alter their susceptibility to suppression by Tregs or cytokine production [238]. Conversely, Etanercept treatment rescued suppression resistance of CD8+ T cells from the SF of JIA patients [232]. Taken together, CD8+ T cells appear to play a part in JIA pathophysiology by the release of inflammatory mediators that cause detriment to the joint tissues.

B cells. A role for the humoral immune response by B cells in the pathophysiology of oligoarticular and poly RF- JIA is shown by the presence of circulating autoantibodies, such as ANAs, antithyroid antibodies, and anti-chromatin antibodies [32, 239, 240]. While their specific impact on disease development has not yet been elucidated, they can serve as biomarkers. For example, uveitis (inflammation of the uvea that can potentially lead to blindness) is the most common extra- articular manifestation of JIA, and the presence of ANAs increases uveitis risk [241]. Therefore, testing for ANA levels allows risk for uveitis to be stratified. Among oligoarticular and poly RF- patients, those that were ANA-positive had a younger age at onset and asymmetric joint involvement, whereas ANA-negative individuals were older and had symmetric disease [32].

Interestingly, the presence of T-B cell aggregates surrounded by plasma cells have been described in the synovial tissues of JIA patients [128, 242]. These lymphoid aggregates resemble germinal centers and are unrelated to disease activity/severity, but appear to be correlated with ANAs [128].

As for individual B cell populations in JIA, studies have discovered an expanded CD5+ B cell population in oligoarticular and poly RF- patients [203, 243]. This B cell population classically generates antibodies directed towards structures of the bacterial cell wall, but can also produce low-affinity antibodies capable of binding various specificities [53]. Whether this B cell population produces JIA autoantibodies is unknown at this time. Furthermore, class-switched memory B cells expressing CD69 and CD80/86, markers of activation and co-stimulatory molecules, respectively, are significantly increased in oligoarticular and polyarticular JIA patients [242, 244, 245]. These cells were able to activate T cells and produce Th1-polarizing cytokines in vitro [245], suggesting that JIA B cells may also act in an antibody-independent mechanism. In the presence or absence of active disease, treatment with MTX alone increases the population of class-switched B cells in

JIA patients; this population also expands during active disease when treated with a combination therapy of MTX and a TNF-α inhibitor, but decreases to levels comparable with healthy controls when disease is in remission [244]. Further investigations into the role of B cells in JIA pathophysiology are likely imminent considering the benefit that Rituximab (antibody targeting

CD20, a protein expressed by B cells throughout their maturity) has had for the treatment of RA

[246].

1.4.3 Resident joint cells in JIA

Diarthrodial joints are organized into two distinct layers, the outer stratum fibrosum and the inner synovial membrane. Under homeostatic conditions, the synovial membrane is one to three cell layers deep and is composed of two different cell types: resident macrophages (type A cells) and fibroblast-like synoviocytes (FLS or type B cells) [247]. Type A cells survey the joint cavity for debris and are able to present antigens in the context of MHC, while type B cells produce components of the SF [247]. During JIA, both type A and B synoviocytes become hyperproliferative and the synovium experiences increased vascularity [248, 249]. This increased vascularity allows inflammation to progress by drawing circulating immune cells into the joint.

These recruited cells, along with resident proliferating synoviocytes, can form a pannus that invades the cartilage and bone [248, 249]. Moreover, synoviocytes have been found to produce a number of pro-inflammatory cytokines, chemokines, and degradative enzymes (e.g. MMPs) in RA

[250]. Overall, resident cells within the joint progress the inflammatory state by recruiting immune cells and promoting tissue pathology, both directly and indirectly.

1.4.4 Cartilage and bone destruction in JIA

Preserving cartilage and bone integrity in the joints of JIA patients is critical to preventing irreversible damage that could cause long-term disability and/or growth disturbances. Whereas bone erosions in childhood arthritis are less common than in RA considering the amount of epiphyseal cartilage present in children, it is estimated that up to one-third of JIA patients experience osteocartilaginous damage [251]. Luckily, these pathologies occur late in the disease process. This, coupled with the fact that current therapeutic strategies (e.g. anti-TNF-α, anti-IL-

6R, etc.) targeting inflammatory pathways significantly improve functional outcomes in children

while delaying/preventing joint damage from occurring, highlights the importance of detecting JIA early. However, in addition to therapies directed at inflammation, treatment strategies that cease and preferably reverse joint pathology are appealing.

In regard to cartilage degradation, children with JIA have a reduced cartilage thickness when compared to healthy controls [252, 253]. Non-human studies have also found the pro- inflammatory environment to impact cartilage integrity. IL-1β has been found to inhibit chondrocyte (cartilage cells) differentiation [254]. TNF-α induces chondrocyte apoptosis and reduces proteoglycan (a cartilage component) synthesis [255, 256]. Moreover, proteoglycan synthesis is further reduced upon TNF-α synergizing with IL-17 [256]. It has also been suggested that these inflammatory cytokines have the potential to destroy the growth plate, a thin cartilage layer near the ends of long bones [257], which could contribute to the low stature affecting 11% of JIA patients [258].

Generally speaking, the balance between the activation of osteoblasts (bone forming cells) and osteoclasts (bone resorbing cells) contributes to the overall bone loss within the joint. Osteoblasts are derived from mesenchymal cells under the regulation of the bone morphogenetic protein, Wnt, and parathyroid signaling pathways [259-261]. Osteoclasts are multinucleated cells derived from monocyte/macrophage lineage cells whose activation is regulated by the RANK-RANKL axis

[260]. Osteoblasts secrete RANKL and produce a soluble decoy receptor known as osteoprotegerin

(OPG) that further regulates osteoclastogenesis by preventing the binding of RANKL to osteoclast-expressed RANK [262, 263]. Thus, a high RANKL/OPG ratio favors bone resorption and an increased RANKL/OPG ratio has been observed in JIA patients [264, 265]. Immune cells,

such as neutrophils and T cells, also express RANKL under inflammatory conditions in the joint to further promote osteoclast activation [149, 266]. The pro-inflammatory environment of the joints also contributes to bone destruction. TNF-α, IL-1β, IL-17, and IL-6 promote osteoclast activation, differentiation, and maturation while suppressing osteoblasts and their expression of

OPG [267-272]. Specifically, TNF-α increases the production of sclerostin and Dickkopf 1 (DKK-

1), inhibitors of the Wnt signaling pathway, which prevent the differentiation of osteoblasts in adult patients with JIA [273]. DKK-1 inhibition results in osteoblast differentiation and subsequent bone formation, as well as increased OPG expression [274]. Therefore, there are multiple ways in which cells of the immune system and their effector cytokines influence bone structure.

Therapeutic targeting of the RANK and Wnt signaling pathways could prove beneficial to bone health in JIA.

Therapeutics used to treat JIA have varied effects on overall bone health. Intense treatment with steroids, particularly glucocorticoids (e.g. prednisolone and dexamethasone), negatively correlate with bone mass. This decreased bone mass increases the risk for osteoporosis and bone fractures into adulthood [275-278]. On the other hand, treatment with low-dose MTX does not appear to negatively affect bone mass [279]. Overall, a therapeutic strategy that reduces inflammation, prevents joint pathology, and promotes tissue repair would be ideal for JIA treatment.

1.5 Mouse Models of Arthritis

In recent decades, significant advances have been made within the field of mouse genetics that have led to the development of various methods to better understand human biology. The creation of innumerable knockout, knockin, and transgenic mice has made mouse research immeasurably

informative. Nevertheless, there are still gaps in understanding JIA pathogenesis. Various mouse models of arthritis exist that differ in their etiologies and none of these fully recapitulates human disease. However, they are still valuable to understanding mechanisms and pathways underlying disease pathophysiology, as well as the effect that various therapeutic interventions have on disease initiation, progression, and reversal. Arthritis models are generally classified into two categories, induced or spontaneous. Induced models include the K/BxN serum-transfer model, collagen induced arthritis (CIA), and collagen antibody-induced arthritis. Spontaneous models include IL-1RA knockout mice, TNFΔARE mice, and K/BxN mice. Here, the K/BxN serum-transfer model of arthritis will be discussed in more detail.

1.5.1 K/BxN serum-transfer model of arthritis

Use of the K/BxN serum-transfer arthritis model has become increasingly popular over the last decade. Similar to JIA, this model is characterized by leukocyte invasion (e.g. neutrophils and macrophages), synovitis, pannus formation, and cartilage/bone destruction of the joint [280]. The model is induced by the injection of serum from K/BxN mice that have spontaneously developed arthritis [281]. Breeding TCR-transgenic KRN mice on a C57/BL6 background that recognize a bovine ribonuclear peptide (RNase 43-56) presented in the context of the MHC class II molecule

I-Ak with non-obese diabetic (NOD) mice results in the generation of K/BxN mice that spontaneously develop arthritis by five weeks of age [282]. Arthritis in these mice is caused by the activation of KRN T cells by APCs presenting a self-peptide, identified as the universally expressed glucose-6-phosphate isomerase (G6PI), in the context of the NOD-derived MHC class

II molecule, I-Ag7 [283]. Subsequently, the activated T cells interact with B cells to induce production of anti-G6PI antibodies [282, 284-286]. Studies have shown that anti-G6PI antibodies

home to the distal joints in the front and rear limbs where they can bind to G6PI deposited on the articular surface and create ICs [287, 288]. Moreover, G6PI is also found in the serum where it can be bound by anti-G6PI antibodies and activate cells, such as neutrophils, to release vasoactive mediators that increase vascular permeability [289]. Thus, facilitating easier access of anti-G6PI antibodies into the joint where they can bind articular G6PI to further mediate pathology.

The K/BxN serum-transfer arthritis model is also mediated by ICs, which drive the activation of the alternative complement pathway and consequent production of pro-inflammatory cytokines, such as IL-1β, TNF-α, and IL-6 [280]. Interestingly, IL-1β is necessary for disease development, whereas TNF-α and IL-6 are expendable [290, 291]. While this model only mirrors the effector phase of JIA (T and B cells are dispensable [285, 292]) and G6PI is not a known JIA autoantigen, the K/BxN serum-transfer arthritis model is advantageous and informative for a number of reasons.

First, it provides a general understanding of the role that autoantibodies play in disease progression and their interaction with the innate immune system [280]. Furthermore, the transfer of anti-G6P1 antibodies is able to induce arthritis in a variety of mouse strains, including C57BL/6 and BALB/c

[293]. Disease is 100% penetrant, becomes apparent rapidly (sometimes in as short as one day) and resolves 10-15 days following injection, unless made persistent by repeated serum injections

[285]. Overall, the use of the K/BxN serum-transfer arthritis model with genetically manipulated mice enables the rapid detection of pathways that contribute to the effector phase of inflammatory arthritis in order to identify potential therapeutic targets.

1.6 Hypothesis and Specific Aims

The central hypothesis of the studies presented here is that both common variants and de novo mutations associated with oligoarticular and poly RF- contribute to disease pathogenesis. This hypothesis was tested using a combination of established genetic and bioinformatic approaches, as well as the K/BxN serum-transfer mouse model of arthritis. The specific influence of each of these forms of genetic variation on the pathogenesis of JIA were evaluated with the following specific aims:

Aim 1: Examine the contribution of common variants to oligoarticular and poly RF- JIA susceptibility. Hypothesis: An appropriately powered genome-wide association study of a homogeneous JIA cohort will identify susceptibility loci.

This hypothesis is tested in Chapter 2 by performing a meta-analysis of three genome-wide SNP datasets imputed to 10 million markers available in the 1000 Genomes Project. Manuscript published in Arthritis and Rheumatology, November 2017; 69(11): 2222-2232, doi:

10.1002/art.40216.

Aim 2: Identify rare, DNMs in the exomes of children with sporadic cases of oligoarticular and poly RF- JIA. Hypothesis: Unique single nucleotide variants, located within genes of biologically- relevant signaling pathways, can be identified in JIA patients that contribute to disease pathogenesis.

This hypothesis is tested in Chapter 3 by performing WES on JIA trios (father, mother, and proband), followed by the use of genetically manipulated gene-deficient mice in the experimental

K/BxN serum-transfer model of arthritis. Manuscript is in preparation.

There is an established contribution of genetics to the risk of JIA. Completing these studies to identify new genes and pathways related to disease will ultimately offer a better understanding of the genetic architecture underlying JIA pathogenesis. By addressing the missing heritability issue discussed in previous sections with the described genetic studies, new therapeutic approaches to successfully treat JIA, as well as other autoimmune diseases, may be developed.

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Chapter 2: Genome-wide association meta-analysis reveals novel juvenile idiopathic arthritis susceptibility loci

Genome-wide association meta-analysis reveals novel juvenile idiopathic arthritis susceptibility loci

Laura A. McIntosh,1 Miranda C. Marion,2 Marc Sudman,3 Mary E. Comeau,2 Mara L. Becker,4 John F. Bohnsack,5 Tasha E. Fingerlin,6 Thomas A. Griffin,7 J. Peter Haas,8 Daniel J. Lovell,1 Lisa A. Maier,6 Peter A. Nigrovic,9 Sampath Prahalad,10 Marilynn Punaro,11 Carlos D. Rosé,12 Carol A. Wallace,13 Carol A. Wise,14 Halima Moncrieffe,1 Timothy D. Howard,15 Carl D. Langefeld,15 and Susan D. Thompson1

1Laura A. McIntosh, BA, Daniel J. Lovell, MD, MPH, Halima Moncrieffe, PhD, Susan D. Thompson, PhD: Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio; 2Miranda C. Marion, MA, Mary E. Comeau, MA: Wake Forest University School of Medicine, Winston-Salem, North Carolina; 3Marc Sudman, BA: Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; 4Mara L. Becker, MD: Children’s Mercy–Kansas City, Kansas City, Missouri; 5John F. Bohnsack, MD: University of Utah, Salt Lake City; 6Tasha E. Fingerlin, PhD, Lisa A. Maier, MD, MSPH, FCCP: National Jewish Health and University of Colorado, Denver; 7Thomas A. Griffin, MD, PhD: Levine Children’s Specialty Center, Charlotte, North Carolina; 8J. Peter Haas, MD: German Center for Pediatric and Adolescent Rheumatology, Garmisch-Partenkirchen, Germany; 9Peter A. Nigrovic, MD: Boston Children’s Hospital and Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts; 10Sampath Prahalad, MD, MSc: Emory University School of Medicine, Atlanta, Georgia; 11Marilynn Punaro, MD: Texas Scottish Rite Hospital for Children and UT Southwestern Medical Center, Dallas; 12Carlos D. Rosé, MD: DuPont Children’s Hospital, Wilmington, Delaware; 13Carol A. Wallace, MD: Seattle Children’s Hospital and Research Institute, Seattle, Washington; 14Carol A. Wise, PhD: Texas Scottish Rite Hospital for Children, McDermott Center for Human Growth and Development, and UT Southwestern Medical Center, Dallas; 15Timothy D. Howard, PhD, Carl D. Langefeld, PhD: University of Cincinnati, Cincinnati, Ohio.

Running Title: Newly Identified JIA Susceptibility Loci

This work was supported in part by the Cincinnati Children's Research Foundation and its Cincinnati Genomic Control Cohort. Recruitment and DNA preparation in the US were supported by the NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases [NIAMS] grants N01-AR-42272, P01-AR-048929, P30-AR-473639, P30-AR-070549, and P30-AR-070253, National Heart, Lung, and Blood Institute grant R01-HL-11487, National Institute of Environmental Health Sciences grant P01-ES-011810, and National Institute for Research Resources grant UL1-RR-025780), the Fundación Bechara, the PhRMA Foundation, and the Rheumatology Research Foundation. Genotyping of JIA and control collections in the US was

supported by the NIH (NIAMS grant RC1-AR-058587). Recruitment and DNA preparation in Germany were supported by the BMBF (grants 01GM0907 and 01ZZ0403).

Correspondence: Susan D. Thompson, Ph.D. Center for Autoimmune Genomics and Etiology Cincinnati Children’s Hospital Medical Center S6.224 3333 Burnet Avenue Cincinnati, OH 45229 Phone (513) 636-3899 Fax (513) 636-3328 [email protected]

Published in Arthritis and Rheumatology, November 2017

Abstract

Objective. Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic disease and has a strong genomic component. To date, JIA genetic association studies have had limited sample sizes, used heterogeneous patient populations, or included only candidate regions. The aim of this study was to identify new associations between JIA patients with oligoarticular disease and those with IgM rheumatoid factor (RF)-negative polyarticular disease, which are clinically similar and the most prevalent JIA disease subtypes.

Methods. Three cohorts comprising 2,751 patients with oligoarticular or RF-negative polyarticular JIA were genotyped using the Affymetrix Genome-Wide SNP Array 6.0 or the

Illumina HumanCoreExome-12+ Array. Overall, 15,886 local and out-of-study controls, typed on these platforms or the Illumina HumanOmni2.5, were used for association analyses. High-quality single nucleotide polymorphisms (SNPs) were used for imputation to 1000 Genomes prior to SNP association analysis.

Results. Meta-analysis showed evidence of association (P < 1x10-6) at 9 regions: PRR9_LOR (P

= 5.12x10-8), ILDR1_CD86 (P = 6.73x10-8), WDFY4 (P = 1.79x10-7), PTH1R (P = 1.87x10-7),

RNF215 (P = 3.09x10-7), AHI1_LINC00271 (P = 3.48x10-7), JAK1 (P = 4.18x10-7), LINC00951 (P

= 5.80x10-7), and HBP1 (P = 7.29x10-7). Of these, PRR9_LOR, ILDR1_CD86, RNF215,

LINC00951, and HBP1 were shown, for the first time, to be autoimmune disease susceptibility loci. Furthermore, associated SNPs included cis expression quantitative trait loci for WDFY4,

CCDC12, MTP18, SF3A1, AHI1, COG5, HBP1, and GPR22.

Conclusion. This study provides evidence of both unique JIA risk loci and risk loci overlapping between JIA and other autoimmune diseases. These newly associated SNPs are shown to influence gene expression, and their bounding regions tie into molecular pathways of immunologic

relevance. Thus, they likely represent regions that contribute to the pathology of oligoarticular JIA and RF-negative polyarticular JIA.

Introduction

Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic disease, with a prevalence of ~1 per 1,000 children [1]. It is a disabling, complex disorder characterized by inflammation of the joints and other tissues that persists for at least 6 weeks. Although there is ethnic diversity in JIA, it is a disease that predominately affects children of European descent [2].

There is a strong genetic component to JIA, with numerous established susceptibility loci [3-5] and a sibling recurrence risk ratio (λs) of 11.6 [6]. Additionally, the prevalence of other autoimmune diseases is increased in relatives of patients with JIA [7].

The International League of Associations for Rheumatology (ILAR) categorizes JIA into 7 subtypes [8]. Two of these subtypes, oligoarticular JIA (persistent and extended forms) and IgM rheumatoid factor (RF)-negative polyarticular JIA, account for ~70% of cases of JIA and are the focus of the current study. These 2 subtypes present similarly in the clinic, are distinguished only by the number of affected joints after a disease duration of 6 months, and share HLA associations

[9, 10].

Genome-wide association studies (GWAS), while widely used across autoimmune diseases, have been somewhat limited in scope for JIA. Previous high-density array-based studies in patients with oligoarticular JIA or RF-negative polyarticular JIA have provided evidence of association for single-nucleotide polymorphisms (SNPs) corresponding to loci near or including PTPN22,

PTPN2, IL2RA, TNFAIP3, COG6, ADAD1/IL2/IL21, STAT4, chromosome 3q13 within C3orf1 and near CD80, and chromosome 10q21 near JMJD1C [4, 5]. Other GWAS included all JIA

subtypes and showed associations with TRAF1/C5 or VTCN1 loci but were limited by either small sample sizes [11] or the number of markers assayed [12].

More recently, the Juvenile Arthritis Consortium for Immunochip studied patients and controls of

European ancestry, using the Illumina Infinium Immunochip genotyping array, which provides dense SNP coverage in the HLA region and is limited to 186 non-HLA regions identified in 12 early studies of autoimmune disease association (not including JIA) [3]. Therefore, it does not reflect the current catalog of autoimmune disease findings. Results from the Immunochip analyses provided convincing evidence of association for a number of JIA risk loci that are also risk loci for other autoimmune diseases, including the HLA region [10] and 27 non-HLA loci [3]. However, a significant proportion of JIA heritability risk remains unexplained. Although there is a partial overlap between the patient and control samples used in this study and the Immunochip studies [3,

10], the current study extends findings to a genome-wide level to further delineate JIA genetic risk factors and allows the findings to be translated to JIA disease mechanisms.

Patients and Methods

Subjects. Three cohorts comprising 2,751 JIA patients of European ancestry with oligoarticular disease or RF-negative polyarticular disease and 15,886 controls (cohort I, 814 cases and 3,058 controls; cohort II, 1,057 cases and 11,843 controls; cohort III, 880 cases and 985 controls) were used for association analyses. Subjects in cohort I were primarily recruited from the Cincinnati

Children’s Hospital Medical Center (CCHMC) or as part of a National Institute of Arthritis and

Musculoskeletal and Skin Diseases-supported registry of JIA-affected sibpairs. Collaborating centers including Children’s Hospital of Wisconsin, Schneider Children’s Hospital, and Children’s

Hospital of Philadelphia provided additional samples [4, 5]. JIA patients in cohort II have been described previously as a validation cohort [4, 5]. Clinics enrolling JIA patients for cohort III were located in Cincinnati, OH, Atlanta, GA, Charlotte, NC, Columbus, OH, Little Rock, AR, Long

Island, NY, Chicago, IL, Salt Lake City, UT, Cleveland, OH, Nashville, TN, and Charleston, SC.

Additional DNA samples, split between cohorts II and III, were collected in Cincinnati, OH (n =

105) or were collected as part of or obtained from the Gene Expression in Pediatric Arthritis Study

(National Institute of Arthritis and Musculoskeletal and Skin Diseases [NIAMS] grant P01-AR-

048929) (n = 117), Children’s Mercy Hospital, Kansas City (n = 75), the Improved Understanding of the Biology and Use of TNF Inhibition in Children with JIA Study (ClinicalTrials.gov identifier:

NCT00792233) (n = 40), Nemours/Alfred I. duPont Hospital for Children (n = 38), the Boston

Children’s Hospital JIA Registry (n = 26), the Trial of Early Aggressive Therapy in JIA Study

(TREAT) (ClinicalTrials.gov identifier:NCT00443431) (n = 25), Emory University School of

Medicine (n = 19), and Cohen Children’s Medical Center (n = 4). Members of the consortia are shown in Appendix A.

All cases met the ILAR or American College of Rheumatology [13] classification criteria for JIA or juvenile rheumatoid arthritis (RA). Both regional and out-of-study controls obtained from the dbGaP database were included in the control cohorts. Controls for cohort I included regional controls recruited from the geographic region served by CCHMC [4,5] and 2,400 out-of-study controls from the Molecular Genetics of Schizophrenia nonGAIN Sample (MGS_nonGAIN; phs000167.v1vp1). Controls for cohort II included “Texas,” “Utah,” and “German” regional controls [4, 5], 7,324 controls from the Atherosclerosis Risk in Communities Study cohort

(phs000280.v3.p1), 2,555 controls from the Genetic Association Information Network (GAIN; phs000021.v3.p2 and phs000017.v3.p1), and 1,792 controls from the Cooperative Health Research in the Region Augsburg (KORA) study [14]. Cohort III contained only regional controls recruited in Denver. Use of these DNA collections has been approved by the Institutional Review Board at all participating centers, and participants or their parents provided written consent prior to study enrollment. Cohorts I and II have been used in previous association studies [4, 5], and overall,

~65% of the JIA samples from the current study were used for Immunochip analyses [3, 10].

Genotyping and quality control. Cohorts I and II were genotyped using the Affymetrix Genome-

Wide Human SNP Array 6.0. Cohort I was genotyped at the Affymetrix Service Center, while cohort II was genotyped at Expression Analysis/Quintiles; cohort III was genotyped with the

Illumina HumanCoreExome-12+ Array (Exome Array), which included 2,508 custom SNP assays derived from initial analyses in cohort I, at CCHMC. All out-of-study controls were genotyped on

SNP Array 6.0, with the exception of the KORA cohort, which was genotyped on the

HumanOmni2.5 Bead-Chip (Infinium). Samples were excluded if their call rates were <98% across the SNPs that passed quality control filters. Duplicates and first-degree relatives were

identified using the software package KING [15], retaining the sample with the highest call rate.

Self-reported and genetically determined sex were compared using chromosome X genotype data.

The program ADMIXTURE [16] was used to compute admixture estimates from a subset of SNPs that met quality control criteria and were pruned to have low linkage disequilibrium (LD) (r2 <

0.2). This study was limited to individuals who self-reported European ancestry, and individuals whose admixture estimates were outliers were removed. Primary inference was based on SNPs that showed no significant evidence of departure from expectation in Hardy-Weinberg equilibrium proportions (P < 1x10-6 and P < 0.01 in cases and controls, respectively), significant differential missingness between cases and controls (P < 0.05), a minor allele frequency of ≥0.01, and a call rate of >95%.

Statistical analysis. Imputation. Because the 3 cohorts were genotyped on 2 different arrays at 3 different times, imputation was performed separately for each cohort, using IMPUTE2 with the

1000 Genomes phase 1 integrated reference panel [17]. Imputed SNPs were retained if their information score was >0.5 and their confidence score was >0.9. To validate imputation, a representative subset of subjects (96 subjects from each of the 3 JIA cohorts and 96 control subjects) were genotyped for 16 SNPs, including 7 of the 9 SNPs shown in Table 1, using TaqMan

SNP Genotyping Assays (Life Technologies) and evaluated for concordance between imputed and

TaqMan-generated genotypes. Reactions were performed on a ViiA 7 real-time polymerase chain reaction system (Applied Biosystems).

Tests of association. Tests of association were performed on the imputed data using SNPTEST under a logistic model, taking imputed genotype uncertainty into account [16]. Admixture

proportions were included as covariates. A weighted inverse normal meta-analysis was conducted to combine results across cohorts. Due to the discrepancy in the control-to-case ratio across cohorts, evidence was weighted by size of the case-only sample. For each cohort, a SNP was included in the meta-analysis if it passed the quality control criteria described previously and the additional requirement of 30 and 10 homozygotes for the minor allele for the additive and recessive models, respectively. For the dominant model, a total of 10 minor allele genotypes (heterozygote or homozygote) was required. Inference was based on the set of SNPs for which the meta-analysis contained data from at least 2 of the 3 cohorts and where the direction of the effect was consistent across contributing cohorts. This additional requirement reduces the Type I error rate.

Functional annotation analysis. The functional potential of the SNPs in the region of association

(r2 ≥ 0.8) were examined using HaploReg version 2 [18] and RegulomeDB, a database that annotates SNPs with known and predicted regulatory elements, expression quantitative trait loci

(eQTLs), DNase hypersensitivity, and binding sites of transcription factors in the intergenic regions of the human genome [19]. Histone data were evaluated using the positions of the original

SNPs as well as proxy SNPs in LD (r2 ≥ 0.8). Three well-studied epigenetic marks (H3K4me1,

H3K4me3, and H3K27ac) from the ENCODE and Roadmap Epigenomic projects were evaluated.

For the ENCODE data, tables for the 3 marks for each of the tier 1 cell lines (GM12878 cells, H1- hESC cells, human skeletal muscle myoblasts [HSMMs], human umbilical vein endothelial cells

[HUVECs], K562 cells, normal HEK cells, and normal human lung fibroblasts [HLFs]) were downloaded from the UCSC Genome Browser (genome.ucsc.edu) using SNP positions. The

Roadmap Epigenomic data were downloaded similarly, using the EpiGenome Browser

(www.epigenomebrowser.org) for available cell types with probable relevance to JIA (CD14,

CD15, CD19, primary peripheral blood mononuclear cells [PBMCs], CD3, primary memory CD4 cells (CD4M), primary CD4-naive cells (CD4N), and primary CD4+CD25+CD127- Treg cells

[CCCTreg]).

Pathway analysis. Relationships between gene products were analyzed using IPA (Qiagen; www.qiagen.com/ingenuity). The genes analyzed were from 2 sources: all genes from the current

JIA GWAS (P < 1x10-6) and all genes associated with oligoarticular and RF-negative polyarticular

JIA using the Immunochip (P < 5x10-8) [3]. Genes included in the analysis were JAK1, PRR9,

LOR, PTH1R, CD86, LINC00951 (FLJ41649), AHI1, LINC00271, HBP1, WDFY4, RNF215,

HLA-DRB1, PTPN22, ATP8B2, IL6R, STAT4, IL2, IL21, ERAP2, LNPEP, C5orf56, IRF1, IL2RA,

PRR5L, COG6, PTPN2, ANKRD55, TYK2, SH2B3, ATXN2, UBE2L3, RUNX1, IL2RB, FAS,

ZFP36L1, and LTBR. LINC00951 (FLJ41649) was not mapped using IPA at the time of analysis

(version release date: December 2016). Only experimentally validated interactions were considered.

Results

Demographics. The 3 JIA cohorts in this study were restricted to patients with either oligoarticular or RF-negative polyarticular disease, in order to reduce phenotypic heterogeneity. Across cohorts,

2,751 patients met individual-level quality control criteria (see Supplementary Table 1). Of these,

1,581 patients had a diagnosis of oligoarticular JIA, and 1,170 patients had a diagnosis of RF- negative polyarticular JIA. Overall, there were 629 male JIA patients (22.9%) and 2,122 female

JIA patients (77.1%). The mean ± SD age at the onset of JIA was 4.37 ± 3.59 years in female patients with oligoarticular JIA, 6.59 ± 4.51 years in female patients with RF-negative polyarticular JIA, 5.93 ± 3.71 years in male patients with oligoarticular JIA, and 7.35 ± 4.08 years in male patients with RF-negative polyarticular JIA. A group of 15,886 genetically well-matched controls was used, which included local controls from the US and Germany as well as out-of-study controls (see Patients and Methods) (details are shown in Supplementary Table 1). The current study is powered to detect associations with odds ratios (ORs) of 1.20, assuming an allele frequency between 0.30 and 0.40 (see Supplementary Figure 1).

Inferential SNP data set. The association analysis accounted for imputation uncertainty and included admixture proportions in the logistic model as covariates. For comparability, scaling the genomic inflation factors (λ) to the equivalent of 1,000 cases and 1,000 controls within each cohort yielded λ1,000 values of 1.04, 1.09, and 1.03, respectively, for the 3 cohorts. A total of 622,740

SNPs (SNP Array 6.0) for cohort I, 535,078 SNPs (SNP Array 6.0) for cohort II, and 256,455

SNPs (Exome Array) for cohort III passed the genotyping quality control measures described in

Patients and Methods. Including the HLA region, 4,710,143 SNPs passed imputation meta- analysis quality control filtering.

Discovery of new oligoarticular and RF-negative polyarticular JIA loci. The association results (P < 1x10-6) of the meta-analysis of 3 cohorts (2,751 patients and 15,886 controls) are shown in Figure 1. The 9 newly identified oligoarticular and RF-negative polyarticular JIA loci include JAK1, PRR9_LOR, PTH1R, ILDR1_CD86, LINC00951 (FLJ41649), AHI1_LINC00271,

HBP1, WDFY4, and RNF215. Regional plots of association (LocusZoom) are shown in

Supplementary Figure 2. Lead SNPs representing novel associations with oligoarticular and RF- negative polyarticular JIA are shown in Table 1. For each region shown in Table 1, no signal remained after conditioning on the lead SNP. The strongest associations included PRR9_LOR

(rs873234 [P = 5.12x10-8, OR 1.43, 95% CI 1.25-1.63]) and ILDR1_CD86 (rs111700762 [P =

6.73x10-8, OR 1.45, 95% CI 1.26-1.66]). In addition, 36 previously unidentified loci achieved suggestive levels of significance (1x10-6 < P < 1x10-5) in the meta-analysis and are shown in

Supplementary Table 2.

A subset of imputed SNPs from Table 1 and Supplementary Table 2 were technically validated by direct genotyping (n = 16). Concordance of >98% between imputed and genotyped SNPs was observed in all SNPs evaluated (>99% concordance in 11 of the SNPs). All remaining SNPs meeting a false discovery rate-corrected P value less than 0.05 (n = 1,782) are shown in

Supplementary Table 3.

Autoimmune disease loci overlap. Support for the 9 newly associated oligoarticular and RF- negative polyarticular JIA loci was gathered using the National Human Genome Research Institute and the European Bioinformatics Institute GWAS Catalog [20] and Immunobase

(https://www.immunobase.org). The lead SNP at each novel locus, as well as proxy SNPs in LD

(r2 ≥ 0.4), were queried in the aforementioned databases to search for overlapping regions of association between oligoarticular and RF-negative polyarticular JIA and other autoimmune diseases. Four regions (JAK1, PTH1R, AHI1_LINC00271, and WDFY4) have been associated in autoimmune diseases (Table 2): JAK1 in celiac disease [21] and multiple sclerosis (MS) [22];

PTH1R in celiac disease [21]; AHI1_LINC00271 in celiac disease [21], MS [22], autoimmune thyroid disease [23], and type 1 diabetes mellitus (DM) [24]; and WDFY4 in systemic lupus erythematosus (SLE) [25]. Despite these shared associated loci, the causal variants of each region may not necessarily be the same among diseases.

Functional implications of oligoarticular JIA- and RF-negative polyarticular JIA-associated loci. In order to elucidate the impact of SNPs located in the oligoarticular JIA- and RF-negative polyarticular JIA-associated loci on gene transcription, each lead SNP and all proxy SNPs (r2 ≥

0.8) were examined for eQTLs in tissues, using 2 public gene expression databases, the eQTL

Browser from the University of Chicago (eqtl.uchicago.edu) and the Blood eQTL Browser [26].

While both cis and trans eQTLs were queried, the results identified evidence of cis eQTLs only.

Strong eQTLs were identified for 5 oligoarticular and RF-negative polyarticular JIA loci: PTH1R

SNPs for CCDC12; AHI1_LINC00271 SNPs for AHI1; HBP1 SNPs for HBP1, COG5, and

GPR22; WDFY4 SNPs for WDFY4; and RNF215 SNPs for MTP18 and SF3A1 (Table 3).

Next, the novel oligoarticular JIA- and RF-negative polyarticular JIA-associated loci were analyzed for histone modifications. Using the 7 cell types in the ENCODE database for which the desired data were available (GM12878 cells, H1-hESC cells, HSMMs, HUVECs, K562 cells,

normal HEK cells, and normal HLFs) and immunologically relevant cell types from the

EpiGenome Browser (CD14, CD15, CD19, PBMCs, CD3, CD4M, CD4N, and CCCTreg [see

Patients and Methods]), the SNP set described above for the eQTL analysis was evaluated for

H3K4me1, H3K4me3, and H3K27ac modifications. H3K4me1 modifications tend to mark enhancer regions, whereas H3K4me3 modifications tend to mark promoter regions. Regions that are transcriptionally activated are associated with H3K27ac marks [27]. Supplementary Table 4 summarizes the histone modification mark data for each of the 9 novel oligoarticular JIA and RF- negative polyarticular JIA associations, indicated by the enrichment score (number of sequences) centered on a 25-bp window size. The maximum enrichment score among cell lines was determined, and the top 5 values for each histone mark were identified. Several SNPs were located in regions with enriched histone marks, mostly in isolated cell types. In addition, some SNPs were in regions with multiple marks (e.g., rs72922282 and rs10511408), indicating a high likelihood that these SNPs are in functionally active chromatin regions.

Comparison of RA- and type 1 DM-associated loci with oligoarticular and RF-negative polyarticular JIA. Many of the risk loci identified for oligoarticular JIA and RF-negative polyarticular JIA are shared with other autoimmune diseases, particularly RA and type 1 DM [3].

However, individual variants identified may vary between diseases. To date, association studies have identified 101 loci for RA [28] and 50 loci for type 1 DM [24]. Supplementary Tables 5 and

6 show the findings from this study for each SNP reported for RA and type 1 DM, respectively.

Within the oligoarticular JIA and RF-negative polyarticular JIA data set, 86 RA and 39 type 1 DM

SNPs met quality control metrics. In total, 9 RA and 6 type 1 DM SNPs, or only 10-15%, reached a Bonferroni-corrected P value less than 5.8x10-4 (calculated based on 86 tests) or P < 1.2x10-3

(calculated based on 39 tests), respectively. These significantly associated SNPs in oligoarticular and RF-negative polyarticular JIA are shown in Supplementary Tables 5 and 6.

Additionally, a power analysis for each of these RA-associated SNPs (see Supplementary Table

5) and type 1 DM-associated SNPs (see Supplementary Table 6) was computed, assuming the OR reported for RA or type 1 DM, the allele frequency in the JIA controls, the JIA patient sample size, and the Type I error rate defined by the Bonferroni corrections described above. The sum of the power across the SNPs is the statistical expectation of the number of associations a cohort of the size observed in this meta-analysis would detect. If the effect sizes in the JIA cohort were consistent with the RA or type 1 DM effect sizes for the respective SNPs, then the expected number of associations the JIA cohort should detect for RA is 25.9 (95% confidence interval [95% CI]

16.5-32.7) and for type 1 DM is 26.1 (95% CI 21.1-31.1).

Discussion

This study includes the largest JIA cohort analyzed on genome-wide platforms to date (2,751 patients with oligoarticular JIA or RF-negative polyarticular JIA and 15,886 controls) and identifies new oligoarticular and RF-negative polyarticular JIA associations (Figure 1). Nine of the 28 loci detected in oligoarticular and RF-negative polyarticular JIA Immunochip studies [3] remained significant (P < 5x10-8) in the current genome-wide analysis (PTPN22, ATP8B2 _ IL6R,

STAT4, IL2_IL21, ERAP2_LNPEP, HLA, IL2RA, COG6, and PTPN2); 2 additional regions,

C5orf56_ IRF1 and PRR5L, achieved suggestive levels of association (P < 1x10-6) (Figure 1). The higher-density SNP coverage provided by the Immunochip platform compared to genome-wide arrays may account for differences in the findings. However, there are comparable magnitudes of effect (Spearman’s correlation coefficient = 0.89) between the OR reported for the most significant

SNPs identified in the Immunochip study [3] and the current GWAS. Use of the Exome Array for the genotyping of cohort III was economically driven, but the lack of SNP inclusion in this array may contribute to these differential findings.

Although ~70% of the patient samples used for this study have been used in previous association studies [3-5], by using genome-wide data sets, we now extend the number of genetic loci associated with JIA. In spite of these efforts, the newly reported associations do not meet the generally used, but somewhat arbitrary, threshold of P < 5x10-8. Genome-wide thresholds assume

1 million independent tests and a genome-wide Type I error rate of 0.05. Yet, it is difficult to determine how many independent tests of association are computed in a GWAS, because LD pruning using r2 < 0.4 reduces the number of loci in this European ancestral cohort to <1 million, and even these remain correlated. Nonetheless, the need remains to validate these findings in other

cohorts, which are difficult to acquire for a rare disease affecting young children. Indeed, the patient cohorts reported were collected over the course of several decades.

Four of the newly identified oligoarticular JIA and RF-negative polyarticular JIA loci (JAK1,

PTH1R, AHI1_LINC00271, and WDFY4) (see Table 2) reported here have been described as being associated with another autoimmune disease, according to the GWAS Catalog and Immunobase, suggesting common pathophysiologic mechanisms. Although the databases cataloging GWAS and

Immunochip findings are incomplete, they begin to allow the findings of this study to be put in the context of other autoimmune diseases. Only a small percentage of the reported lead RA [28] and type 1 DM [24] SNPs reaching the Bonferroni-corrected P value cutoffs in our data set (see

Supplementary Tables 5 and 6). This is markedly less than expected and well outside the confidence intervals. Given that the RA- and type 1 DM-associated SNPs were discovered in predominately European ancestral groups, it is unlikely that this deficit is merely due to differences in LD among the different disease populations. Rather, these results support the notion that although JIA (at least the oligoarticular and RF-negative polyarticular subtypes) shares some risk loci, it is genetically distinct from seropositive RA (despite similar clinical presentations) and type

1 DM (another autoimmune disease with childhood onset). The remaining 5 unique newly identified oligoarticular and RF-negative polyarticular JIA loci reveal additional regions of the genome that will require further investigation to fully delineate their importance in JIA and autoimmune diseases in general.

The PRR9_LOR locus was the most strongly associated novel region, approaching genome-wide significance (P = 5.12x10-8). PRR9 encodes a protein of unknown function, with the highest

expression levels in the skin [29], while LOR encodes loricrin, a component of the cornified cell envelope in terminally differentiated epidermal cells. Interestingly, association analyses in patients with psoriasis, an inflammatory skin disorder, have identified PRR9 as a susceptibility locus [30,

31]. Although this may represent overlap of disease risk loci between JIA and psoriasis, there is also the possibility that the JIA cohorts include psoriasis patients, given that ~20-25% of patients present with arthritis before skin disease, which is difficult to define in younger children.

Biologic pathways that feature gene products suggested by the results of this study and previous

Immunochip studies [3, 10] may offer insight into disease pathophysiology (see Figure 2). While some of the associated regions observed in the current study may not have direct functional relationships with other loci, loci such as CD86 and JAK1 appear to be central to key signaling pathways involving T cell differentiation and proliferation. JAK1 encodes a tyrosine kinase that interacts with the common γ-chain to elicit signals from cytokines, such as interleukin-2 (IL-2) and IL-21, to induce interferon-γ, IL-17, and IL-6 production [32]. Further bioinformatic analysis revealed the presence of H3K4me1 histone modifications near JAK1 in CD14+ cells and CD15+ cells, suggesting the presence of an enhancer region at this locus (see Supplementary Table 4).

Notably, a JAK inhibitor, tofacitinib, is already used for the treatment of RA. With clinical trials underway, it remains to be seen whether inhibitors of the JAK1 pathway are efficacious in children with JIA.

Given that JIA is an autoimmune disease, it was expected that additional immune-related disease loci that were not found on Immunochip would be identified by genome-wide approaches.

Specifically, CD86 is important in the immune regulation of multiple immune cell types [33]. It is

expressed on antigen-presenting cells and interacts with both CD28 and CTLA-4 on T cells, resulting in T cell stimulation or inhibition, respectively [34]. CD86 signaling has been shown to lead to increased antibody production [35]. Modulation of CD86 with CTLA-4 Ig has been shown to down-regulate proinflammatory cytokine production (including IL-6 and tumor necrosis factor

α) by synovial macrophages in vitro [36]. Conditional analysis showed that the CD86 association signal is independent of the previously reported signal at Chr3q13 that includes the nearby gene

CD80 [4].

As expected, most associated regions fall within noncoding, regulatory regions. An exception, the association in PTH1R, is represented by a synonymous coding region mutation (Table 1). Although this SNP does not alter the amino acid sequence of the protein, it still may potentially contribute to disease through epigenetic [37-39] or other mechanisms, making it an interesting region for future investigation. Furthermore, PTH1R is expressed at high levels in the bone and activates

RANKL expression, which promotes thymic tolerization and the dendritic cell-T cell interaction for T cell activation [40]. In addition, a functional polymorphism in the RANKL promoter region

(rs7984870) has been associated with early age at onset of RA (~50 years) [41], suggesting the potential mechanistic importance of PTH1R in JIA.

Gene expression and chromatin accessibility analyses suggest that many of the associated SNPs located in noncoding portions of the genome are functionally relevant and therefore could impact disease. Results of the current study appear to be consistent with this hypothesis. For example,

SNPs near the AHI1_LINC00271 locus can lead to alterations in AHI1 expression and show evidence of H3K4me1 histone modifications in CD14+ cells (Table 3 and Supplementary Table

4). AHI1 expression is critical to hematopoietic cell differentiation, and dysregulation may have significant consequences [42].

Other mechanisms are also probable. For example, several East Asian GWAS showed associations of WDFY4 with SLE [43, 44]. Functional studies using peripheral blood mononuclear cells revealed decreased messenger RNA expression of WDFY4 in SLE patients when compared to controls. This may be due to the fact that intronic SNP rs877819 has a decreased binding affinity to transcription factor Yin Yang 1 (YY1). Binding of YY1 to this intronic region was shown to directly influence WDFY4 expression [45]. This SNP is marginally associated with JIA (P =

1.3x10-3 [genotyped in cohorts I and II]) but is in LD with the lead JIA SNP in the WDFY4 region

(rs1904603; r2 = 0.47). Although the functional relevance of these eQTLs and histone analyses is limited to the cell and tissue types available in public data sets, the information provided is, nonetheless, important to prioritizing future functional studies.

Expression QTL analysis also showed that SNP variations near HBP1 and RNF215 are related to the expression levels of nearby genes COG5 and MTP18/SF3A1, respectively (Table 3 and

Supplementary Table 4). Intriguingly, COG5, like COG6, is a member of the conserved oligomeric

Golgi (COG) complex that regulates protein glycosylation and Golgi trafficking. We previously reported COG6 genetic associations in JIA, and associations with the COG6 region have also been described in RA and SLE [3, 5, 46]. Thus, the findings that risk variants for multiple COG proteins in JIA were identified, that COG6 associations have been reported for other autoimmune disease, and that COG defects result in systemic pathologies [47] suggests that Golgi complex pathways may be important in autoimmune disease. In addition, results of the eQTL analysis also implicate

MTP18, which represents a plausible candidate because it is a mitochondrial protein downstream of phosphatidylinositol 3-kinase signaling, potentially playing a role in the induction of apoptosis.

Although there is no direct support for the associated region nearest LINC00951 (FLJ41649), the genetic data, including numerous directly genotyped SNPs, support inclusion as a JIA risk locus

(see Supplementary Figure 2).

In conclusion, the results of this study further emphasize the role of common genetic variation and add to the understanding of the genomic architecture influencing the risk of oligoarticular and RF- negative polyarticular JIA. As seen in other autoimmune diseases, the majority of these JIA- associated SNPs are located in regulatory regions, supporting the notion that JIA is also a disease of disordered gene regulation. Further work, including evaluation of chromatin interactions and regulatory regions, is essential to understanding the contributions of associated SNPs to disease risk and the genomics influencing oligoarticular and RF-negative polyarticular JIA [48]. There is also evidence of interplay among associated regions, suggesting dysregulated pathways as potential targets in clinical care.

Acknowledgements

We would like to thank the Wake Forest School of Medicine Center for Public Health Genomics for providing computational resources and data analytics support.

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Appendix A

Consortia Involved in the Study and Their Participating Members

Boston Children’s JIA Registry: Fatma Dedeoglu, Robert C. Fuhlbrigge, Melissa M. Hazen, Lauren A. Henderson, Erin Janssen, Susan Kim, Mindy S. Lo, Mary Beth F. Son, Robert P. Sundel, Irit Tirosh, Heather O. Tory (Boston Children’s Hospital); Peter A. Nigrovic (Boston Children’s Hospital and Brigham and Women’s Hospital).

German Society for Pediatric Rheumatology: Guenther Dannecker, Gerd Ganser, J. Peter Haas, Hartmut Michels (German Center for Pediatric and Adolescent Rheumatology, Garmisch- Partenkirchen).

Gene Expression in Pediatric Arthritis Study: Mara L. Becker (Children’s Mercy Kansas City); Robert A. Colbert (National Institute of Arthritis and Musculoskeletal and Skin Diseases [NIAMS], Bethesda, MD); Jason Dare (Arkansas Children’s Hospital, Little Rock); Beth S. Gottleib (Steven and Alexandra Cohen Children’s Medical Center, New Hyde Park. NY), Thomas A. Griffin (Levine Children’s Hospital, Charlotte, NC); Alexie A. Grom, Daniel J. Lovell, Halima Moncrieffe, Susan D. Thompson (Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH); Norman T. Ilowite (Albert Einstein College of Medicine and Children’s Hospital at Montefiore, Bronx, NY); Peter A. Nigrovic (Boston Children’s Hospital and Brigham and Women’s Hospital); Judy Ann Olsen (Indiana University School of Medicine, Indianapolis); Sampath Prahalad (Emory University School of Medicine, Atlanta, GA); Margalit Rosenkranz (Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA); David D. Sherry (Children’s Hospital of Philadelphia, Philadelphia, PA).

NIAMS JIA Genetic Registry: John F. Bohnsack (University of Utah Health Sciences Center, Salt Lake City); Gloria Higgins (Nationwide Children’s Hospital and Ohio State University, Columbus, OH); Marissa Klein-Gittelman (Northwestern University Feinberg School of Medicine and Children’s Memorial Hospital, Chicago, IL); T. Brent Graham (Vanderbilt University, Nashville, TN); Thomas A. Griffin (Levine Children’s Hospital, Charlotte, NC); Paula W. Morris (University of Arkansas for Medical Sciences, Little Rock); Natasha Ruth, Murray H. Passo (Medical University of South Carolina, Charleston), Sampath Prahalad (Emory University School of Medicine, Atlanta, GA); Stephen J. Spaulding (Cleveland Clinic, Cleveland, OH); Susan D. Thompson (Cincinnati Children’s Hospital Medical Center [CCHMC] and University of Cincinnati, Cincinnati, OH).

Trial of Early Aggressive Therapy in JIA (TREAT): Carol A.Wallace, Sarah Ringold, Stephanie Hamilton (Seattle Children’s Hospital and Seattle Children’s Research Institute, Seattle, WA); Edward H. Giannini, Hermine I. Brunner, Anne L. Johnson, Bin Huang, Daniel J. Lovell (CCHMC and University of Cincinnati, Cincinnati, OH); Steven J. Spalding, Andrew S. Zeft (Cleveland Clinic, Cleveland, OH); Philip J. Hashkes (Shaare Zedek Medical Center, Jerusalem, Israel); Kathleen M. O’Neil, Peter Chira (Indiana University, Indianapolis); Ilona S. Szer (Rady

Children’s Hospital San Diego, San Diego, CA); Laura E. Schanberg (Duke University Medical Center, Durham, NC); Robert P. Sundel (Children’s Hospital of Boston, Boston, MA); Diana Milojevic (University of California, San Francisco); Marilynn G. Punaro (Texas Scottish Rite Hospital, Dallas); Beth S. Gottlieb (Steven and Alexandra Cohen Children’s Medical Center, New Hyde Park, NY); Gloria C. Higgins (Nationwide Children’s Hospital and Ohio State University, Columbus, OH); Norman T. Ilowite (Albert Einstein College of Medicine and Children’s Hospital at Montefiore, Bronx, NY); Yukiko Kimura (Joseph M. Sanzari Children’s Hospital at Hackensack University Medical Center, Hackensack, NJ).

Improved Understanding of the Biology and Use of TNF Inhibition in Children with JIA Study: Daniel J. Lovell, Alexie A. Grom, Anne L. Johnson, Janalee Taylor, Hermine I. Brunner, Jennifer L. Huggins, Tracy V. Ting, Bin Huang, Edward H. Giannini (CCHMC and University of Cincinnati, Cincinnati, OH); Steven J. Spalding, Andrew Zeft (Cleveland Clinic, Cleveland, OH); Beth S. Gottlieb, Calvin B. Williams, Anne B. Eberhard (Steven and Alexandra Cohen Children’s Medical Center, New Hyde Park, NY); Paula W. Morris (University of Arkansas for Medical Sciences, Little Rock); Yukiko Kimura, Suzanne C. Li, Kathleen A. Haines, Jennifer E. Weiss (Joseph M. Sanzari Children’s Hospital at Hackensack University Medical Center, Hackensack, NJ); Karen Onel, Melissa S. Tesher, Linda Wagner-Weiner (University of Chicago Comer Children’s Hospital, Chicago, IL); James J. Nocton, James W. Verbsky, Judyann C. Olson (Medical College of Wisconsin, Milwaukee); Barbara S. Edelheit, Lawrence S. Zemel (Connecticut Children’s Medical Center, Hartford); Michael Shishov, Kaleo C. Ede (Phoenix Children’s Hospital, Phoenix, AZ); Lawrence K. Jung, Denise M. Costanzo (Children’s National Medical Center, Washington, DC; Cleveland Clinic Foundations, Cleveland, OH); Jason A. Dare (Arkansas Children’s Hospital, Little Rock); Murray H. Passo (Medical University of South Carolina, Charleston); Elaine A. Cassidy, Daniel Kietz (Children’s Hospital of Pittsburgh, Pittsburgh, PA); Thomas A. Griffin (Levine Children’s Hospital, Charlotte, NC); Larry B. Vogler, Kelly A. Rouster-Stevens (Emory University School of Medicine, Atlanta, GA); Timothy Beukelman, Randy Q. Cron (University of Alabama at Birmingham); Kara M. Schmidt, Kenneth Schikler (University of Louisville Kosair Charities Pediatric Clinical Research Unit, Louisville, KY); Jay Mehta (Children’s Hospital at Montefiore, Bronx, NY).

Figures

Figure 1. Manhattan plot of genome-wide genetic association statistics for oligoarticular and rheumatoid factor–negative polyarticular juvenile idiopathic arthritis (JIA) risk loci. The upper gray line indicates the genome-wide significance (P < 5x10-8) threshold. The lower gray line indicates the suggestive association (P < 1x10-6) threshold. Loci reaching this threshold and individual single-nucleotide polymorphisms mapping to these loci are shown in dark blue. Loci in gray have been reported for association by Hinks et al (see ref. 3). The loci are named using the genes bounding the regions of association and do not necessarily reflect a functional link with a specific gene.

Figure 2. IPA showing interactions between products of genes located in the juvenile idiopathic arthritis–associated regions from the current study and previous Immunochip studies. Solid lines represent direct interactions, where 2 molecules make direct physical contact with each other.

Dashed lines represent indirect interactions. Only experimentally validated interactions are shown.

GWAS = genome-wide association study.

Tables

Table 1. SNPs representing top statistical associations (P < 1x10-6) with oligoarticular JIA and RF-negative polyarticular JIA

Minor MAF MAF SNP Lead SNP Gene Region Chr:Positiona P-value Model OR (95% CI) Allele Casesb Controlsb Position rs10889504 JAK1 1:65390503 C 0.11 0.13 4.18x10-7 Add 0.78 (0.71-0.86) Intron

rs873234 PRR9_LOR 1:153227177 A 0.40 0.37 5.12x10-8 Rec 1.43 (1.25-1.63) Intergenic

rs1138518 PTH1R 3:46944274 T 0.42 0.37 1.87x10-7 Add 1.23 (1.14-1.34) Coding (Syn) rs111700762 ILDR1_CD86 3:121780807 A 0.08 0.06 6.73x10-8 Dom 1.45 (1.26-1.66) Intron

rs10807228 LINC00951 6:40188351 T 0.36 0.33 5.80x10-7 Rec 1.42 (1.23-1.65) Intergenic

rs9321502 AHI1_LINC00271 6:135656252 C 0.43 0.40 3.48x10-7 Add 1.18 (1.11-1.26) Intron rs111865019 HBP1 7:106812246 G 0.24 0.27 7.29x10-7 Add 0.84 (0.78-0.90) Intron

rs1904603 WDFY4 10:50013840 G 0.29 0.25 1.79x10-7 Dom 1.27 (1.16-1.39) Intron

rs5753109 RNF215 22:30777888 C 0.31 0.28 3.09x10-7 Add 1.19 (1.11-1.28) Intron aCoordinates are based on the GRCh37 assembly bCase n=2,751, Control n=15,886; rs1138518 did not pass QC in all cohorts – case-control counts are 1,937 and 12,828, respectively

Add=Additive, Rec=Recessive, D=Dominant, MAF=Minor Allele Frequency, OR=Odds Ratio, CI=Confidence Interval,

Syn=synonymous

Table 2. Overlapping regions of association between oligoarticular and RF-negative polyarticular JIA and other autoimmune diseases

JIA Loci Susceptibility Loci for Other Autoimmune Diseasesa

Lead SNP Gene Region Chr:Position Disease SNP Chr:Positionb r2c P-value OR Risk RAF Allele CeD rs12409333 1:65417839 0.90 3.80x10-5 0.89 G 0.25 rs10889504 JAK1 1:65390503 MS rs12409333 1:65417839 0.90 2.70x10-4 0.91 G 0.25

rs1138518 PTH1R 3:46944274 CeD rs2061197 3:47001350 0.41 8.55x10-6 1.09 A 0.37

MS rs11154801 6:135739355 0.74 1.80x10-20 1.12 A 0.37

CeD rs12206850 6:135797808 0.70 6.89x10-4 1.07 C 0.27 rs9321502 AHI1_LINC00271 6:135656252 ATD rs2179781 6:135719500 0.76 4.84x10-4 NR NR NR

T1D rs11154801 6:135739355 0.74 2.55x10-5 1.08 A 0.29

rs1904603 WDFY4 10:50013840 SLE rs877819 10:50042951 0.47 8.00x10-9 1.46 A 0.18 aOther autoimmune disease loci information taken from the (NHGRI)-European Bioinformatics Institute (EBI) GWAS Catalog

(https://www.ebi.ac.uk/gwas/) and Immunobase (https://www.immunobase.org); published findings: CeD [20], MS [21, 22], ATD

[23], T1D [24], and SLE [25] bCoordinates are based on the GRCh37 assembly cr2 with JIA loci lead SNP

Table 3. Expression of quantitative trait locus (eQTL) genes in novel oligoarticular- and RF-negative polyarticular JIA-associated regions

Lead SNP Gene Region eQTL SNPa Chr:Positionb r2c eQTL Gene

rs1138518 PTH1R rs2242116 3:46941116 1.00 CCDC12

rs9321502 AHI1_LINC00271 rs2614276 6:135681704 0.83 AHI1

rs7790080 7:107031322 0.82 COG5 rs111865019 HBP1 rs2301801 7:106870746 0.82 HBP1

rs2237659 7:106847492 0.82 GPR22

rs1904603 WDFY4 rs2940707 10:49989792 0.95 WDFY4

rs757870 22:30776419 0.91 MTP18 rs5753109 RNF215 rs4820003 22:30711624 0.91 SF3A1 aThe SNP with the highest eQTL score for each eQTL gene is shown; data were gathered from the University of Chicago

(eqtl.uchicago.edu) and Blood eQTL Browsers [25] bCoordinates are based on the GRCh37 assembly cr2 with JIA loci lead SNP

Supplemental Figure 1. Power analysis over range of minor allele frequencies (MAF) for meta-analysis with type 1 error rate of

1x10-6.

Supplemental Figure 2. LocusZoom plots for the nine novel regions associated with JIA (P < 1x10-6). The –log10 p-value is on the left y-axis, and the recombination rate for the region is on the right y-axis. The x-axis is the chromosomal position (Mb). Coordinates are based on the GRCh37 assembly. Dots are colored according to LD with the lead SNP as based on 1000 Genomes Nov 2014 EUR.

Square dots indicate that the SNP was genotyped in at least one cohort, while circle dots indicate imputed SNPs.

Supplemental Table 1. Sample collection breakdown by gender and ILAR subtype post-QC

ILAR Subtype (% Female)

Population Persistent Extended Oligoarthritis Polyarthritis Cases (Controls) Sample Oligoarthritis Oligoarthritis Unknown RF Negative Cohort I 814 (3,058) 343 (79%) 118 (84%) 0 (0%) 353 (78%)

Cohort II 1,057 (11,843) 521 (73%) 104 (91%) 55 (85%) 377 (73%)

Cohort III 880 (985) 296 (76%) 102 (82%) 42 (69%) 440 (77%)

Meta 2,751 (15,886) 1,160 (75%) 324 (86%) 97 (78%) 1,170 (76%)

Supplemental Table 2. Second tier findings of genetic association with oligoarticular and polyarticular RF negative JIA

1.0x10-6 < P < 1.0x10-5

Minor MAF MAF SNP Lead SNP Gene Region Chr:Positiona P-value Model OR (95% CI) Allele Casesb Controlsb Position rs390026 Chr1q56 1:55953105 G 0.10 0.09 1.88x10-6 Rec 3.76 (2.21-6.41) Intergenic

rs1860915 Chr1q187 1:187746363 G 0.33 0.29 1.70x10-6 Add 1.21 (1.11-1.32) Intergenic

rs77032963 MBOAT2_ASAP2 2:9268701 A 0.29 0.32 7.73x10-6 Dom 0.78 (0.70-0.87) Intergenic

rs12712262 ST6GAL2 2:107516533 C 0.27 0.24 5.25x10-6 Add 1.20 (1.11-1.30) Intergenic

rs77522562 IKZF2 2:214085918 T 0.06 0.07 8.38x10-6 Dom 0.74 (0.65-0.85) Intergenic

rs17073988 MAGI1 3:65848944 G 0.11 0.09 3.12x10-6 Dom 1.30 (1.16-1.47) Intron

rs6441629 NFKBIZ c 3:101633203 T 0.28 0.26 3.81x10-6 Dom 1.24 (1.13-1.35) Intergenic

rs771761 NFKBIZ c 3:101741311 T 0.44 0.42 2.03x10-5 Add 1.16 (1.09-1.24) Intergenic

rs9832537 BBX_LINC00635 3:107545050 C 0.32 0.34 6.74x10-6 Add 0.86 (0.80-0.92) Intergenic

rs62296577 TBL1XR1 3:176849740 T 0.36 0.34 6.87x10-6 Dom 1.30 (1.16-1.45) Intron

rs9865310 LPP 3:188466638 A 0.30 0.28 9.98x10-6 Add 1.16 (1.08-1.25) Intron

rs17036097 ARHGEF38 4:106597295 C 0.13 0.15 6.44x10-6 Add 0.82 (0.75-0.89) Intron

rs10515295 FAM174A 5:99387360 T 0.31 0.33 4.49x10-6 Dom 0.82 (0.75-0.89) Intergenic

Coding rs10068763 BTNL9 5:180486785 G 0.37 0.35 9.13x10-6 Rec 1.43 (1.23-1.67) (Missense)

rs1205005 PXDC1 6:3713222 C 0.06 0.05 5.04x10-6 Add 1.45 (1.24-1.70) Intron

rs2145771 Chr6q23 6:23634097 C 0.37 0.40 3.40x10-6 Rec 0.75 (0.66-0.85) Intergenic

rs9389248 HBS1L 6:135282656 C 0.47 0.44 5.90x10-6 Add 1.16 (1.09-1.23) 3' UTR

rs6980284 Chr7q13 7:13116330 C 0.11 0.12 5.83x10-6 Dom 0.79 (0.71-0.87) Intergenic

rs10230459 ELMO1 7:37431559 G 0.12 0.10 5.87x10-6 Dom 1.28 (1.14-1.44) Intron

rs73200246 Chr7q115 7:114960443 T 0.15 0.18 2.86x10-6 Dom 0.78 (0.69-0.88) Intergenic rs145245620 LVCAT5 7:119284745 T 0.18 0.16 3.42x10-6 Dom 1.26 (1.14-1.39) Intron

rs6987422 LY96_JPH1 8:75026885 T 0.15 0.14 6.00x10-6 Dom 1.30 (1.17-1.45) Intergenic

rs2513910 AZIN1 8:103817106 G 0.43 0.46 3.22x10-6 Dom 0.80 (0.73-0.89) Intergenic

SAMD12-AS1_ rs3103971 8:119858126 C 0.38 0.40 4.28x10-6 Dom 0.80 (0.73-0.88) Intron TNFRSF11B

rs10217572 PTPRD 9:10258159 T 0.44 0.47 3.87x10-6 Dom 0.78 (0.71-0.86) Intron

rs12772903 TET1 10:70390134 A 0.19 0.16 9.72x10-6 Add 1.23 (1.12-1.35) Intron

rs11195449 ADRA2A 10:112928036 C 0.15 0.14 1.77x10-6 Rec 2.04 (1.51-2.77) Intergenic

3' UTR rs61886888 CCDC88B 11:64124622 A 0.15 0.18 6.50x10-6 Dom 0.80 (0.72-0.88) (Missense)

rs7141573 RAD51B 14:69135753 G 0.45 0.48 5.79x10-6 Rec 0.76 (0.68-0.86) Intron

rs78413762 SV2B 15:91794183 A 0.12 0.10 2.14x10-6 Dom 1.33 (1.18-1.49) Intron

rs513000 SOX8_SSTR5-AS1 16:1092871 T 0.07 0.10 1.83x10-6 Add 0.69 (0.59-0.81) Intergenic

rs4786718 RBFOX1 16:5625681 C 0.15 0.13 3.49x10-6 Add 1.26 (1.14-1.38) Intron

rs7228926 Chr18q36 18:36160294 T 0.27 0.24 1.59x10-6 Dom 1.25 (1.14-1.37) Intergenic

rs77275636 CDH7 18:63177860 A 0.22 0.19 2.29x10-6 Add 1.21 (1.11-1.31) Intergenic

CEACAM19_ rs2965150 19:45190608 C 0.48 0.46 9.24x10-6 Rec 1.26 (1.13-1.40) Intergenic CEACAM16

rs6022755 SUMO1P1 20:52415871 A 0.35 0.40 6.64x10-6 Dom 0.76 (0.67-0.86) Intergenic rs142391047 SCAF4_HUNK 21:33169880 C 0.07 0.05 9.27x10-6 Add 1.40 (1.20-1.64) Intergenic aCoordinates are based on the GRCh37 assembly bCase n=2,751, Control n=15,886; the following SNPs did not pass QC in all cohorts: case-control numbers for rs1860915, rs77032963, rs62296577, and rs73200246 are 1,937 and 12,828, respectively; case-controls numbers for rs390026, rs12712262, rs10068763, rs1205005, rs12772903, rs7141573, and rs142391047 are 1,871 and 14,901, respectively; case-controls numbers for rs513000 and rs6022755 are 1,694 and 4,043, respectively

cThe NFKBIZ region showed additional effects after conditioning on the lead SNP; the p-value shown for rs771761 is adjusted for lead SNP rs6441629

Add=Additive, Rec=Recessive, Dom= Dominant, MAF=Minor Allele Frequency, OR=Odds Ratio, CI=Confidence Interval

Supplemental Table 3. Association findings for all SNPs showing evidence of association with oligoarticular and RF negative polyarticular JIA (FDR < 0.05)

SNP Chr:Positiona Model Minor Allele FDR OR (95% CI)

rs58860179 1:25294902 Add T 4.95x10-2 0.81 (0.73-0.89)

rs2395858 1:25295580 Dom G 4.95x10-2 0.81 (0.73-0.9)

rs76400732 1:25296478 Add G 4.95x10-2 0.81 (0.73-0.89)

rs566255 1:38202206 Dom T 4.94x10-2 1.16 (1.08-1.25)

rs1893607 1:38206027 Dom C 4.94x10-2 1.17 (1.09-1.26)

rs10142466 1:38212465 Rec A 4.93x10-2 1.17 (1.09-1.26)

rs12825103 1:38213310 Rec G 4.93x10-2 1.17 (1.09-1.26)

rs7574909 1:38214463 Add C 4.93x10-2 1.17 (1.08-1.25)

rs2614267 1:38216333 Add T 4.93x10-2 1.16 (1.08-1.25)

rs72769550 1:38220109 Dom A 4.92x10-2 1.17 (1.09-1.26)

rs58044109 1:53927649 Add G 4.92x10-2 1.22 (1.11-1.34)

rs6719707 1:54961241 Add T 4.92x10-2 1.16 (1.09-1.24)

rs9806871 1:55953105 Dom C 4.92x10-2 3.76 (2.21-6.41)

100

rs6705162 1:55953404 Add A 4.90x10-2 3.82 (2.19-6.68)

rs7655436 1:60658917 Rec C 4.90x10-2 2.15 (1.52-3.05)

rs11256516 1:65390503 Add G 4.90x10-2 0.78 (0.71-0.86)

rs2164061 1:65392905 Add A 4.90x10-2 0.79 (0.72-0.87)

rs3851347 1:65417839 Rec G 4.89x10-2 0.78 (0.71-0.86) rs186764876 1:65419504 Add A 4.88x10-2 0.78 (0.71-0.86)

rs77516568 1:65420067 Add C 4.88x10-2 0.78 (0.7-0.86)

rs2513898 1:65420190 Add C 4.87x10-2 0.78 (0.7-0.86)

rs12760683 1:65420642 Rec A 4.87x10-2 0.78 (0.71-0.86)

rs35699864 1:65423071 Dom C 4.87x10-2 0.78 (0.7-0.86)

rs17651181 1:65423447 Add C 4.87x10-2 0.77 (0.68-0.87)

rs2436845 1:65429257 Add A 4.87x10-2 0.78 (0.7-0.86)

rs2436846 1:65429319 Add C 4.87x10-2 0.76 (0.67-0.86)

rs68173595 1:65431920 Rec A 4.87x10-2 0.77 (0.7-0.85)

rs7494834 1:65434040 Rec T 4.87x10-2 0.78 (0.7-0.86)

rs2757647 1:65435425 Add C 4.86x10-2 0.78 (0.7-0.86)

101

rs150959082 1:65436242 Dom A 4.86x10-2 1.26 (1.13-1.39)

rs2436848 1:65440764 Add G 4.86x10-2 0.77 (0.7-0.86)

rs13432744 1:65455477 Dom A 4.85x10-2 0.76 (0.68-0.86)

rs1667676 1:76757661 Add T 4.85x10-2 0.88 (0.83-0.94)

rs7645278 1:76758231 Add T 4.84x10-2 0.88 (0.83-0.94)

rs13069310 1:80967857 Rec G 4.84x10-2 0.84 (0.77-0.91)

rs79871905 1:113914184 Dom T 4.83x10-2 3.19 (2.11-4.81)

rs17164401 1:114075796 Dom C 4.83x10-2 1.2 (1.11-1.29)

rs2293765 1:114077939 Rec C 4.82x10-2 0.81 (0.74-0.88)

rs6462922 1:114080071 Rec A 4.81x10-2 1.15 (1.07-1.23)

rs1660149 1:114081002 Add G 4.81x10-2 1.15 (1.07-1.23)

rs2963436 1:114084544 Rec T 4.81x10-2 1.2 (1.11-1.29)

rs34493746 1:114086821 Dom T 4.81x10-2 1.15 (1.08-1.23)

rs3133585 1:114087710 Dom A 4.81x10-2 0.86 (0.81-0.92)

rs1559355 1:114088416 Dom G 4.80x10-2 1.2 (1.11-1.29)

rs11066309 1:114089316 Add A 4.80x10-2 1.19 (1.11-1.28)

102

rs1468751 1:114092915 Add G 4.79x10-2 0.81 (0.74-0.88) rs12712125 1:114093834 Dom G 4.78x10-2 1.2 (1.11-1.29) rs76884671 1:114094044 Add T 4.78x10-2 0.81 (0.74-0.88) rs6442040 1:114094286 Add C 4.78x10-2 1.2 (1.11-1.29) rs62400871 1:114095339 Dom C 4.78x10-2 1.2 (1.11-1.29) rs2159276 1:114095750 Dom C 4.78x10-2 0.81 (0.74-0.88) rs2570942 1:114096097 Add G 4.78x10-2 1.2 (1.11-1.29) rs13261467 1:114096460 Rec C 4.78x10-2 1.15 (1.08-1.23) rs2947345 1:114098499 Dom C 4.78x10-2 0.8 (0.74-0.88) rs79692137 1:114101115 Add C 4.78x10-2 1.2 (1.11-1.29) rs35578504 1:114101719 Rec C 4.78x10-2 1.16 (1.08-1.24) rs11119328 1:114102229 Add A 4.77x10-2 1.16 (1.08-1.24) rs10271355 1:114105476 Dom A 4.77x10-2 1.2 (1.11-1.29) rs28374324 1:114106769 Add C 4.77x10-2 0.8 (0.73-0.88) rs9890608 1:114106807 Add A 4.77x10-2 1.2 (1.11-1.29)

rs910118 1:114106923 Dom A 4.77x10-2 1.2 (1.11-1.29)

103

rs10030620 1:114107044 Add G 4.77x10-2 0.8 (0.73-0.88) rs10918925 1:114108252 Dom G 4.77x10-2 1.2 (1.11-1.29) rs6678817 1:114108711 Dom C 4.77x10-2 1.16 (1.08-1.24) rs1028795 1:114109088 Add C 4.77x10-2 1.2 (1.11-1.29) rs2679751 1:114109621 Add G 4.77x10-2 1.2 (1.11-1.29) rs77871209 1:114110836 Add T 4.77x10-2 1.2 (1.11-1.29) rs7496614 1:114110901 Rec A 4.77x10-2 1.16 (1.08-1.24) rs4683297 1:114111036 Add C 4.76x10-2 1.2 (1.11-1.29) rs7541437 1:114113225 Dom T 4.76x10-2 1.16 (1.08-1.24) rs7713127 1:114114537 Dom G 4.76x10-2 1.2 (1.11-1.29) rs2007241 1:114114717 Dom C 4.75x10-2 1.19 (1.1-1.29) rs7862508 1:114114843 Rec T 4.74x10-2 1.2 (1.12-1.29) rs7185730 1:114116574 Dom G 4.74x10-2 1.2 (1.12-1.3) rs4796018 1:114116845 Rec A 4.72x10-2 1.16 (1.08-1.24) rs6704054 1:114116889 Add C 4.72x10-2 1.16 (1.08-1.24) rs2594113 1:114118574 Add A 4.72x10-2 0.8 (0.73-0.88)

104

rs17607405 1:114118742 Dom A 4.72x10-2 0.8 (0.73-0.88) rs34329425 1:114119237 Add G 4.71x10-2 1.2 (1.12-1.3) rs16885824 1:114119620 Add C 4.71x10-2 1.2 (1.12-1.3) rs17573327 1:114119751 Dom C 4.71x10-2 1.16 (1.08-1.24)

rs830647 1:114123773 Add C 4.71x10-2 1.2 (1.12-1.3) rs35182282 1:114125259 Add A 4.70x10-2 1.21 (1.12-1.3) rs6685952 1:114126107 Dom A 4.70x10-2 1.21 (1.12-1.3) rs9610686 1:114126220 Dom T 4.70x10-2 1.21 (1.12-1.3) rs11750025 1:114127526 Dom C 4.70x10-2 0.83 (0.75-0.9) rs12817097 1:114129474 Rec T 4.70x10-2 1.21 (1.12-1.3) rs12809528 1:114130098 Rec G 4.70x10-2 1.21 (1.12-1.3) rs3095413 1:114131740 Add G 4.70x10-2 1.21 (1.12-1.3) rs59484179 1:114132073 Add T 4.69x10-2 0.83 (0.75-0.9) rs10953781 1:114132358 Add C 4.69x10-2 0.83 (0.75-0.9) rs13103083 1:114132712 Add T 4.69x10-2 1.21 (1.12-1.3) rs11635689 1:114134977 Rec T 4.69x10-2 1.21 (1.12-1.3)

105

rs2568918 1:114135346 Add T 4.69x10-2 1.21 (1.12-1.3)

rs79277175 1:114135526 Add T 4.69x10-2 0.83 (0.76-0.9)

rs13167902 1:114135555 Dom A 4.69x10-2 0.83 (0.76-0.91)

rs742763 1:114135708 Rec A 4.69x10-2 1.21 (1.12-1.3)

rs1660148 1:114136037 Add A 4.67x10-2 1.21 (1.12-1.3)

rs11123907 1:114138534 Dom A 4.67x10-2 1.21 (1.12-1.3)

rs233912 1:114139359 Dom G 4.67x10-2 1.21 (1.12-1.3) rs191220852 1:114139616 Dom C 4.67x10-2 1.21 (1.12-1.3)

rs10809043 1:114139922 Dom G 4.67x10-2 1.2 (1.12-1.3)

rs9852082 1:114140889 Add T 4.66x10-2 1.21 (1.12-1.3)

rs11242115 1:114141492 Rec C 4.66x10-2 1.21 (1.12-1.3)

rs2746419 1:114141775 Add A 4.66x10-2 1.21 (1.12-1.3)

rs10900809 1:114144746 Rec A 4.66x10-2 0.83 (0.76-0.91)

rs28678122 1:114146334 Add C 4.66x10-2 1.21 (1.12-1.3)

rs16970563 1:114147381 Add T 4.66x10-2 1.21 (1.12-1.3)

rs683647 1:114147865 Dom A 4.66x10-2 1.21 (1.12-1.3)

106

rs9603595 1:114148921 Dom A 4.66x10-2 1.21 (1.12-1.3)

rs12899496 1:114149792 Add T 4.66x10-2 1.21 (1.12-1.3)

rs12408934 1:114149945 Dom A 4.66x10-2 0.83 (0.76-0.9)

rs13076475 1:114151847 Rec T 4.66x10-2 1.2 (1.11-1.3)

rs2303209 1:114154652 Dom C 4.66x10-2 1.21 (1.12-1.3)

rs62474673 1:114155409 Add T 4.66x10-2 0.83 (0.76-0.9)

rs9901262 1:114157023 Add C 4.66x10-2 0.83 (0.76-0.91)

rs11807619 1:114157788 Add T 4.66x10-2 1.21 (1.12-1.3)

rs13388616 1:114160758 Dom T 4.66x10-2 1.22 (1.13-1.31)

rs6939234 1:114161116 Dom C 4.65x10-2 1.22 (1.13-1.31)

rs4722180 1:114162194 Add A 4.64x10-2 1.21 (1.13-1.31)

rs1963381 1:114162619 Dom G 4.64x10-2 1.21 (1.13-1.31) rs141007190 1:114164508 Rec T 4.64x10-2 1.22 (1.13-1.31)

rs28778716 1:114166561 Add T 4.64x10-2 0.82 (0.75-0.9)

rs35521046 1:114166835 Add C 4.63x10-2 1.21 (1.13-1.31)

rs1559267 1:114167099 Dom T 4.63x10-2 0.82 (0.75-0.9)

107

rs4646871 1:114170837 Add A 4.62x10-2 1.21 (1.13-1.31)

rs6133998 1:114171796 Dom T 4.62x10-2 1.21 (1.13-1.31)

rs11071919 1:114171838 Dom A 4.60x10-2 0.83 (0.76-0.9)

rs3734015 1:114173410 Dom G 4.60x10-2 1.36 (1.24-1.48)

rs62474669 1:114173758 Add T 4.60x10-2 0.83 (0.76-0.9)

rs6134004 1:114173800 Dom A 4.60x10-2 1.21 (1.13-1.31)

rs10918018 1:114177174 Dom C 4.60x10-2 0.83 (0.76-0.9)

rs3759057 1:114178996 Dom A 4.60x10-2 0.83 (0.76-0.91) rs113493309 1:114182594 Dom A 4.59x10-2 0.83 (0.76-0.91)

rs11818897 1:114182622 Add A 4.58x10-2 1.21 (1.13-1.31)

rs12127441 1:114182841 Add C 4.58x10-2 1.22 (1.13-1.31)

rs6743232 1:114183714 Dom A 4.58x10-2 1.21 (1.12-1.3)

rs1292057 1:114183751 Add T 4.57x10-2 1.21 (1.12-1.3)

rs6134001 1:114183779 Dom T 4.56x10-2 1.21 (1.13-1.31)

rs6420104 1:114185590 Add T 4.56x10-2 1.22 (1.13-1.31)

rs17154040 1:114185855 Add C 4.56x10-2 0.82 (0.75-0.9)

108

rs10519114 1:114186138 Rec C 4.55x10-2 0.83 (0.76-0.91) rs55805865 1:114186964 Add C 4.55x10-2 1.21 (1.12-1.3)

rs975404 1:114187226 Add C 4.55x10-2 0.83 (0.76-0.91) rs74463896 1:114187371 Dom A 4.55x10-2 1.21 (1.13-1.31) rs7324478 1:114187619 Add C 4.55x10-2 0.83 (0.76-0.91) rs13017109 1:114191173 Add C 4.55x10-2 1.21 (1.13-1.31) rs73687149 1:114191647 Dom C 4.55x10-2 0.83 (0.75-0.9) rs4597940 1:114194206 Dom G 4.53x10-2 1.21 (1.13-1.31) rs12520361 1:114196364 Dom C 4.53x10-2 0.83 (0.76-0.91) rs3843503 1:114196495 Add A 4.52x10-2 0.83 (0.76-0.91) rs10305457 1:114196883 Rec T 4.52x10-2 1.22 (1.13-1.31) rs1325483 1:114199267 Add A 4.51x10-2 1.22 (1.13-1.31) rs12911192 1:114207314 Add C 4.51x10-2 1.21 (1.13-1.3)

rs152088 1:114210745 Rec T 4.50x10-2 1.21 (1.13-1.3) rs4279124 1:114211450 Add T 4.49x10-2 0.83 (0.76-0.9) rs11948786 1:114212571 Dom C 4.48x10-2 1.22 (1.13-1.31)

109

rs1600025 1:114214760 Dom A 4.48x10-2 0.83 (0.76-0.9)

rs4590913 1:114216449 Rec G 4.48x10-2 0.83 (0.76-0.91)

rs12580772 1:114216831 Dom T 4.48x10-2 0.88 (0.82-0.94)

rs12537312 1:114217355 Dom C 4.48x10-2 0.83 (0.76-0.9)

rs13145977 1:114217527 Rec C 4.48x10-2 0.83 (0.76-0.91) rs147068700 1:114218261 Rec A 4.48x10-2 1.22 (1.13-1.31)

rs17026588 1:114219085 Dom G 4.48x10-2 0.83 (0.76-0.9)

rs1551442 1:114219601 Add G 4.47x10-2 1.22 (1.13-1.31)

rs6434440 1:114220305 Add T 4.47x10-2 1.2 (1.11-1.29)

rs9990063 1:114221123 Add G 4.47x10-2 1.22 (1.13-1.31)

rs6134005 1:114222325 Dom G 4.47x10-2 1.22 (1.13-1.31)

rs9716560 1:114222516 Dom T 4.47x10-2 1.22 (1.13-1.31)

rs974759 1:114222591 Add T 4.46x10-2 1.22 (1.13-1.31)

rs4740446 1:114223635 Dom T 4.46x10-2 0.83 (0.75-0.9)

rs10863314 1:114225306 Add T 4.46x10-2 1.22 (1.13-1.31) rs114271952 1:114231398 Dom A 4.46x10-2 1.2 (1.11-1.29)

110

rs9321323 1:114233871 Dom A 4.46x10-2 1.22 (1.13-1.31) rs11135483 1:114234433 Dom C 4.46x10-2 0.83 (0.76-0.9) rs1434235 1:114235054 Add G 4.45x10-2 0.83 (0.76-0.9) rs34655485 1:114235379 Add G 4.44x10-2 1.19 (1.11-1.28) rs2255721 1:114242250 Add G 4.43x10-2 0.81 (0.73-0.89) rs34906043 1:114243899 Add T 4.43x10-2 1.19 (1.11-1.28) rs2256440 1:114244177 Add C 4.43x10-2 1.21 (1.13-1.3)

rs830650 1:114246453 Add G 4.43x10-2 1.21 (1.13-1.31)

rs861231 1:114249382 Add G 4.43x10-2 1.21 (1.13-1.31) rs2179500 1:114253639 Dom G 4.43x10-2 1.21 (1.13-1.3) rs62154115 1:114253892 Add A 4.43x10-2 1.21 (1.13-1.3) rs1717281 1:114255495 Add G 4.43x10-2 1.21 (1.12-1.3)

rs862689 1:114256379 Add G 4.43x10-2 1.19 (1.11-1.28) rs13132933 1:114258263 Add C 4.43x10-2 1.19 (1.11-1.28) rs35734533 1:114258882 Dom T 4.43x10-2 1.21 (1.12-1.31) rs2679755 1:114259069 Add C 4.43x10-2 1.21 (1.13-1.3)

111

rs1447895 1:114259557 Add A 4.43x10-2 1.21 (1.13-1.3)

rs9885219 1:114261479 Dom T 4.42x10-2 0.82 (0.75-0.9)

rs12439188 1:114261576 Add A 4.42x10-2 0.83 (0.76-0.9)

rs17134155 1:114262556 Dom T 4.42x10-2 1.21 (1.13-1.3)

rs10905718 1:114262561 Dom G 4.41x10-2 1.21 (1.13-1.3)

rs6702100 1:114263735 Add C 4.41x10-2 1.21 (1.13-1.3) rs115750224 1:114264625 Add T 4.41x10-2 1.21 (1.13-1.3)

rs1020658 1:114265244 Add G 4.41x10-2 1.21 (1.13-1.3)

rs10429892 1:114265491 Add A 4.41x10-2 1.21 (1.12-1.31)

rs10738155 1:114265928 Rec C 4.40x10-2 1.21 (1.13-1.3)

rs62154116 1:114267347 Add A 4.40x10-2 1.21 (1.13-1.3)

rs9394673 1:114267645 Rec G 4.40x10-2 1.21 (1.13-1.3)

rs7635480 1:114268791 Add T 4.40x10-2 0.83 (0.76-0.9)

rs7305643 1:114269977 Rec A 4.40x10-2 1.19 (1.11-1.28)

rs153142 1:114270159 Rec C 4.39x10-2 0.83 (0.76-0.91)

rs2328423 1:114270326 Rec A 4.39x10-2 1.21 (1.11-1.32)

112

rs12090218 1:114270738 Add C 4.39x10-2 0.83 (0.76-0.9)

rs35367733 1:114270907 Rec A 4.39x10-2 1.21 (1.13-1.3)

rs34110097 1:114271128 Add T 4.38x10-2 1.21 (1.13-1.3)

rs4722179 1:114271423 Add C 4.38x10-2 1.21 (1.12-1.31)

rs9590762 1:114275434 Dom C 4.37x10-2 0.83 (0.76-0.9)

rs1551441 1:114275437 Add G 4.36x10-2 1.21 (1.13-1.3)

rs93882 1:114275601 Dom G 4.36x10-2 1.21 (1.13-1.3) rs183463645 1:114276725 Dom C 4.35x10-2 1.2 (1.12-1.29)

rs9594943 1:114277330 Dom T 4.35x10-2 1.21 (1.12-1.3)

rs1201296 1:114280717 Add A 4.35x10-2 1.17 (1.09-1.26)

rs6684439 1:114285860 Add T 4.35x10-2 1.95 (1.52-2.49)

rs1469149 1:114287902 Add C 4.35x10-2 1.21 (1.12-1.3)

rs697943 1:114288280 Dom G 4.35x10-2 1.21 (1.12-1.3)

rs10858001 1:114290959 Add C 4.34x10-2 1.21 (1.12-1.3)

rs1533236 1:114291406 Add T 4.34x10-2 1.19 (1.11-1.28) rs138271680 1:114292544 Dom A 4.33x10-2 1.21 (1.12-1.3)

113

rs6131113 1:114293247 Dom G 4.33x10-2 1.21 (1.12-1.3)

rs1078633 1:114293526 Add T 4.33x10-2 1.19 (1.11-1.28)

rs975515 1:114295054 Dom A 4.33x10-2 1.21 (1.12-1.3)

rs13378681 1:114295438 Dom G 4.33x10-2 1.19 (1.11-1.28)

rs13249101 1:114297775 Dom A 4.33x10-2 1.21 (1.13-1.3)

rs2513919 1:114298420 Add G 4.32x10-2 1.21 (1.13-1.3)

rs17635690 1:114299516 Dom T 4.31x10-2 1.21 (1.13-1.31)

rs17748089 1:114301335 Add A 4.31x10-2 1.21 (1.13-1.31)

rs10071975 1:114302966 Dom C 4.31x10-2 1.21 (1.13-1.3) rs148385197 1:114303808 Add T 4.30x10-2 1.51 (1.36-1.67)

rs9594941 1:114311768 Dom C 4.30x10-2 1.21 (1.13-1.3)

rs1206732 1:114312435 Dom A 4.30x10-2 1.21 (1.13-1.31)

rs9594942 1:114316220 Dom A 4.30x10-2 1.21 (1.13-1.31)

rs9594940 1:114317791 Dom T 4.30x10-2 1.21 (1.13-1.3)

rs6773335 1:114318727 Add T 4.30x10-2 1.19 (1.11-1.28)

rs11071283 1:114319233 Add G 4.30x10-2 1.21 (1.13-1.31)

114

rs17635556 1:114319416 Dom A 4.30x10-2 1.21 (1.13-1.31) rs1681650 1:114319513 Add G 4.30x10-2 0.82 (0.75-0.9) rs73311211 1:114328921 Rec T 4.30x10-2 0.82 (0.75-0.9) rs1296279 1:114329408 Add A 4.29x10-2 1.22 (1.13-1.31) rs1206731 1:114330202 Dom G 4.29x10-2 1.22 (1.13-1.31) rs9430071 1:114330453 Add C 4.28x10-2 0.82 (0.75-0.9) rs4363026 1:114331315 Rec A 4.28x10-2 1.15 (1.08-1.23) rs2166837 1:114334222 Dom G 4.28x10-2 1.15 (1.08-1.23) rs73987896 1:114334690 Dom G 4.28x10-2 1.15 (1.08-1.23) rs6716872 1:114335092 Dom A 4.27x10-2 0.82 (0.75-0.9)

rs704254 1:114335483 Add G 4.27x10-2 0.82 (0.75-0.9) rs13320178 1:114338236 Add C 4.27x10-2 1.22 (1.13-1.31) rs9846214 1:114341332 Add C 4.27x10-2 0.82 (0.75-0.9) rs1206722 1:114343336 Dom G 4.27x10-2 1.22 (1.13-1.31) rs11856958 1:114344083 Rec T 4.27x10-2 1.15 (1.08-1.23) rs2128765 1:114345418 Add G 4.27x10-2 1.15 (1.08-1.23)

115

rs1295923 1:114345750 Add G 4.27x10-2 1.22 (1.13-1.31)

rs10039263 1:114346749 Dom A 4.27x10-2 1.22 (1.13-1.31)

rs9471274 1:114348942 Rec A 4.27x10-2 0.82 (0.75-0.9)

rs2237660 1:114350489 Add A 4.26x10-2 0.82 (0.75-0.9)

rs12189125 1:114351706 Dom C 4.25x10-2 1.15 (1.08-1.23)

rs10760212 1:114353324 Dom A 4.25x10-2 0.82 (0.75-0.9)

rs10807230 1:114356125 Rec A 4.25x10-2 1.15 (1.08-1.23)

rs7003297 1:114357211 Rec G 4.24x10-2 1.21 (1.13-1.31) rs146399390 1:114357750 Dom A 4.24x10-2 1.22 (1.13-1.31)

rs2679754 1:114360067 Add A 4.24x10-2 1.18 (1.09-1.28)

rs2128172 1:114364104 Add T 4.23x10-2 1.22 (1.13-1.31)

rs2684380 1:114364476 Add T 4.23x10-2 1.22 (1.13-1.31)

rs1206729 1:114365752 Dom T 4.23x10-2 1.22 (1.13-1.31)

rs2153977 1:114366434 Add T 4.23x10-2 0.82 (0.75-0.9)

rs9594937 1:114367116 Dom T 4.23x10-2 1.15 (1.08-1.23)

rs12619030 1:114367343 Add C 4.23x10-2 0.82 (0.75-0.9)

116

rs2946178 1:114368777 Rec T 4.23x10-2 1.22 (1.13-1.31) rs11154662 1:114369259 Dom T 4.22x10-2 1.15 (1.08-1.23) rs12901021 1:114369468 Add A 4.22x10-2 1.15 (1.08-1.23) rs35452057 1:114369734 Add A 4.22x10-2 1.15 (1.08-1.23) rs6434439 1:114373503 Add A 4.22x10-2 1.15 (1.08-1.23) rs9846404 1:114374435 Add A 4.22x10-2 1.22 (1.13-1.31) rs2679756 1:114377093 Dom G 4.22x10-2 1.22 (1.13-1.31) rs2679757 1:114377568 Dom G 4.22x10-2 1.52 (1.38-1.69) rs11071282 1:114381457 Add A 4.22x10-2 0.82 (0.75-0.9) rs2192008 1:114382025 Rec A 4.22x10-2 1.15 (1.08-1.23) rs12514868 1:114383637 Dom C 4.21x10-2 1.21 (1.13-1.31) rs17696419 1:114384259 Dom G 4.21x10-2 0.8 (0.73-0.88) rs1830915 1:114384431 Rec C 4.21x10-2 0.82 (0.75-0.9) rs7415298 1:114384474 Add G 4.20x10-2 0.82 (0.75-0.9)

rs32500 1:114384600 Add G 4.20x10-2 0.82 (0.75-0.9) rs11241384 1:114385679 Dom G 4.20x10-2 0.82 (0.75-0.9)

117

rs17764255 1:114387905 Dom G 4.20x10-2 0.82 (0.75-0.9) rs17707689 1:114389748 Dom T 4.20x10-2 0.82 (0.75-0.9) rs2045848 1:114392559 Dom G 4.20x10-2 1.15 (1.08-1.23) rs2045847 1:114392632 Dom G 4.20x10-2 1.15 (1.08-1.23) rs9321322 1:114393153 Dom A 4.20x10-2 1.15 (1.08-1.23) rs28893316 1:114393748 Add C 4.20x10-2 1.22 (1.14-1.32)

rs943521 1:114396369 Add A 4.20x10-2 0.82 (0.75-0.9) rs10041735 1:114396466 Dom C 4.20x10-2 0.82 (0.75-0.9) rs6466526 1:114396735 Dom G 4.19x10-2 1.16 (1.08-1.23) rs17670540 1:114396816 Add A 4.19x10-2 1.23 (1.14-1.32) rs10991899 1:114397799 Rec G 4.19x10-2 0.82 (0.75-0.9) rs10076136 1:114400804 Dom C 4.19x10-2 1.24 (1.14-1.33)

rs206834 1:114401231 Dom G 4.18x10-2 1.16 (1.08-1.23)

rs830646 1:114401904 Add C 4.18x10-2 1.16 (1.08-1.23)

rs709355 1:114402751 Dom T 4.18x10-2 1.16 (1.08-1.23)

rs864934 1:114402846 Add T 4.17x10-2 1.23 (1.14-1.32)

118

rs13098781 1:114404901 Add G 4.17x10-2 1.23 (1.13-1.35) rs145725349 1:114406002 Dom A 4.17x10-2 1.24 (1.13-1.36)

rs6507728 1:114406451 Rec T 4.17x10-2 1.22 (1.12-1.34)

rs1292059 1:114420328 Add A 4.17x10-2 1.24 (1.13-1.36) rs115770474 1:114420462 Dom G 4.16x10-2 1.23 (1.12-1.35)

rs11711564 1:114421313 Add G 4.16x10-2 1.24 (1.13-1.36)

rs1594884 1:114426001 Rec A 4.16x10-2 1.31 (1.19-1.45)

rs10236256 1:114427450 Dom C 4.16x10-2 1.2 (1.13-1.29)

rs72769584 1:114428086 Dom A 4.16x10-2 0.87 (0.81-0.93)

rs32499 1:114429461 Add A 4.15x10-2 1.29 (1.17-1.43)

rs206836 1:114429515 Dom T 4.14x10-2 1.29 (1.17-1.43)

rs2862701 1:114430356 Add G 4.14x10-2 0.87 (0.81-0.93)

rs2946177 1:114431463 Rec T 4.14x10-2 1.29 (1.17-1.43)

rs10905719 1:114431465 Add A 4.14x10-2 0.87 (0.81-0.93)

rs6953420 1:114433659 Dom C 4.14x10-2 0.87 (0.81-0.93)

rs11971918 1:114433970 Dom A 4.14x10-2 1.2 (1.13-1.28)

119

rs2894428 1:114434471 Rec G 4.14x10-2 0.87 (0.81-0.93) rs34472769 1:114436482 Dom T 4.13x10-2 1.2 (1.12-1.28) rs9864066 1:114436970 Add C 4.13x10-2 1.2 (1.12-1.28) rs9566471 1:114440258 Add G 4.13x10-2 0.87 (0.81-0.93)

rs830626 1:114443035 Add T 4.13x10-2 1.2 (1.12-1.28) rs4276892 1:114443419 Dom A 4.12x10-2 1.2 (1.12-1.28) rs10227392 1:114445880 Dom T 4.11x10-2 1.31 (1.19-1.45) rs10253410 1:114446341 Dom G 4.11x10-2 1.2 (1.12-1.28) rs12110028 1:114447034 Dom G 4.11x10-2 1.2 (1.12-1.28) rs11858656 1:114447776 Dom G 4.11x10-2 0.87 (0.81-0.93) rs10751775 1:114448389 Dom T 4.11x10-2 1.38 (1.22-1.55) rs55961200 1:114448752 Add G 4.11x10-2 1.2 (1.12-1.28) rs3752953 1:118129970 Dom T 4.11x10-2 3.24 (1.86-5.63) rs11127215 1:153200839 Dom C 4.11x10-2 1.35 (1.19-1.54) rs76190748 1:153205819 Add A 4.11x10-2 1.61 (1.29-2.01) rs7702667 1:153207087 Dom G 4.11x10-2 1.61 (1.29-2.01)

120

rs35081938 1:153210760 Add A 4.11x10-2 1.62 (1.29-2.02) rs7794020 1:153212171 Dom C 4.11x10-2 1.63 (1.3-2.05) rs7795769 1:153212558 Dom T 4.11x10-2 1.61 (1.29-2.02) rs7795545 1:153217580 Dom T 4.11x10-2 1.37 (1.19-1.58) rs10279364 1:153217977 Dom C 4.11x10-2 1.18 (1.11-1.26) rs4518596 1:153219984 Dom C 4.11x10-2 1.37 (1.19-1.58) rs4132827 1:153220716 Dom A 4.11x10-2 1.59 (1.28-1.98) rs78489180 1:153221604 Dom G 4.11x10-2 1.38 (1.2-1.59) rs10239992 1:153221635 Dom G 4.11x10-2 1.58 (1.28-1.97) rs10270209 1:153224594 Dom T 4.11x10-2 1.37 (1.19-1.58) rs10275167 1:153224608 Dom A 4.11x10-2 1.38 (1.19-1.59) rs1481686 1:153225168 Dom T 4.11x10-2 1.58 (1.27-1.96) rs2038869 1:153225688 Rec T 4.11x10-2 1.37 (1.19-1.58) rs3806040 1:153226033 Dom G 4.10x10-2 1.37 (1.19-1.58) rs12528717 1:153226587 Rec T 4.10x10-2 1.37 (1.19-1.58) rs1288126 1:153226983 Add T 4.10x10-2 1.37 (1.19-1.58)

121

rs2080079 1:153227177 Add C 4.09x10-2 1.43 (1.25-1.63)

rs864380 1:153227274 Add C 4.09x10-2 1.43 (1.25-1.63) rs10494296 1:153227608 Rec C 4.08x10-2 1.43 (1.25-1.63) rs12822443 1:153228359 Rec T 4.08x10-2 1.42 (1.24-1.62) rs8031549 1:153228775 Add A 4.07x10-2 1.41 (1.24-1.61) rs11117820 1:153233701 Add A 4.07x10-2 1.42 (1.23-1.63) rs1575765 1:153235048 Rec G 4.07x10-2 1.43 (1.25-1.63) rs2080078 1:153236224 Add A 4.06x10-2 1.43 (1.25-1.64) rs1891969 1:153236735 Dom A 4.06x10-2 1.43 (1.25-1.63) rs73987900 1:153237921 Dom C 4.06x10-2 1.44 (1.25-1.65) rs55912359 1:153239238 Dom T 4.06x10-2 1.43 (1.25-1.64) rs67385647 1:153240303 Add A 4.06x10-2 1.43 (1.25-1.64) rs1830917 1:153240622 Rec A 4.06x10-2 1.43 (1.25-1.64) rs7749106 1:153242498 Add A 4.06x10-2 1.47 (1.25-1.72) rs2357193 1:154291718 Dom T 4.06x10-2 1.34 (1.2-1.5) rs12830219 1:154298374 Rec C 4.06x10-2 1.34 (1.2-1.5)

122

rs6978631 1:154305010 Dom C 4.06x10-2 1.34 (1.2-1.5) rs2513921 1:154311911 Dom G 4.06x10-2 1.34 (1.2-1.5) rs9425673 1:154320191 Add C 4.06x10-2 1.35 (1.2-1.5) rs1830916 1:154347784 Rec G 4.06x10-2 1.43 (1.27-1.6) rs12540033 1:154355501 Dom T 4.06x10-2 1.42 (1.27-1.59) rs1206724 1:154355875 Dom A 4.05x10-2 1.46 (1.25-1.7) rs1795230 1:154359411 Add G 4.05x10-2 1.43 (1.27-1.6) rs7700332 1:154360492 Dom A 4.05x10-2 1.43 (1.27-1.6) rs9349144 1:154360684 Rec A 4.05x10-2 1.43 (1.27-1.6) rs1118077 1:154361226 Rec G 4.05x10-2 1.43 (1.27-1.6) rs76713317 1:154361788 Dom C 4.05x10-2 1.43 (1.27-1.6)

rs972142 1:154363137 Add G 4.05x10-2 1.43 (1.27-1.6) rs8032689 1:154364140 Rec T 4.05x10-2 1.43 (1.27-1.6) rs8026557 1:154365886 Rec G 4.05x10-2 1.43 (1.27-1.6) rs6496487 1:154367754 Rec A 4.05x10-2 1.43 (1.27-1.6) rs6496488 1:154367898 Rec C 4.05x10-2 1.43 (1.27-1.6)

123

rs77883455 1:154368095 Dom T 4.05x10-2 1.43 (1.28-1.61) rs11770085 1:154368098 Dom T 4.05x10-2 1.43 (1.28-1.61) rs9788760 1:154368224 Rec T 4.05x10-2 1.42 (1.27-1.6) rs76236917 1:154369683 Add T 4.05x10-2 1.43 (1.27-1.6) rs2089160 1:154369981 Dom T 4.05x10-2 1.43 (1.27-1.6) rs78878024 1:154379369 Rec T 4.04x10-2 1.43 (1.27-1.61) rs72994717 1:154395839 Add A 4.04x10-2 0.88 (0.83-0.94) rs6496490 1:157891609 Rec A 4.04x10-2 2.13 (1.49-3.04) rs4292427 1:164474258 Dom G 4.04x10-2 0.82 (0.75-0.9) rs6496491 1:168499204 Rec G 4.03x10-2 1.21 (1.11-1.32) rs12822095 1:168500458 Rec G 4.03x10-2 0.82 (0.75-0.9) rs1329100 1:168500984 Rec T 4.03x10-2 0.82 (0.75-0.9) rs1206723 1:168501453 Dom C 4.03x10-2 1.21 (1.11-1.32) rs7163110 1:168503277 Rec T 4.03x10-2 0.82 (0.75-0.9) rs1795229 1:168504641 Add T 4.02x10-2 0.82 (0.75-0.9) rs1681651 1:168506535 Add C 4.02x10-2 0.82 (0.75-0.9)

124

rs1681649 1:168512021 Add A 4.02x10-2 0.82 (0.75-0.9)

rs13125087 1:168515827 Add T 4.02x10-2 0.82 (0.75-0.9)

rs4377781 1:168518892 Rec A 4.02x10-2 0.83 (0.75-0.9)

rs10836533 1:168525247 Dom G 4.02x10-2 0.83 (0.75-0.9)

rs12653964 1:187705737 Dom A 4.02x10-2 1.23 (1.11-1.36)

rs7779234 1:187724052 Dom A 4.02x10-2 1.2 (1.1-1.3)

rs1030970 1:187724610 Rec T 4.01x10-2 1.19 (1.1-1.3) rs146907331 1:187728079 Add T 4.01x10-2 1.2 (1.1-1.3)

rs3760684 1:187728120 Add C 4.01x10-2 1.2 (1.1-1.3)

rs11815653 1:187729284 Add T 4.01x10-2 1.2 (1.1-1.3)

rs12875655 1:187729787 Dom T 4.00x10-2 1.19 (1.1-1.3)

rs17784604 1:187730546 Dom T 4.00x10-2 1.19 (1.09-1.29)

rs13189819 1:187733465 Dom G 3.98x10-2 1.18 (1.09-1.28)

rs62483627 1:187734230 Add A 3.98x10-2 1.2 (1.1-1.31)

rs9316024 1:187734284 Dom A 4.99x10-2 1.19 (1.1-1.3)

rs34913965 1:187734329 Dom T 4.99x10-2 1.19 (1.1-1.3)

125

rs11083632 1:187734821 Dom A 4.99x10-2 1.19 (1.09-1.29) rs7529070 1:187735085 Dom G 4.99x10-2 1.2 (1.1-1.31) rs3095415 1:187735093 Add T 4.99x10-2 1.2 (1.1-1.31) rs7623898 1:187735094 Add T 4.99x10-2 1.2 (1.1-1.31) rs1677283 1:187737717 Dom C 4.99x10-2 1.23 (1.11-1.37)

rs525850 1:187738109 Dom T 4.99x10-2 1.22 (1.1-1.35) rs10958738 1:187738168 Rec C 4.99x10-2 1.22 (1.1-1.36) rs9594936 1:187741775 Dom A 4.99x10-2 1.22 (1.1-1.35) rs77715818 1:187741836 Add A 4.98x10-2 1.22 (1.1-1.35) rs7608760 1:187743788 Dom C 4.98x10-2 1.22 (1.11-1.35) rs4555370 1:187746363 Add T 4.98x10-2 1.21 (1.11-1.32) rs6715714 1:195497267 Add T 4.98x10-2 1.67 (1.3-2.14) rs4764181 1:209881373 Dom G 4.98x10-2 0.83 (0.77-0.91) rs34881088 1:209882900 Add T 4.98x10-2 0.83 (0.77-0.91) rs4843547 1:209882906 Rec G 4.98x10-2 0.83 (0.77-0.91) rs7448744 1:209884387 Add C 4.98x10-2 0.83 (0.77-0.91)

126

rs13271512 1:209884730 Dom T 4.98x10-2 0.83 (0.77-0.91) rs11711478 1:209884953 Add A 4.97x10-2 0.83 (0.77-0.91) rs9548896 1:209885318 Add C 4.97x10-2 0.84 (0.77-0.91) rs10046817 1:210650052 Rec A 4.97x10-2 1.37 (1.19-1.58) rs4409129 1:210650461 Rec T 4.97x10-2 1.38 (1.2-1.6)

rs131656 1:211737647 Dom A 4.97x10-2 1.32 (1.16-1.5) rs1667702 1:217373249 Add G 4.96x10-2 1.21 (1.1-1.32) rs10905713 1:217378208 Add T 4.96x10-2 1.2 (1.1-1.32) rs17595027 1:217380725 Dom T 4.96x10-2 1.2 (1.1-1.32)

rs14484 1:217385077 Add G 4.96x10-2 1.21 (1.11-1.32) rs11100598 1:217418732 Dom T 4.96x10-2 1.16 (1.08-1.24) rs17696305 1:217427868 Dom C 4.95x10-2 1.14 (1.07-1.22) rs13273348 1:231205893 Rec T 4.95x10-2 1.36 (1.19-1.55) rs12142970 1:231205928 Rec T 4.95x10-2 1.36 (1.19-1.55) rs56346965 1:231205935 Rec A 4.95x10-2 1.35 (1.19-1.55) rs4997835 1:243504108 Add C 4.95x10-2 1.59 (1.3-1.93)

127

rs4683296 1:243505950 Add C 4.95x10-2 1.58 (1.3-1.93)

rs1343128 2:9268701 Add A 3.90x10-3 0.78 (0.7-0.87)

rs7909519 2:9269387 Add G 3.90x10-3 0.79 (0.7-0.88)

rs2548532 2:9273762 Dom C 3.90x10-3 0.82 (0.75-0.9)

rs7721882 2:11978602 Add G 3.89x10-3 3.22 (1.9-5.44)

rs4456089 2:29525654 Add T 3.89x10-3 0.83 (0.76-0.91)

rs56818621 2:31709417 Add G 3.86x10-3 0.83 (0.75-0.91) rs145060323 2:31711568 Add C 4.94x10-3 0.82 (0.75-0.9)

rs3001369 2:38482924 Add T 4.93x10-3 1.4 (1.21-1.62)

rs74993771 2:40069356 Add T 4.87x10-3 2.07 (1.5-2.86)

rs9467831 2:43542480 Add G 4.85x10-3 0.72 (0.61-0.85)

rs2069778 2:100230714 Add A 4.79x10-3 4.18 (2.28-7.69)

rs55770741 2:102690693 Dom C 4.75x10-3 1.24 (1.12-1.37)

rs6931735 2:102690727 Add G 4.60x10-3 1.24 (1.12-1.37)

rs35696821 2:102692723 Add T 4.57x10-3 1.23 (1.11-1.35)

rs3827780 2:102694456 Add G 4.56x10-3 1.22 (1.11-1.35)

128

rs41295065 2:102700493 Add A 4.56x10-3 1.22 (1.11-1.35) rs12409333 2:102702919 Add G 4.55x10-3 1.22 (1.11-1.35) rs2327613 2:102706835 Add T 4.55x10-3 1.22 (1.11-1.35) rs2246943 2:102708730 Add A 4.55x10-3 1.22 (1.11-1.35) rs10478998 2:106371699 Add A 4.51x10-3 0.87 (0.81-0.93) rs4361509 2:106371929 Add A 4.50x10-3 0.87 (0.81-0.93) rs17508814 2:106371946 Dom C 4.48x10-3 0.87 (0.81-0.93) rs56257513 2:106372358 Dom G 4.47x10-3 0.87 (0.81-0.93) rs6556942 2:106376199 Dom A 4.42x10-3 0.87 (0.81-0.93) rs6914831 2:107504396 Add C 4.41x10-3 1.19 (1.1-1.29) rs12722496 2:107516533 Add G 4.41x10-3 1.2 (1.11-1.3) rs10900804 2:107523808 Add T 4.39x10-3 1.19 (1.1-1.29) rs3792894 2:111752151 Add A 4.31x10-3 3.29 (2.06-5.25) rs56399423 2:119538982 Add C 5.90x10-3 0.83 (0.75-0.91) rs2179781 2:139598602 Add C 5.90x10-3 0.78 (0.69-0.88) rs6896703 2:169602676 Add G 5.87x10-3 1.25 (1.12-1.39)

129

rs7327824 2:169604336 Add A 5.87x10-3 1.25 (1.12-1.38) rs1050152 2:190663606 Add T 5.86x10-3 2.16 (1.5-3.1) rs2064430 2:191512371 Add T 5.86x10-3 1.36 (1.19-1.55) rs12722552 2:191520845 Add T 5.86x10-3 1.25 (1.12-1.4) rs3805681 2:191541366 Add G 5.86x10-3 1.25 (1.12-1.4) rs10052046 2:191545147 Add T 5.85x10-3 1.25 (1.12-1.4) rs3828675 2:191706440 Add A 5.83x10-3 1.29 (1.15-1.45)

rs721121 2:191738071 Add G 5.79x10-3 1.3 (1.15-1.46) rs34566917 2:191789907 Add T 5.74x10-3 1.3 (1.15-1.46) rs2278398 2:191806277 Add G 5.70x10-3 1.3 (1.15-1.46) rs10075459 2:191900449 Add G 5.69x10-3 1.19 (1.1-1.28) rs2463773 2:191902758 Add A 5.68x10-3 1.19 (1.1-1.28) rs1012645 2:191912540 Add C 5.65x10-3 1.19 (1.1-1.29) rs12035317 2:191913642 Add G 5.60x10-3 1.19 (1.1-1.29) rs4682845 2:191921874 Add G 5.59x10-3 1.23 (1.12-1.35) rs3805683 2:191925424 Add G 5.57x10-3 1.2 (1.1-1.29)

130

rs5753083 2:191933254 Add C 5.46x10-3 1.2 (1.11-1.3)

rs228957 2:191935804 Add G 5.42x10-3 1.2 (1.1-1.3) rs7701237 2:191943742 Add T 5.32x10-3 1.27 (1.17-1.36) rs3749756 2:191953864 Add T 5.31x10-3 0.83 (0.76-0.9) rs2301579 2:191953998 Add A 5.27x10-3 1.22 (1.13-1.33) rs2237658 2:191954047 Dom G 5.27x10-3 0.83 (0.76-0.9) rs6660436 2:191958656 Add A 5.25x10-3 1.26 (1.17-1.36) rs10858000 2:191959489 Add T 5.25x10-3 1.26 (1.16-1.35) rs17031716 2:191960109 Add A 5.25x10-3 1.25 (1.16-1.35) rs3846728 2:191961970 Add A 5.25x10-3 0.83 (0.76-0.9) rs10836538 2:191962096 Dom T 5.25x10-3 1.25 (1.16-1.35) rs9402703 2:191964633 Add A 5.24x10-3 1.28 (1.17-1.41) rs45545833 2:191966452 Add C 5.18x10-3 1.27 (1.16-1.4) rs12074958 2:191969341 Add G 5.16x10-3 1.27 (1.16-1.39) rs7703009 2:191969879 Add G 5.16x10-3 1.28 (1.16-1.4) rs13140464 2:191970120 Add T 5.12x10-3 1.28 (1.17-1.41)

131

rs2897096 2:191991459 Add G 5.03x10-3 1.14 (1.07-1.22)

rs35439287 2:191992160 Add T 5.03x10-3 1.14 (1.07-1.22)

rs2614264 2:191992611 Add G 5.03x10-3 1.14 (1.07-1.22)

rs11102652 2:191992989 Add T 5.02x10-3 1.14 (1.07-1.22)

rs1860217 2:191993626 Add C 4.98x10-3 1.14 (1.07-1.22)

rs10836535 2:191994100 Dom C 4.30x10-3 1.15 (1.07-1.22)

rs9461288 2:191994335 Add C 4.21x10-3 1.14 (1.07-1.22)

rs12722495 2:191994603 Add C 4.20x10-3 1.15 (1.07-1.22)

rs80262450 2:191996132 Add A 4.20x10-3 1.14 (1.07-1.22)

rs4755450 2:191996138 Dom A 4.19x10-3 1.14 (1.07-1.22)

rs2746420 2:191996262 Add C 4.19x10-3 1.14 (1.07-1.22)

rs4896143 2:191997584 Add G 4.17x10-3 1.14 (1.07-1.22)

rs2746433 2:191997769 Add T 4.15x10-3 1.14 (1.07-1.22)

rs2283865 2:191997946 Add A 4.15x10-3 1.14 (1.07-1.22)

rs11749300 2:214044798 Add C 4.11x10-3 0.75 (0.66-0.86) rs116749111 2:214044876 Add T 4.11x10-3 0.75 (0.65-0.85)

132

rs7536360 2:214050972 Add C 4.10x10-3 0.75 (0.65-0.85) rs12037873 2:214051744 Add A 4.10x10-3 0.75 (0.66-0.86)

rs715285 2:214053501 Add G 4.07x10-3 0.75 (0.66-0.86) rs72687980 2:214055787 Add T 4.07x10-3 0.75 (0.66-0.86) rs12077419 2:214056379 Add A 4.05x10-3 0.75 (0.66-0.86)

rs251343 2:214056867 Dom T 4.05x10-3 0.75 (0.66-0.86) rs41295049 2:214056895 Add A 4.04x10-3 0.75 (0.66-0.86) rs11102653 2:214059732 Add A 4.04x10-3 0.75 (0.65-0.85) rs7533391 2:214060161 Dom T 4.03x10-3 0.75 (0.65-0.85) rs13111615 2:214061453 Add C 4.02x10-3 0.75 (0.65-0.85) rs2549794 2:214061704 Dom C 4.01x10-3 0.75 (0.65-0.85) rs2614287 2:214063025 Add G 4.01x10-3 0.75 (0.66-0.86) rs6898270 2:214064050 Add T 4.00x10-3 0.75 (0.66-0.86) rs2375551 2:214064601 Add A 3.98x10-3 0.75 (0.66-0.86) rs12722508 2:214065112 Add T 3.98x10-3 0.75 (0.66-0.86) rs41295063 2:214065640 Add G 3.94x10-3 0.75 (0.66-0.86)

133

rs45472292 2:214065880 Add G 3.90x10-3 0.75 (0.66-0.86) rs2494697 2:214066039 Add A 3.48x10-3 0.75 (0.65-0.85) rs8002731 2:214066652 Add C 3.86x10-3 0.75 (0.66-0.86) rs12731969 2:214067888 Dom T 3.83x10-3 0.75 (0.66-0.86) rs11102654 2:214068641 Add A 3.82x10-3 0.74 (0.65-0.85) rs2451739 2:214070064 Add T 3.81x10-3 0.75 (0.65-0.85) rs34799402 2:214070327 Dom T 3.80x10-3 0.75 (0.66-0.86) rs10745339 2:214071102 Add G 3.79x10-3 0.75 (0.65-0.85) rs10858005 2:214071685 Add T 3.79x10-3 0.75 (0.66-0.86) rs3091338 2:214071702 Add T 3.79x10-3 0.75 (0.65-0.85) rs41295061 2:214075322 Add A 3.79x10-3 0.75 (0.65-0.85) rs11256611 2:214075749 Add A 3.79x10-3 0.75 (0.65-0.85) rs1418958 2:214075840 Add T 3.70x10-3 0.75 (0.66-0.85) rs11102657 2:214076577 Add T 3.70x10-3 0.75 (0.65-0.85) rs13252244 2:214076834 Dom C 3.68x10-3 0.74 (0.65-0.85) rs72922272 2:214076954 Add A 3.67x10-3 0.75 (0.65-0.85)

134

rs4869313 2:214077820 Dom T 3.67x10-3 0.75 (0.66-0.85) rs2757653 2:214077848 Add G 3.67x10-3 0.75 (0.65-0.85) rs2549783 2:214077940 Dom T 3.67x10-3 0.75 (0.66-0.85) rs3864277 2:214080455 Add A 3.67x10-3 0.74 (0.65-0.85) rs4316001 2:214081839 Dom T 3.64x10-3 0.74 (0.65-0.85) rs34394770 2:214082792 Add C 3.64x10-3 0.75 (0.65-0.85) rs10889513 2:214083780 Add A 3.64x10-3 0.75 (0.66-0.86) rs1466275 2:214084868 Dom G 3.64x10-3 0.74 (0.65-0.85) rs3849749 2:214085563 Dom A 3.64x10-3 0.74 (0.65-0.85) rs6929908 2:214085672 Add C 3.64x10-3 0.75 (0.65-0.85)

rs251340 2:214086286 Dom A 3.57x10-3 0.75 (0.65-0.85)

rs251341 2:214090290 Dom T 3.57x10-3 0.74 (0.65-0.85) rs6534347 2:214091363 Add A 3.48x10-3 0.74 (0.65-0.85) rs2910793 2:214091786 Dom G 3.48x10-3 0.74 (0.65-0.85) rs6873866 2:214091971 Dom T 3.48x10-3 0.74 (0.65-0.85) rs2859491 2:214092847 Dom T 3.48x10-3 0.74 (0.65-0.85)

135

rs2351011 2:214092929 Dom A 3.48x10-3 0.74 (0.65-0.85) rs2927609 2:214093089 Dom A 3.48x10-3 0.74 (0.65-0.85) rs1363907 2:214093530 Dom A 3.48x10-3 0.74 (0.65-0.85) rs1820148 2:214093762 Dom G 3.48x10-3 0.74 (0.65-0.85) rs1363908 2:214094200 Dom C 3.48x10-3 0.74 (0.65-0.85) rs10058476 2:214094244 Dom A 3.48x10-3 0.74 (0.65-0.85) rs3999476 2:214094513 Add G 3.48x10-3 0.74 (0.65-0.85) rs2451735 2:214094520 Add T 3.48x10-3 0.74 (0.65-0.85) rs9603605 2:214094576 Add C 3.48x10-3 0.74 (0.65-0.85) rs9379903 2:214094718 Add T 3.48x10-3 0.74 (0.65-0.85) rs5753093 2:214098403 Add C 3.46x10-3 0.74 (0.64-0.84)

rs757870 2:214099371 Add C 3.45x10-3 0.74 (0.64-0.84) rs8138401 3:3296010 Add C 3.44x10-3 3.84 (2.22-6.63) rs2746438 3:12494894 Add T 2.75x10-3 2.06 (1.51-2.81)

rs38034 3:18751611 Dom T 2.74x10-3 0.84 (0.78-0.92) rs10476696 3:18752892 Dom G 2.74x10-3 0.85 (0.78-0.92)

136

rs7320598 3:18752923 Add T 3.42x10-3 0.85 (0.78-0.92)

rs5753092 3:18753080 Add A 3.42x10-3 0.85 (0.78-0.92)

rs5997628 3:18753337 Add A 3.42x10-3 0.85 (0.78-0.92)

rs56877097 3:18753446 Add A 3.40x10-3 0.85 (0.78-0.92)

rs7746643 3:18755345 Add G 3.40x10-3 0.84 (0.77-0.92)

rs1001284 3:18755348 Dom C 3.37x10-3 0.84 (0.78-0.92)

rs6859168 3:18756230 Dom T 3.37x10-3 0.85 (0.78-0.92)

rs10857090 3:18756369 Add C 3.37x10-3 0.85 (0.78-0.92)

rs2451715 3:18756731 Add C 3.36x10-3 0.85 (0.78-0.92)

rs6827756 3:18756742 Add T 3.36x10-3 0.85 (0.78-0.92)

rs9461273 3:18757342 Add A 3.36x10-3 0.85 (0.78-0.92)

rs4587600 3:18757512 Add A 3.34x10-3 0.85 (0.78-0.92)

rs12251307 3:18757683 Add T 3.34x10-3 0.85 (0.78-0.92)

rs6836189 3:18758203 Add G 3.34x10-3 0.85 (0.78-0.92) rs144844167 3:18758419 Add C 3.32x10-3 0.85 (0.78-0.92)

rs34962169 3:18758646 Dom T 3.32x10-3 0.85 (0.78-0.92)

137

rs7553101 3:18759119 Add C 3.32x10-3 0.85 (0.78-0.92) rs4539969 3:18759213 Dom G 3.32x10-3 0.85 (0.78-0.92) rs2548530 3:18759430 Dom T 3.30x10-3 0.85 (0.78-0.92) rs11208557 3:18759764 Add C 3.29x10-3 0.85 (0.78-0.92) rs2746432 3:18760020 Add C 3.29x10-3 0.85 (0.78-0.92) rs1343125 3:18760062 Add G 3.29x10-3 0.84 (0.77-0.91) rs6911540 3:18760094 Add T 3.26x10-3 0.84 (0.78-0.92) rs6931849 3:18760116 Add A 3.26x10-3 0.85 (0.78-0.92) rs9379902 3:18760244 Add G 3.19x10-3 0.85 (0.78-0.92) rs6919391 3:18760434 Add G 3.18x10-3 0.85 (0.78-0.92) rs1216571 3:18760884 Dom T 3.17x10-3 0.84 (0.77-0.91) rs1216567 3:18762567 Dom T 3.17x10-3 0.84 (0.78-0.92) rs1216566 3:18762789 Dom G 3.17x10-3 0.84 (0.78-0.92) rs7453669 3:18763330 Rec C 3.09x10-3 0.84 (0.78-0.92) rs2617447 3:18763701 Dom G 3.07x10-3 0.85 (0.78-0.92)

rs716848 3:18764274 Dom A 3.05x10-3 0.84 (0.77-0.92)

138

rs2614275 3:18764275 Add C 3.02x10-3 0.84 (0.77-0.91)

rs10836537 3:18764713 Dom A 3.02x10-3 0.84 (0.78-0.92)

rs2451749 3:20433955 Add C 2.94x10-3 25.27 (3.54-180.57)

rs2161548 3:46053778 Dom A 2.93x10-3 1.34 (1.16-1.54)

rs2884703 3:46082102 Add A 2.92x10-3 1.16 (1.08-1.24)

rs2451742 3:46094623 Add A 2.92x10-3 1.16 (1.08-1.24)

rs2614266 3:46123839 Add A 2.91x10-3 1.16 (1.08-1.24)

rs2494710 3:46931478 Add A 2.87x10-3 1.23 (1.11-1.37)

rs2451752 3:46932057 Add C 2.87x10-3 1.34 (1.19-1.51)

rs6935146 3:46933266 Add T 2.87x10-3 1.34 (1.19-1.51)

rs2494705 3:46933960 Add T 2.84x10-3 1.34 (1.19-1.51)

rs6534354 3:46934292 Add T 2.84x10-3 1.35 (1.2-1.51)

rs2451753 3:46935681 Add C 2.82x10-3 1.35 (1.2-1.51)

rs2494711 3:46935734 Add T 2.81x10-3 1.35 (1.2-1.51) rs147237535 3:46941116 Add A 2.79x10-3 1.23 (1.13-1.33)

rs925549 3:46943028 Add C 2.78x10-3 1.34 (1.2-1.51)

139

rs113267846 3:46944274 Dom T 2.77x10-3 1.23 (1.14-1.34)

rs3800302 3:46947087 Add A 2.77x10-3 1.22 (1.11-1.34)

rs10038651 3:46949379 Dom A 2.74x10-3 1.23 (1.13-1.33)

rs10044354 3:46955404 Dom T 2.74x10-3 1.22 (1.12-1.32)

rs9314181 3:46957298 Dom C 2.74x10-3 1.21 (1.12-1.32)

rs6915555 3:46960742 Add G 2.74x10-3 1.16 (1.08-1.24)

rs3807029 3:46963035 Add T 2.74x10-3 1.15 (1.07-1.23)

rs2494706 3:46963502 Add C 2.74x10-3 1.15 (1.08-1.23)

rs2451754 3:46965197 Add C 2.74x10-3 1.15 (1.08-1.23)

rs2494714 3:46965856 Add A 2.74x10-3 1.15 (1.08-1.23)

rs27436 3:46968227 Dom T 2.74x10-3 1.15 (1.07-1.23)

rs6902411 3:46969970 Add A 2.74x10-3 1.15 (1.08-1.23)

rs38033 3:46972377 Dom G 2.73x10-3 1.15 (1.07-1.23)

rs38038 3:46973673 Dom G 2.73x10-3 1.15 (1.07-1.23)

rs61839660 3:46973820 Add T 2.71x10-3 1.15 (1.07-1.23)

rs1217201 3:46974100 Add G 2.70x10-3 1.15 (1.07-1.23)

140

rs12876235 3:46974172 Add G 2.70x10-3 1.15 (1.07-1.23) rs9603616 3:65848944 Add T 2.70x10-3 1.3 (1.16-1.47) rs11618582 3:65849333 Add G 2.70x10-3 1.34 (1.15-1.55) rs2451716 3:65850962 Add T 2.69x10-3 1.33 (1.15-1.54) rs2498342 3:65851664 Add G 2.69x10-3 1.31 (1.16-1.48) rs2757649 3:65852328 Add C 2.67x10-3 1.3 (1.16-1.47) rs4299827 3:65852471 Add G 2.67x10-3 1.29 (1.14-1.46) rs72922282 3:65852474 Add C 2.54x10-3 1.29 (1.14-1.46)

rs38043 3:65853285 Dom A 2.54x10-3 1.3 (1.15-1.47) rs9357008 3:65853434 Add G 2.51x10-3 1.3 (1.15-1.47) rs2663031 3:65853521 Dom C 2.50x10-3 1.3 (1.15-1.46) rs12872801 3:65853706 Add T 2.50x10-3 1.3 (1.15-1.46) rs9594366 3:71658162 Add T 2.50x10-3 1.15 (1.08-1.23) rs10858008 3:71660415 Add T 2.49x10-3 1.14 (1.07-1.22) rs1143390 3:71660572 Rec C 2.49x10-3 1.14 (1.07-1.22)

rs27711 3:71661256 Dom A 2.49x10-3 1.14 (1.07-1.22)

141

rs4591839 3:71661339 Add C 2.48x10-3 1.14 (1.07-1.22) rs186303011 3:71661862 Dom G 2.47x10-3 1.14 (1.07-1.22)

rs1477364 3:71662264 Dom T 2.46x10-3 1.14 (1.07-1.22)

rs2614257 3:71663132 Add C 2.46x10-3 1.14 (1.07-1.22)

rs10858007 3:71663248 Add G 2.44x10-3 1.14 (1.07-1.22)

rs1398553 3:71663447 Add A 2.43x10-3 1.14 (1.07-1.22)

rs1217226 3:71663533 Add C 2.29x10-3 1.14 (1.07-1.22)

rs2910687 3:71664374 Dom T 2.26x10-3 1.14 (1.07-1.22)

rs9379892 3:71665123 Add G 2.25x10-3 1.14 (1.07-1.22)

rs9603608 3:71666535 Add C 2.25x10-3 1.14 (1.07-1.22)

rs1217221 3:71675525 Add G 2.23x10-3 1.15 (1.07-1.22)

rs7733312 3:71678949 Dom G 2.23x10-3 1.15 (1.07-1.23)

rs2940707 3:101633203 Dom T 2.22x10-3 1.24 (1.13-1.35)

rs7719705 3:101662803 Dom A 2.22x10-3 1.23 (1.12-1.35)

rs3797796 3:101721602 Dom T 2.20x10-3 0.86 (0.81-0.92)

rs27993 3:101733377 Dom A 2.18x10-3 0.86 (0.81-0.92)

142

rs3118470 3:101734490 Add C 2.17x10-3 0.86 (0.81-0.92) rs6814458 3:101736664 Add G 2.16x10-3 0.86 (0.81-0.92) rs1217203 3:107545050 Add A 2.12x10-3 0.86 (0.8-0.92) rs1398554 3:121747796 Add G 2.12x10-3 1.41 (1.19-1.67) rs1217223 3:121753355 Add A 2.11x10-3 1.43 (1.2-1.69) rs1235688 3:121754819 Add C 2.11x10-3 1.43 (1.2-1.69) rs2548226 3:121755812 Dom T 2.11x10-3 1.43 (1.2-1.69) rs6456739 3:121755948 Add T 2.11x10-3 1.43 (1.2-1.69) rs1217227 3:121758232 Add C 2.09x10-3 1.43 (1.2-1.69) rs1217228 3:121759322 Add T 2.09x10-3 1.43 (1.21-1.7) rs6456729 3:121767098 Add A 2.08x10-3 1.43 (1.21-1.7) rs1235687 3:121767413 Add G 2.06x10-3 1.43 (1.21-1.7) rs1217208 3:121768743 Add G 2.05x10-3 1.44 (1.21-1.7) rs1217233 3:121780807 Add G 2.05x10-3 1.45 (1.26-1.66) rs1217232 3:121788368 Add C 2.05x10-3 1.45 (1.26-1.67) rs1217199 3:121789974 Add C 2.05x10-3 1.45 (1.26-1.67)

143

rs1046395 3:121793508 Dom A 2.05x10-3 1.45 (1.26-1.66) rs7319041 3:121795029 Add A 2.05x10-3 1.45 (1.26-1.66) rs1217204 3:121795506 Add G 2.04x10-3 1.45 (1.26-1.66) rs12875311 3:121796232 Add A 2.04x10-3 1.45 (1.26-1.66) rs2242116 3:121797956 Add A 2.02x10-3 1.45 (1.26-1.66) rs1217230 3:121798288 Add A 2.00x10-3 1.45 (1.26-1.66) rs7128640 3:121802247 Dom A 2.00x10-3 1.45 (1.26-1.66) rs7676523 3:121803207 Add G 2.00x10-3 1.45 (1.26-1.66) rs6833591 3:121806048 Add G 2.00x10-3 1.44 (1.26-1.66) rs9960807 3:121806725 Dom G 2.00x10-3 1.44 (1.26-1.66) rs1217236 3:121820906 Add G 1.97x10-3 1.42 (1.24-1.64) rs11242103 3:122664907 Rec G 1.97x10-3 0.77 (0.68-0.87)

rs9943 3:165166869 Add G 1.97x10-3 0.71 (0.61-0.84) rs1217215 3:165168292 Add C 1.95x10-3 0.71 (0.6-0.83) rs9992580 3:171631672 Add T 1.95x10-3 1.28 (1.14-1.43) rs1217214 3:176830302 Add G 1.94x10-3 1.19 (1.1-1.28)

144

rs1217234 3:176832562 Add C 1.94x10-3 1.19 (1.1-1.29) rs1237289 3:176832797 Add G 1.94x10-3 1.19 (1.1-1.28)

rs38031 3:176832845 Dom A 1.94x10-3 1.19 (1.1-1.29) rs7114403 3:176832875 Dom A 1.94x10-3 1.19 (1.1-1.29) rs7676741 3:176833230 Add G 1.94x10-3 1.19 (1.1-1.29)

rs27660 3:176836261 Dom C 1.92x10-3 1.19 (1.1-1.28) rs1217235 3:176846493 Add T 1.92x10-3 1.19 (1.1-1.28) rs7705093 3:176849740 Dom T 1.92x10-3 1.3 (1.16-1.45)

rs27712 3:183762614 Dom C 1.90x10-3 1.29 (1.14-1.47) rs1217211 3:184601074 Add A 1.89x10-3 3.57 (2.02-6.31)

rs867796 3:188406217 Add G 1.88x10-3 1.19 (1.09-1.29) rs7993214 3:188412858 Add T 1.88x10-3 1.15 (1.07-1.24) rs6906521 3:188412997 Add T 1.87x10-3 1.15 (1.07-1.24) rs7698404 3:188413119 Add G 1.82x10-3 1.15 (1.07-1.24) rs1926234 3:188416876 Add G 1.82x10-3 1.16 (1.08-1.24) rs7646906 3:188426256 Add G 1.81x10-3 1.16 (1.08-1.24)

145

rs38029 3:188431954 Dom C 1.81x10-3 1.16 (1.08-1.24)

rs4711112 3:188466638 Add A 1.81x10-3 1.16 (1.08-1.25)

rs868190 3:188467161 Add G 1.81x10-3 1.43 (1.2-1.7)

rs6925193 4:14768378 Add T 1.80x10-3 1.18 (1.09-1.28)

rs1217237 4:24408684 Add T 1.79x10-3 0.74 (0.64-0.85)

rs1230642 4:24408787 Add G 1.77x10-3 0.74 (0.64-0.85)

rs4833837 4:24410367 Add G 1.76x10-3 0.75 (0.65-0.86)

rs1531137 4:24415511 Dom T 1.75x10-3 0.75 (0.65-0.86)

rs1228280 4:24416173 Add A 1.74x10-3 0.78 (0.69-0.87)

rs11930030 4:24416896 Add A 1.74x10-3 0.75 (0.66-0.86)

rs2221903 4:24424114 Add C 1.73x10-3 0.74 (0.64-0.85)

rs9532434 4:40308368 Add T 1.72x10-3 1.41 (1.2-1.65) rs144565908 4:106574536 Add T 1.69x10-3 0.83 (0.76-0.91)

rs28635831 4:106578151 Add G 1.68x10-3 0.83 (0.75-0.9)

rs61819459 4:106583826 Add T 1.54x10-3 0.82 (0.75-0.9)

rs7526209 4:106588509 Add C 1.67x10-3 0.83 (0.76-0.91)

146

rs1230637 4:106593850 Add T 1.66x10-3 0.82 (0.75-0.9)

rs724449 4:106597295 Dom C 1.65x10-3 0.82 (0.75-0.89) rs10858011 4:106603098 Add A 1.61x10-3 0.83 (0.76-0.9) rs2617439 4:106613821 Dom A 1.59x10-3 0.82 (0.75-0.9) rs6819371 4:106621643 Add A 1.59x10-3 0.82 (0.75-0.9) rs6848834 4:106629246 Add T 1.59x10-3 0.82 (0.75-0.9) rs13358339 4:106630007 Dom C 1.57x10-3 0.82 (0.75-0.9) rs11727369 4:106645771 Add A 1.55x10-3 0.82 (0.75-0.9) rs2636002 4:106655830 Add G 1.54x10-3 0.82 (0.75-0.9)

rs724448 4:106662004 Dom A 1.54x10-3 0.82 (0.75-0.9) rs4380544 4:106662118 Add C 1.54x10-3 0.82 (0.75-0.9) rs7547478 4:122616166 Add A 9.14x10-4 1.5 (1.24-1.83) rs6835745 4:122620565 Add T 9.14x10-4 1.44 (1.21-1.73) rs4683300 4:123010587 Dom C 1.54x10-3 0.84 (0.77-0.91) rs1113523 4:123017541 Add A 1.52x10-3 0.84 (0.77-0.91) rs11098666 4:123018593 Add A 1.52x10-3 0.84 (0.77-0.91)

147

rs6913550 4:123026426 Add T 1.52x10-3 0.83 (0.76-0.91) rs7716222 4:123031494 Dom A 1.51x10-3 0.83 (0.77-0.89) rs1230646 4:123043662 Add T 1.48x10-3 0.83 (0.76-0.9) rs2359167 4:123049592 Add A 1.48x10-3 0.82 (0.75-0.89) rs12745499 4:123067808 Add T 1.48x10-3 1.19 (1.12-1.28) rs6829845 4:123073009 Add A 1.47x10-3 0.82 (0.76-0.88) rs61817589 4:123076007 Add T 1.46x10-3 1.2 (1.12-1.29) rs7703341 4:123087957 Dom A 1.44x10-3 1.17 (1.1-1.25) rs7731592 4:123110656 Dom A 1.42x10-3 0.81 (0.76-0.88) rs12760067 4:123110956 Add A 1.40x10-3 0.81 (0.76-0.88) rs9532433 4:123114622 Add C 1.38x10-3 0.82 (0.76-0.88) rs4145859 4:123115502 Add C 1.37x10-3 0.82 (0.75-0.89) rs9548932 4:123116862 Add G 1.37x10-3 1.2 (1.12-1.28) rs12041547 4:123116995 Add C 1.35x10-3 1.2 (1.12-1.28) rs2351010 4:123117201 Dom A 1.34x10-3 0.81 (0.76-0.88) rs1363974 4:123122440 Dom G 1.34x10-3 0.81 (0.76-0.88)

148

rs7096384 4:123124327 Add T 1.34x10-3 0.81 (0.76-0.88)

rs7073236 4:123126450 Add C 1.32x10-3 1.2 (1.12-1.28)

rs12750414 4:123132492 Add T 1.31x10-3 1.2 (1.12-1.28)

rs4360063 4:123141054 Dom G 1.30x10-3 1.2 (1.12-1.28)

rs1423357 4:123146225 Dom A 1.23x10-3 1.2 (1.12-1.28)

rs9532430 4:123152938 Add A 1.23x10-3 0.82 (0.75-0.89)

rs62626322 4:123161619 Dom G 1.21x10-3 0.81 (0.76-0.88)

rs1217413 4:123163274 Add G 1.18x10-3 0.82 (0.75-0.89)

rs11205252 4:123164800 Rec A 1.18x10-3 0.81 (0.76-0.87)

rs10858017 4:123171318 Add G 1.17x10-3 0.82 (0.75-0.89)

rs6835457 4:123175900 Add G 1.16x10-3 0.81 (0.76-0.88) rs113484440 4:123184285 Dom T 1.16x10-3 0.81 (0.76-0.88)

rs27997 4:123184411 Dom G 1.16x10-3 1.17 (1.1-1.25) rs111943850 4:123188449 Dom G 1.13x10-3 0.81 (0.76-0.88)

rs12612769 4:123188501 Add C 1.11x10-3 1.2 (1.12-1.28)

rs13103766 4:123193870 Add A 1.10x10-3 1.19 (1.12-1.27)

149

rs112593922 4:123194274 Dom T 1.09x10-3 0.82 (0.76-0.88)

rs12063216 4:123198435 Add A 1.08x10-3 1.17 (1.1-1.25)

rs4565712 4:123203573 Add G 1.08x10-3 0.82 (0.76-0.88)

rs10795791 4:123205143 Add G 1.08x10-3 0.81 (0.76-0.88)

rs2494691 4:123208349 Add G 1.07x10-3 0.81 (0.76-0.88)

rs1230661 4:123210503 Add A 1.06x10-3 0.81 (0.76-0.88)

rs1230687 4:123215381 Add A 1.06x10-3 1.2 (1.12-1.28)

rs7072793 4:123218313 Add C 1.05x10-3 0.82 (0.75-0.89)

rs1237682 4:123223980 Add T 1.03x10-3 0.81 (0.76-0.88)

rs1230656 4:123228113 Add C 1.03x10-3 0.81 (0.76-0.88)

rs1230685 4:123235583 Add C 1.01x10-3 1.2 (1.12-1.29)

rs10026154 4:123238964 Add A 1.00x10-3 0.81 (0.76-0.88)

rs1230683 4:123241047 Add A 9.87x10-4 0.82 (0.76-0.9)

rs79373789 4:123263446 Dom T 9.87x10-4 0.81 (0.76-0.88)

rs12642902 4:123264485 Add A 9.77x10-4 1.2 (1.12-1.28)

rs3909451 4:123265089 Dom T 9.58x10-4 0.81 (0.75-0.87)

150

rs111903554 4:123271668 Dom T 9.52x10-4 1.2 (1.12-1.28) rs112991263 4:123273766 Dom A 9.52x10-4 0.81 (0.75-0.89)

rs907715 4:123283993 Add T 9.52x10-4 0.82 (0.75-0.89)

rs45605540 4:123286227 Add C 9.51x10-4 1.18 (1.11-1.26) rs112481526 4:123293508 Add G 9.49x10-4 0.81 (0.75-0.89)

rs36226551 4:123309902 Dom G 9.45x10-4 0.8 (0.75-0.86)

rs1230679 4:123316076 Add A 9.44x10-4 1.21 (1.13-1.29)

rs36226875 4:123318542 Dom C 9.43x10-4 0.81 (0.75-0.86)

rs17203439 4:123320707 Dom G 9.43x10-4 0.8 (0.75-0.86)

rs1230678 4:123321526 Add G 9.42x10-4 0.81 (0.75-0.86)

rs2358994 4:123323926 Add C 9.42x10-4 0.81 (0.75-0.86)

rs2358995 4:123325969 Add C 9.42x10-4 0.8 (0.75-0.86)

rs75887175 4:123327216 Rec T 9.42x10-4 0.81 (0.75-0.86)

rs1685633 4:123329362 Dom A 9.42x10-4 1.21 (1.13-1.3)

rs27300 4:123331316 Dom G 9.42x10-4 0.8 (0.75-0.86)

rs10511408 4:123333177 Dom C 9.37x10-4 1.22 (1.14-1.3)

151

rs2093436 4:123336918 Add G 9.05x10-4 1.21 (1.13-1.29) rs10077945 4:123339756 Dom T 8.92x10-4 0.81 (0.75-0.89) rs7726445 4:123341159 Dom T 8.91x10-4 0.8 (0.75-0.86) rs1230639 4:123342114 Add A 8.90x10-4 1.21 (1.13-1.3) rs1230638 4:123351431 Add A 8.90x10-4 0.81 (0.75-0.87) rs2927608 4:123351925 Dom A 8.90x10-4 1.21 (1.13-1.3) rs2910686 4:123352201 Dom C 8.90x10-4 0.8 (0.75-0.86) rs1996077 4:123355923 Add A 8.88x10-4 1.21 (1.13-1.3) rs12061482 4:123358961 Add T 8.87x10-4 0.81 (0.75-0.89) rs6537795 4:123363029 Add T 8.87x10-4 1.21 (1.13-1.29) rs2797412 4:123363109 Add T 8.83x10-4 1.21 (1.13-1.3) rs6887500 4:123368516 Dom A 8.83x10-4 0.8 (0.75-0.86) rs1230640 4:123369776 Add C 8.72x10-4 1.22 (1.14-1.3) rs12136773 4:123371049 Rec G 8.72x10-4 0.8 (0.75-0.86) rs11205256 4:123371976 Rec C 8.67x10-4 0.8 (0.75-0.86)

rs2762 4:123373133 Dom T 8.67x10-4 1.22 (1.13-1.3)

152

rs2910788 4:123376135 Dom T 8.67x10-4 0.81 (0.75-0.89) rs7750131 4:123377482 Add G 8.62x10-4 1.22 (1.14-1.3) rs6871162 4:123384460 Dom A 8.55x10-4 0.8 (0.75-0.86) rs2451714 4:123385164 Add T 8.55x10-4 0.81 (0.76-0.87) rs2432142 4:123386013 Dom A 8.54x10-4 1.22 (1.14-1.3) rs2295853 4:123386720 Add A 8.53x10-4 1.21 (1.14-1.3) rs2636013 4:123387600 Add G 8.44x10-4 0.8 (0.75-0.86) rs2636014 4:123391464 Add T 8.44x10-4 0.8 (0.75-0.86) rs1981319 4:123392504 Add C 8.42x10-4 0.81 (0.75-0.89) rs1205591 4:123392830 Dom T 8.33x10-4 0.81 (0.75-0.86) rs7553188 4:123395109 Add C 8.30x10-4 0.81 (0.74-0.88) rs8087237 4:123396028 Add A 8.30x10-4 1.22 (1.14-1.3) rs4423005 4:123398148 Add C 8.28x10-4 1.22 (1.14-1.31) rs1230645 4:123402770 Add C 8.27x10-4 0.8 (0.75-0.86) rs6663679 4:123403126 Add T 8.27x10-4 0.81 (0.75-0.87) rs10051637 4:123410252 Dom G 8.25x10-4 0.8 (0.75-0.86)

153

rs10047240 4:123413566 Rec C 8.24x10-4 0.8 (0.75-0.86) rs10858018 4:123417564 Add A 8.22x10-4 1.22 (1.14-1.31) rs4422954 4:123420095 Rec A 8.21x10-4 1.22 (1.14-1.31) rs13170029 4:123422563 Dom T 8.16x10-4 0.8 (0.75-0.86) rs1743605 4:123423316 Add G 8.14x10-4 0.8 (0.75-0.86) rs2451746 4:123425785 Add G 8.13x10-4 1.22 (1.14-1.31) rs1230671 4:123431998 Add T 8.11x10-4 1.22 (1.14-1.3) rs1230647 4:123440074 Add C 8.07x10-4 0.81 (0.73-0.89) rs1512973 4:123443984 Add A 8.88x10-4 0.81 (0.74-0.88) rs4600045 4:123446714 Add T 8.07x10-4 0.8 (0.73-0.88) rs1935838 4:123448562 Add T 8.07x10-4 1.22 (1.14-1.3) rs34196325 4:123452231 Rec C 8.07x10-4 1.22 (1.14-1.31) rs1209264 4:123456457 Dom A 8.07x10-4 1.23 (1.15-1.31) rs2910792 4:123460115 Dom G 8.07x10-4 1.22 (1.14-1.31)

rs27298 4:123462620 Dom T 8.07x10-4 0.8 (0.73-0.88)

rs27998 4:123471665 Dom G 8.07x10-4 1.22 (1.13-1.3)

154

rs1217193 4:123472786 Add C 8.05x10-4 0.8 (0.75-0.86) rs2910789 4:123472816 Dom C 8.07x10-4 1.22 (1.14-1.31) rs4559442 4:123473487 Rec T 8.05x10-4 0.8 (0.75-0.86) rs1230649 4:123475979 Add G 8.04x10-4 1.22 (1.14-1.31) rs1046396 4:123492417 Dom A 8.04x10-4 1.22 (1.14-1.31) rs1423566 4:123494381 Dom C 8.04x10-4 0.81 (0.74-0.89) rs2548516 4:123498431 Dom T 7.98x10-4 0.8 (0.75-0.86) rs1217386 4:123499745 Add A 7.88x10-4 0.81 (0.75-0.89)

rs641085 4:123503492 Add T 7.82x10-4 0.8 (0.74-0.86) rs2798138 4:123506056 Add A 7.79x10-4 0.84 (0.78-0.9) rs61820160 4:123507053 Add G 7.79x10-4 1.19 (1.11-1.27)

rs27290 4:123507914 Dom G 7.79x10-4 1.19 (1.11-1.27) rs1777237 4:123508501 Add G 7.78x10-4 0.84 (0.79-0.9) rs1217210 4:123509421 Add G 7.74x10-4 0.82 (0.76-0.9) rs6698586 4:123509713 Add C 7.74x10-4 1.19 (1.11-1.27) rs1928342 4:123509786 Rec C 7.74x10-4 0.84 (0.79-0.9)

155

rs27293 4:123510766 Dom A 7.74x10-4 1.19 (1.11-1.27)

rs27295 4:123511012 Dom C 7.74x10-4 0.84 (0.79-0.9)

rs39602 4:123511126 Dom C 7.74x10-4 0.84 (0.79-0.9)

rs2498343 4:123517085 Add G 7.74x10-4 1.19 (1.11-1.27)

rs1217192 4:123517233 Add G 7.72x10-4 0.84 (0.79-0.9)

rs2798135 4:123519319 Add G 7.72x10-4 0.81 (0.75-0.86)

rs27289 4:123520842 Dom G 7.72x10-4 1.18 (1.11-1.27)

rs1777238 4:123521292 Add C 7.70x10-4 0.87 (0.81-0.93)

rs1936398 4:123522569 Add C 7.70x10-4 1.18 (1.11-1.27)

rs12044534 4:123523279 Add C 7.70x10-4 1.19 (1.11-1.27) rs148299382 4:123523441 Dom T 7.70x10-4 1.19 (1.11-1.27)

rs592390 4:123523625 Add C 7.68x10-4 0.83 (0.78-0.89)

rs2481065 4:123526195 Dom G 7.65x10-4 1.19 (1.11-1.27)

rs17281953 4:123526627 Dom A 7.65x10-4 0.84 (0.79-0.9) rs113455950 4:123527817 Dom G 7.65x10-4 0.81 (0.75-0.86)

rs2094638 4:123530993 Rec G 7.63x10-4 1.18 (1.11-1.26)

156

rs1777234 4:123533142 Add A 7.62x10-4 0.82 (0.76-0.9)

rs588447 4:123536963 Add C 7.50x10-4 1.19 (1.11-1.27)

rs706778 4:123538912 Add T 7.43x10-4 1.19 (1.11-1.27) rs13147049 4:123539854 Add A 7.37x10-4 0.82 (0.75-0.9) rs1146180 4:123540758 Add T 7.34x10-4 0.8 (0.75-0.86) rs10858019 4:123541341 Add C 7.29x10-4 1.17 (1.1-1.25) rs12957037 4:123546282 Add G 7.29x10-4 0.84 (0.79-0.9) rs1217412 4:123548068 Add G 7.23x10-4 1.18 (1.11-1.27) rs1777241 4:123551032 Add G 7.12x10-4 0.84 (0.79-0.9) rs4838997 4:123551114 Add G 7.12x10-4 0.83 (0.76-0.9) rs1217388 4:123552125 Add G 7.12x10-4 1.18 (1.11-1.26) rs2847293 4:123554707 Dom A 7.10x10-4 0.83 (0.76-0.9)

rs478582 4:123554790 Add C 7.09x10-4 0.83 (0.76-0.9) rs11102669 4:123555178 Add A 7.07x10-4 0.83 (0.77-0.9) rs1217200 4:123564458 Add C 7.07x10-4 0.86 (0.8-0.92) rs6537792 4:154066513 Add G 7.05x10-4 3.04 (1.81-5.12)

157

rs1146187 4:154084081 Add A 6.99x10-4 3.1 (1.82-5.28) rs1230663 4:158386596 Add A 6.98x10-4 1.23 (1.12-1.35) rs1146182 4:166019082 Add C 6.98x10-4 1.23 (1.11-1.35) rs4839335 4:181370087 Add G 6.98x10-4 0.8 (0.72-0.88) rs2797408 5:18961778 Add T 6.91x10-4 2.66 (1.78-3.99) rs12565589 5:38121423 Add A 6.80x10-4 1.45 (1.24-1.7) rs11205251 5:38518432 Rec C 6.80x10-4 2.63 (1.65-4.19) rs1893217 5:38518442 Dom G 6.80x10-4 2.63 (1.65-4.19) rs11102661 5:52308374 Add A 6.79x10-4 1.75 (1.34-2.27) rs1217376 5:52309015 Add A 6.79x10-4 1.74 (1.34-2.27) rs1217389 5:55057652 Add C 6.79x10-4 0.52 (0.39-0.7) rs1217395 5:55581060 Add C 6.79x10-4 0.84 (0.78-0.91) rs11938795 5:55588333 Add C 6.79x10-4 0.84 (0.78-0.91) rs7693745 5:55588343 Add G 6.79x10-4 0.84 (0.78-0.91) rs2548224 5:55602029 Dom G 6.79x10-4 0.83 (0.76-0.9) rs34920518 5:55608476 Dom G 6.79x10-4 0.83 (0.76-0.9)

158

rs8096138 5:55608881 Dom G 6.77x10-4 0.83 (0.76-0.9)

rs1230674 5:55609214 Add A 6.73x10-4 0.83 (0.76-0.91)

rs1230659 5:55611438 Add T 6.73x10-4 0.83 (0.76-0.9)

rs2359170 5:55615232 Add G 6.73x10-4 0.83 (0.77-0.91)

rs1230655 5:55615736 Add A 6.73x10-4 0.83 (0.77-0.91)

rs1217380 5:55616027 Add G 6.73x10-4 0.83 (0.76-0.9)

rs1217377 5:55616455 Add C 6.73x10-4 0.83 (0.77-0.91)

rs1599971 5:55617171 Add A 6.73x10-4 0.83 (0.77-0.91)

rs2432141 5:55619992 Dom T 6.73x10-4 0.83 (0.76-0.91)

rs27659 5:55622159 Dom A 6.73x10-4 0.83 (0.76-0.9)

rs27302 5:55622233 Dom G 6.73x10-4 0.83 (0.77-0.91)

rs3134882 5:55622861 Add A 6.73x10-4 0.83 (0.76-0.9)

rs10858021 5:55624522 Add G 6.68x10-4 0.83 (0.77-0.9)

rs7907829 5:55624578 Add T 6.68x10-4 0.83 (0.77-0.9) rs115699904 5:55624617 Dom A 6.63x10-4 0.83 (0.77-0.91)

rs8179673 5:55624873 Add C 6.63x10-4 0.84 (0.78-0.91)

159

rs4147359 5:55624905 Add A 6.63x10-4 0.84 (0.78-0.91)

rs2797409 5:55625333 Add C 6.44x10-4 0.84 (0.78-0.91)

rs1217396 5:55641055 Add C 6.24x10-4 0.84 (0.77-0.91)

rs62323898 5:55901945 Add G 6.23x10-4 0.86 (0.8-0.92)

rs7986796 5:55904312 Dom G 5.98x10-4 0.86 (0.8-0.92)

rs56035021 5:55909048 Add A 5.84x10-4 0.86 (0.8-0.93) rs188855124 5:55928713 Dom A 5.76x10-4 0.85 (0.79-0.91)

rs38044 5:73731932 Dom T 5.37x10-4 1.37 (1.18-1.59)

rs1217421 5:79912540 Add G 5.29x10-4 0.72 (0.63-0.84)

rs6819058 5:96220087 Add G 5.09x10-4 1.26 (1.14-1.39)

rs7671357 5:96221011 Add A 5.09x10-4 1.24 (1.12-1.37)

rs72687044 5:96221341 Add G 4.98x10-4 1.24 (1.12-1.37)

rs28854492 5:96221565 Add T 4.91x10-4 1.24 (1.12-1.37)

rs4505848 5:96222020 Add G 4.90x10-4 1.24 (1.12-1.37)

rs2175679 5:96222183 Add A 4.90x10-4 1.24 (1.12-1.38)

rs11552449 5:96222185 Dom T 4.86x10-4 1.24 (1.12-1.37)

160

rs7664452 5:96222627 Add G 4.86x10-4 1.24 (1.12-1.38) rs1217407 5:96222779 Add A 4.48x10-4 1.24 (1.12-1.38) rs1217416 5:96223045 Add C 4.45x10-4 1.24 (1.12-1.38) rs7513707 5:96223100 Add A 4.35x10-4 1.24 (1.12-1.38) rs55904957 5:96223302 Add C 4.20x10-4 1.24 (1.12-1.38) rs10858023 5:96223480 Add T 4.20x10-4 1.24 (1.12-1.38) rs1217410 5:96223760 Add C 4.13x10-4 1.24 (1.12-1.38) rs2292759 5:96223880 Add A 4.13x10-4 1.27 (1.15-1.4)

rs960550 5:96224121 Add T 4.07x10-4 1.24 (1.12-1.38) rs7699742 5:96224176 Add C 4.07x10-4 1.24 (1.12-1.38) rs7677139 5:96224579 Add A 4.05x10-4 1.24 (1.12-1.38) rs13124788 5:96225252 Add T 4.05x10-4 1.24 (1.12-1.38) rs55969942 5:96225522 Add G 4.04x10-4 1.24 (1.12-1.38) rs7568275 5:96225774 Add G 3.97x10-4 1.24 (1.12-1.38) rs66570627 5:96226196 Add A 3.96x10-4 1.26 (1.15-1.39) rs11731632 5:96226535 Add T 3.96x10-4 1.24 (1.12-1.38)

161

rs13104615 5:96226695 Add G 3.96x10-4 1.24 (1.12-1.37) rs13114649 5:96227586 Add G 3.96x10-4 1.24 (1.12-1.38) rs13137682 5:96228428 Add A 3.96x10-4 1.24 (1.12-1.37) rs13151966 5:96228782 Add T 3.96x10-4 1.24 (1.12-1.38) rs13111671 5:96230122 Add A 3.96x10-4 1.25 (1.13-1.39) rs7657746 5:96230178 Add G 3.94x10-4 1.27 (1.14-1.41) rs13114358 5:96230403 Add T 3.79x10-4 1.26 (1.14-1.4) rs13102768 5:96231000 Add G 3.78x10-4 1.26 (1.14-1.4) rs7687716 5:96231372 Add G 3.78x10-4 1.26 (1.15-1.39) rs13143416 5:96231504 Add C 3.78x10-4 1.26 (1.13-1.39) rs11941093 5:96231520 Add T 3.78x10-4 1.26 (1.14-1.4) rs10181656 5:96232142 Add G 3.72x10-4 1.26 (1.14-1.4) rs6534344 5:96232222 Add C 3.66x10-4 1.26 (1.14-1.4) rs6851362 5:96232286 Add C 3.60x10-4 1.26 (1.14-1.4) rs17388568 5:96232402 Add A 3.58x10-4 1.26 (1.14-1.4) rs2847273 5:96232699 Add C 3.58x10-4 1.26 (1.14-1.4)

162

rs3789613 5:96232806 Add G 3.50x10-4 1.26 (1.14-1.4) rs7523862 5:96233450 Add A 3.50x10-4 1.26 (1.14-1.4) rs10776775 5:96233608 Add A 3.49x10-4 1.26 (1.14-1.4) rs11734090 5:96234212 Add C 3.45x10-4 1.27 (1.14-1.41) rs10858022 5:96234214 Add G 3.31x10-4 1.27 (1.14-1.41) rs13119119 5:96234306 Add G 3.31x10-4 1.27 (1.14-1.4) rs11102694 5:96234315 Add A 3.26x10-4 1.26 (1.15-1.39) rs4797709 5:96234352 Add C 3.26x10-4 1.27 (1.14-1.41) rs6661817 5:96234375 Add C 3.26x10-4 1.27 (1.14-1.4) rs2847297 5:96234533 Add G 3.12x10-4 1.26 (1.15-1.39) rs11722421 5:96234578 Add C 3.10x10-4 1.26 (1.14-1.4) rs35914000 5:96234621 Add A 2.96x10-4 1.26 (1.14-1.4) rs10745340 5:96234872 Add C 2.74x10-4 1.26 (1.14-1.4) rs7574865 5:96235896 Add T 2.74x10-4 1.26 (1.14-1.4) rs2852151 5:96236318 Add A 2.59x10-4 1.26 (1.14-1.4) rs3118469 5:96236412 Add T 2.41x10-4 1.26 (1.15-1.39)

163

rs2884603 5:96236620 Add G 2.40x10-4 1.26 (1.15-1.39) rs11729811 5:96236843 Add G 2.39x10-4 1.26 (1.14-1.4) rs1217392 5:96237114 Add T 2.38x10-4 1.26 (1.14-1.4) rs2542162 5:96237326 Add T 2.34x10-4 1.26 (1.14-1.4) rs7582694 5:96237413 Add C 2.34x10-4 1.26 (1.14-1.4) rs3134883 5:96238401 Add A 2.30x10-4 1.26 (1.14-1.4) rs3118471 5:96238578 Add G 2.30x10-4 1.26 (1.14-1.39)

rs674222 5:96239294 Add C 2.30x10-4 1.26 (1.14-1.4) rs13114759 5:96239645 Add A 2.27x10-4 1.26 (1.14-1.4) rs12969241 5:96239837 Add T 2.16x10-4 1.26 (1.14-1.4) rs35967540 5:96239927 Add C 2.16x10-4 1.26 (1.15-1.39) rs35320197 5:96240220 Add A 2.16x10-4 1.26 (1.14-1.4) rs3826557 5:96240386 Add T 2.11x10-4 1.26 (1.14-1.4) rs72669165 5:96242074 Add C 1.57x10-4 1.26 (1.14-1.4) rs4145717 5:96242270 Add T 1.38x10-4 1.26 (1.14-1.4) rs34416003 5:96242412 Add C 1.38x10-4 1.27 (1.14-1.4)

164

rs34153303 5:96242442 Add A 1.19x10-4 1.27 (1.14-1.41) rs1479918 5:96242462 Add T 1.18x10-4 1.27 (1.14-1.41) rs2847281 5:96242866 Add G 1.15x10-4 1.26 (1.14-1.4) rs56360035 5:96242981 Add T 1.12x10-4 1.26 (1.14-1.4) rs12964314 5:96244549 Add G 1.04x10-4 1.26 (1.15-1.39) rs71353227 5:96244585 Add A 1.04x10-4 1.26 (1.14-1.4) rs1904522 5:96244638 Add A 9.64x10-5 1.26 (1.14-1.4) rs59294813 5:96245343 Add G 9.42x10-5 1.26 (1.13-1.4) rs34880409 5:96245439 Add A 9.28x10-5 1.26 (1.13-1.39) rs12963474 5:96245518 Add A 9.13x10-5 1.26 (1.14-1.4) rs12968719 5:96245617 Add A 8.50x10-5 1.26 (1.14-1.4) rs55896948 5:96245892 Add G 8.25x10-5 1.26 (1.13-1.4)

rs716501 5:96245903 Add A 8.25x10-5 1.25 (1.13-1.39) rs56267605 5:96245910 Add C 8.15x10-5 1.26 (1.13-1.4) rs35923716 5:96246338 Add G 7.43x10-5 1.26 (1.14-1.4) rs58939053 5:96246601 Add T 6.85x10-5 1.26 (1.14-1.4)

165

rs45599938 5:96246940 Add A 6.18x10-5 1.26 (1.14-1.4)

rs3136534 5:96247434 Add G 6.13x10-5 1.26 (1.15-1.39)

rs35954636 5:96247750 Add G 6.04x10-5 0.78 (0.7-0.87)

rs12971201 5:96247810 Add A 2.09x10-4 1.26 (1.15-1.39)

rs2069772 5:96247827 Add C 1.98x10-4 1.26 (1.14-1.4)

rs45485691 5:96247993 Add A 1.88x10-4 1.26 (1.13-1.4)

rs34799913 5:96248707 Add G 1.84x10-4 1.26 (1.14-1.4)

rs12955302 5:96248795 Add G 1.84x10-4 1.29 (1.15-1.46)

rs59867199 5:96248886 Add T 1.78x10-4 1.26 (1.14-1.4)

rs72669172 5:96249115 Add T 1.78x10-4 1.26 (1.14-1.4) rs146583707 5:96249323 Add A 1.78x10-4 1.26 (1.14-1.4)

rs45454992 5:96249351 Add G 1.57x10-4 1.26 (1.14-1.4)

rs8026706 5:96249378 Add T 3.97x10-2 1.26 (1.14-1.4)

rs2278597 5:96249634 Rec C 3.97x10-2 1.26 (1.14-1.4)

rs74683759 5:96249648 Add T 3.97x10-2 1.26 (1.15-1.39)

rs4869311 5:96250264 Dom A 3.97x10-2 1.26 (1.14-1.4)

166

rs62483629 5:96250457 Add C 3.97x10-2 1.26 (1.13-1.4)

rs74626076 5:96250928 Add G 3.97x10-2 1.26 (1.14-1.4)

rs16835093 5:96251003 Rec G 3.97x10-2 1.26 (1.14-1.4)

rs4869312 5:96251675 Dom C 3.96x10-2 1.26 (1.15-1.39)

rs8114049 5:96251701 Add C 3.94x10-2 1.26 (1.14-1.4)

rs11790577 5:96252079 Rec A 3.94x10-2 1.26 (1.15-1.39)

rs6682237 5:96252432 Dom C 3.94x10-2 1.29 (1.17-1.42)

rs11711641 5:96252589 Add G 3.94x10-2 1.29 (1.17-1.42)

rs11719571 5:96252803 Add T 3.94x10-2 1.26 (1.15-1.39)

rs1559354 5:96252998 Dom A 3.94x10-2 1.26 (1.15-1.39) rs112885202 5:96253104 Dom A 3.94x10-2 1.26 (1.15-1.39)

rs233914 5:96254209 Dom C 3.94x10-2 1.26 (1.13-1.4)

rs2223259 5:96254354 Dom C 3.94x10-2 1.26 (1.13-1.4)

rs62428886 5:96254817 Dom A 3.94x10-2 1.26 (1.13-1.4)

rs6134006 5:96257829 Dom A 3.94x10-2 1.26 (1.15-1.39)

rs12654015 5:96258723 Dom A 3.97x10-2 1.26 (1.13-1.39)

167

rs78992409 5:96258927 Dom C 3.94x10-2 1.26 (1.13-1.39) rs13436636 5:96260561 Dom G 3.94x10-2 1.27 (1.15-1.39) rs11958885 5:96261717 Dom G 3.94x10-2 1.26 (1.14-1.4) rs2419316 5:96262534 Add G 3.94x10-2 1.26 (1.14-1.4) rs10159119 5:96263646 Rec C 3.94x10-2 1.26 (1.13-1.39) rs2278018 5:96263839 Dom C 3.93x10-2 1.27 (1.15-1.39) rs12535099 5:96264056 Dom G 3.93x10-2 1.27 (1.15-1.39) rs7804536 5:96265000 Dom G 3.93x10-2 1.27 (1.15-1.39) rs1206726 5:96265879 Dom T 3.93x10-2 1.26 (1.14-1.4) rs13063740 5:96267655 Add A 3.93x10-2 1.27 (1.15-1.39) rs13063584 5:96268862 Add T 3.93x10-2 1.26 (1.14-1.4) rs13068182 5:96271638 Add A 3.93x10-2 1.27 (1.15-1.41) rs35687972 5:96272420 Add A 3.93x10-2 1.3 (1.18-1.43) rs13068836 5:96273180 Add A 3.93x10-2 1.27 (1.16-1.4) rs13086597 5:96273187 Add A 3.93x10-2 1.29 (1.17-1.42) rs4269103 5:96273298 Add C 3.93x10-2 1.29 (1.17-1.42)

168

rs73170251 5:96273767 Add A 3.93x10-2 1.29 (1.17-1.42) rs73170252 5:96274223 Add A 3.93x10-2 1.26 (1.14-1.4) rs34420486 5:96274720 Add T 3.93x10-2 1.29 (1.17-1.42) rs34587988 5:96275154 Add G 3.93x10-2 1.28 (1.16-1.41) rs35614865 5:96275166 Add G 3.93x10-2 1.3 (1.18-1.43) rs34776738 5:96275186 Add T 3.93x10-2 1.28 (1.16-1.41) rs11714078 5:96275201 Add C 3.93x10-2 1.29 (1.17-1.43) rs11706286 5:96275413 Add C 3.93x10-2 1.29 (1.17-1.42) rs34852778 5:96276386 Add A 3.93x10-2 1.29 (1.17-1.42) rs58146266 5:96276395 Add A 3.93x10-2 1.29 (1.17-1.42) rs11707962 5:96276877 Add C 3.93x10-2 1.27 (1.15-1.4) rs11711604 5:96277721 Add G 3.93x10-2 1.29 (1.17-1.42) rs10865943 5:96279053 Add T 3.93x10-2 1.29 (1.17-1.42) rs2278019 5:96279490 Dom G 3.93x10-2 1.29 (1.17-1.42) rs28659973 5:96281043 Dom A 3.93x10-2 1.29 (1.17-1.42) rs12522639 5:96281402 Dom C 3.93x10-2 1.29 (1.17-1.42)

169

rs10040809 5:96281469 Add C 3.93x10-2 1.26 (1.13-1.39)

rs233918 5:96281662 Dom G 3.93x10-2 1.29 (1.17-1.42)

rs693712 5:96283821 Dom C 3.93x10-2 1.26 (1.14-1.4) rs79902674 5:96284803 Add C 3.93x10-2 1.26 (1.14-1.4) rs6970147 5:96284892 Dom G 3.93x10-2 1.27 (1.15-1.4) rs7809802 5:96285821 Dom A 3.93x10-2 1.27 (1.16-1.4) rs62474708 5:96286286 Dom A 3.93x10-2 1.27 (1.16-1.4) rs12538263 5:96286969 Dom A 3.93x10-2 1.26 (1.13-1.4) rs10246845 5:96288138 Dom A 3.93x10-2 1.25 (1.12-1.39) rs1030969 5:96288960 Rec C 3.93x10-2 1.28 (1.16-1.42) rs71409368 5:96290230 Add G 3.93x10-2 1.28 (1.16-1.42) rs2074651 5:96290647 Add C 3.93x10-2 1.28 (1.16-1.41) rs2614277 5:96293006 Add A 3.92x10-2 1.28 (1.16-1.42) rs2303208 5:96293153 Dom A 3.92x10-2 1.29 (1.17-1.42) rs12534695 5:96293816 Dom A 3.92x10-2 1.29 (1.17-1.42) rs12539668 5:96293929 Dom T 3.92x10-2 1.29 (1.17-1.42)

170

rs17164419 5:96295121 Dom A 3.92x10-2 1.29 (1.17-1.42) rs12534013 5:96295810 Dom A 3.92x10-2 1.28 (1.16-1.42) rs56140431 5:96297527 Dom G 3.92x10-2 1.27 (1.15-1.4) rs7793742 5:96298758 Dom G 3.92x10-2 1.29 (1.17-1.42) rs10434708 5:96301142 Dom A 3.91x10-2 1.25 (1.13-1.39) rs79758729 5:96303148 Dom G 3.91x10-2 1.25 (1.13-1.39) rs2244745 5:96303698 Add T 3.91x10-2 1.25 (1.12-1.39) rs4377782 5:96307158 Rec A 3.91x10-2 1.26 (1.13-1.4) rs10434709 5:96307612 Dom T 3.90x10-2 1.25 (1.13-1.39) rs4821114 5:96307636 Dom C 3.90x10-2 1.26 (1.13-1.4)

rs233916 5:96313108 Dom A 3.89x10-2 1.26 (1.13-1.4)

rs233939 5:96314230 Dom G 3.89x10-2 1.31 (1.17-1.48) rs10044906 5:96314502 Dom G 3.88x10-2 1.26 (1.14-1.4) rs7801092 5:96316758 Dom A 3.88x10-2 1.34 (1.19-1.51) rs7712833 5:96318145 Dom A 3.88x10-2 1.34 (1.19-1.51)

rs158346 5:96319491 Add T 3.88x10-2 1.26 (1.14-1.4)

171

rs56197090 5:96319607 Dom A 3.87x10-2 1.34 (1.19-1.51)

rs10062292 5:96319930 Dom A 3.87x10-2 1.26 (1.14-1.4)

rs6893256 5:96320411 Dom C 3.87x10-2 1.34 (1.19-1.51)

rs9369183 5:96320495 Rec T 3.87x10-2 1.34 (1.19-1.51)

rs4644041 5:96320586 Rec C 3.87x10-2 1.34 (1.19-1.51) rs112999567 5:96321887 Dom G 3.87x10-2 1.32 (1.17-1.48)

rs12516397 5:96322136 Dom A 3.86x10-2 1.34 (1.19-1.51)

rs5754344 5:96322419 Dom G 3.86x10-2 1.34 (1.19-1.51) rs190793737 5:96323280 Dom T 3.86x10-2 1.26 (1.14-1.4)

rs11102651 5:96323503 Add C 3.86x10-2 1.26 (1.14-1.4)

rs6767892 5:96324199 Add A 3.85x10-2 1.26 (1.14-1.4)

rs233910 5:96325101 Dom T 3.85x10-2 0.75 (0.66-0.85)

rs4626412 5:96325109 Rec C 3.85x10-2 0.75 (0.66-0.85)

rs12485367 5:96327138 Add G 3.85x10-2 1.34 (1.19-1.51)

rs12516666 5:96327289 Dom A 3.85x10-2 1.31 (1.17-1.48)

rs17630235 5:96327663 Add A 3.85x10-2 1.26 (1.13-1.39)

172

rs4821104 5:96330302 Dom G 3.85x10-2 1.26 (1.13-1.4)

rs2237661 5:96330966 Add C 3.84x10-2 1.34 (1.19-1.51)

rs9906843 5:96333334 Rec C 3.84x10-2 1.26 (1.13-1.4) rs116964597 5:96334558 Add G 3.84x10-2 1.32 (1.17-1.48)

rs17132288 5:96335350 Add T 3.84x10-2 1.26 (1.13-1.4)

rs10019217 5:96336791 Add T 3.84x10-2 1.34 (1.19-1.51)

rs483499 5:96337649 Dom C 3.84x10-2 1.26 (1.13-1.39)

rs11627551 5:96337790 Rec G 3.83x10-2 1.31 (1.18-1.44)

rs72771042 5:96339273 Dom C 3.82x10-2 1.26 (1.13-1.39)

rs17150854 5:96339488 Dom G 3.82x10-2 1.29 (1.17-1.42)

rs13402932 5:96340616 Dom T 3.82x10-2 1.26 (1.14-1.4)

rs16849932 5:96343552 Dom A 3.82x10-2 1.3 (1.18-1.43)

rs1581809 5:96345739 Rec C 3.82x10-2 1.27 (1.15-1.4)

rs13190001 5:96346278 Rec T 3.81x10-2 1.29 (1.17-1.42)

rs7006328 5:96347775 Rec A 3.81x10-2 1.27 (1.16-1.4)

rs4143851 5:96350088 Rec G 3.81x10-2 1.29 (1.17-1.42)

173

rs56328476 5:96353223 Add C 3.80x10-2 1.28 (1.16-1.4)

rs12907667 5:96355448 Add T 3.80x10-2 1.27 (1.16-1.4)

rs6903048 5:96355603 Rec T 3.80x10-2 1.27 (1.16-1.4)

rs2394483 5:96357178 Add A 3.80x10-2 1.29 (1.17-1.42)

rs11241340 5:96358687 Dom A 3.80x10-2 1.29 (1.17-1.42)

rs9380941 5:96362800 Rec C 3.80x10-2 1.29 (1.17-1.42)

rs76782785 5:96363407 Dom G 3.79x10-2 1.29 (1.17-1.42) rs190735379 5:96364063 Dom C 3.79x10-2 1.27 (1.16-1.4)

rs170030 5:96364454 Add G 3.79x10-2 1.29 (1.17-1.43)

rs2195933 5:96367408 Add T 3.79x10-2 1.29 (1.17-1.42)

rs28722874 5:96373750 Dom G 3.79x10-2 1.3 (1.18-1.44)

rs1504531 5:99323236 Dom G 3.79x10-2 0.78 (0.7-0.88)

rs4774389 5:99328586 Rec G 3.76x10-2 0.78 (0.7-0.88)

rs28830569 5:99334618 Add T 3.76x10-2 0.78 (0.7-0.88)

rs6871659 5:99335604 Add C 3.75x10-2 0.78 (0.7-0.87)

rs7721944 5:99338430 Dom C 3.97x10-2 0.83 (0.75-0.9)

174

rs72769531 5:99339674 Dom T 3.97x10-2 0.83 (0.75-0.91)

rs17696519 5:99341737 Dom T 3.97x10-2 0.83 (0.75-0.9)

rs1857735 5:99341849 Dom T 3.97x10-2 0.83 (0.76-0.9)

rs233915 5:99342047 Dom G 3.97x10-2 0.82 (0.75-0.9)

rs1206736 5:99342478 Dom G 3.97x10-2 0.82 (0.75-0.9) rs142310905 5:99343552 Add A 3.98x10-2 0.83 (0.76-0.91)

rs12655858 5:99344000 Dom G 3.97x10-2 0.83 (0.75-0.9)

rs13118145 5:99347065 Add C 3.97x10-2 0.83 (0.75-0.9)

rs482160 5:99349315 Add A 5.46x10-5 0.83 (0.76-0.91)

rs11098659 5:99351584 Add C 4.86x10-5 0.84 (0.77-0.92)

rs547268 5:99351666 Add G 4.86x10-5 0.83 (0.76-0.91)

rs16939895 5:99352463 Add A 4.81x10-5 0.83 (0.76-0.91)

rs12499753 5:99364014 Add C 4.65x10-5 0.83 (0.76-0.91)

rs8091566 5:99364178 Add G 4.64x10-5 0.83 (0.76-0.91)

rs658158 5:99364598 Add T 4.39x10-5 0.83 (0.76-0.91)

rs534911 5:99365582 Add G 3.86x10-5 0.83 (0.76-0.9)

175

rs514000 5:99365958 Add C 3.77x10-5 0.83 (0.76-0.91) rs2069763 5:99366276 Add A 5.91x10-5 0.83 (0.76-0.91) rs6816311 5:99366350 Add C 5.86x10-5 0.83 (0.76-0.91) rs1383048 5:99369490 Add C 3.75x10-5 0.83 (0.76-0.91)

rs484020 5:99370207 Add G 3.59x10-5 0.83 (0.76-0.91) rs9996350 5:99372610 Add C 3.31x10-5 0.83 (0.76-0.91) rs72669154 5:99374569 Add T 3.27x10-5 0.83 (0.76-0.91) rs7696237 5:99377741 Add T 3.22x10-5 0.83 (0.76-0.91) rs4833823 5:99383586 Add G 3.20x10-5 0.83 (0.76-0.91) rs1824969 5:99384252 Add A 3.20x10-5 0.83 (0.76-0.91) rs1960859 5:99384831 Add C 3.20x10-5 0.83 (0.76-0.91) rs1121242 5:99385089 Add A 3.20x10-5 0.82 (0.75-0.9) rs4380538 5:99386517 Add T 3.20x10-5 0.83 (0.76-0.9) rs72698115 5:99387066 Dom C 2.95x10-5 0.83 (0.76-0.91) rs11728796 5:99387360 Add G 2.95x10-5 0.82 (0.75-0.89) rs13122023 5:99387658 Add C 2.95x10-5 0.83 (0.76-0.91)

176

rs7684187 5:99388170 Add G 2.95x10-5 0.83 (0.76-0.91) rs13145929 5:99388523 Add G 2.95x10-5 0.83 (0.76-0.91) rs10027390 5:99388803 Add C 2.95x10-5 0.83 (0.76-0.91) rs1479924 5:99388920 Add G 2.95x10-5 0.83 (0.76-0.91) rs11725823 5:99389071 Add C 2.95x10-5 0.83 (0.76-0.91)

rs612058 5:99398396 Add T 2.95x10-5 0.83 (0.76-0.9) rs13108723 5:99400751 Add A 2.94x10-5 0.83 (0.75-0.9) rs6823186 5:99404110 Add T 2.94x10-5 0.83 (0.75-0.91) rs11575812 5:99406620 Add G 2.94x10-5 0.83 (0.76-0.91) rs2069776 5:99407901 Add G 2.94x10-5 0.83 (0.76-0.91) rs4438772 5:99408424 Add A 2.94x10-5 0.83 (0.76-0.91) rs7241016 5:99409253 Add G 2.94x10-5 0.83 (0.76-0.91)

rs657555 5:99413565 Add C 2.88x10-5 0.83 (0.76-0.91) rs4833830 5:99414158 Add G 2.84x10-5 0.83 (0.76-0.91) rs6814718 5:99416314 Add T 2.76x10-5 0.83 (0.76-0.91) rs13143866 5:99416507 Add A 2.76x10-5 0.83 (0.75-0.91)

177

rs487273 5:99416952 Add T 2.69x10-5 0.83 (0.76-0.91)

rs515151 5:99420626 Add G 2.69x10-5 0.82 (0.75-0.9) rs148505069 5:99422325 Add G 2.68x10-5 0.83 (0.75-0.91) rs138582043 5:99422361 Dom T 2.67x10-5 0.83 (0.75-0.9)

rs35077420 5:99423066 Add A 2.61x10-5 0.83 (0.76-0.91)

rs11724582 5:99423303 Add G 2.61x10-5 0.83 (0.76-0.91)

rs11875687 5:99424756 Add C 2.61x10-5 0.83 (0.76-0.91)

rs6849238 5:99425682 Add A 2.55x10-5 0.83 (0.76-0.91)

rs72696301 5:99427143 Dom C 2.54x10-5 0.83 (0.76-0.91)

rs4853459 5:99429393 Add T 2.54x10-5 0.83 (0.76-0.91)

rs6854504 5:99429785 Add G 2.54x10-5 0.82 (0.75-0.9)

rs13144509 5:99430384 Add C 2.54x10-5 0.83 (0.76-0.91)

rs11736927 5:99433410 Add C 2.54x10-5 0.83 (0.76-0.91)

rs4572894 5:99434080 Add G 2.54x10-5 0.83 (0.76-0.91)

rs7662182 5:99435027 Add G 2.54x10-5 0.83 (0.76-0.91) rs144111494 5:99437487 Dom T 2.49x10-5 0.83 (0.76-0.91)

178

rs579052 5:99437782 Add T 2.43x10-5 0.82 (0.75-0.9)

rs58548028 5:99437871 Dom A 2.39x10-5 0.83 (0.76-0.91) rs111810442 5:99445397 Dom G 2.39x10-5 0.83 (0.76-0.91)

rs73026617 5:99446345 Dom T 2.39x10-5 0.83 (0.76-0.91)

rs4853458 5:99451233 Add A 2.39x10-5 0.83 (0.76-0.91) rs139605600 5:99451954 Add T 2.39x10-5 0.83 (0.76-0.91)

rs10212786 5:99455354 Add G 2.39x10-5 0.83 (0.76-0.91)

rs9651053 5:99456186 Dom A 2.39x10-5 0.83 (0.76-0.91)

rs9651036 5:99456551 Dom A 2.39x10-5 0.83 (0.76-0.91)

rs9651055 5:99456900 Dom G 2.39x10-5 0.83 (0.76-0.91) rs111920902 5:99463767 Dom T 2.39x10-5 0.83 (0.76-0.91)

rs12026876 5:99465158 Dom A 2.39x10-5 0.83 (0.76-0.91) rs151220053 5:99465564 Dom T 2.39x10-5 0.83 (0.76-0.91)

rs11265608 5:99471222 Dom A 2.39x10-5 0.83 (0.76-0.91)

rs12033701 5:99472683 Dom T 2.39x10-5 0.83 (0.76-0.91) rs113057497 5:99472901 Dom T 2.26x10-5 0.83 (0.76-0.91)

179

rs9959425 5:99479651 Add C 2.26x10-5 0.83 (0.76-0.91) rs111908494 5:99479714 Dom G 2.17x10-5 0.83 (0.76-0.91) rs113639721 5:99479977 Dom C 2.17x10-5 0.83 (0.76-0.91)

rs4274624 5:99483182 Add C 2.17x10-5 0.83 (0.76-0.91)

rs62322747 5:99489038 Add G 2.17x10-5 0.83 (0.76-0.91)

rs6916321 5:99490269 Add A 2.17x10-5 0.83 (0.76-0.91)

rs7234029 5:99492606 Add G 1.78x10-5 0.83 (0.76-0.91)

rs8083786 5:99500554 Add G 1.62x10-5 0.83 (0.76-0.91)

rs11889341 5:99503303 Add T 1.57x10-5 0.83 (0.76-0.91)

rs34846641 5:99507580 Add G 8.22x10-6 0.83 (0.76-0.91)

rs60751993 5:99507641 Add A 5.81x10-6 0.83 (0.76-0.91)

rs60474474 5:99509569 Add T 3.79x10-6 0.83 (0.76-0.91)

rs60735058 5:99520575 Add A 3.72x10-6 0.83 (0.76-0.91)

rs11663253 5:99522095 Add G 3.59x10-6 0.83 (0.76-0.91)

rs45450798 5:99524639 Add G 2.92x10-6 0.83 (0.76-0.91)

rs2014857 5:99527579 Add C 6.12x10-7 0.83 (0.76-0.91)

180

rs2542148 5:99528892 Add C 5.62x10-7 0.83 (0.76-0.91)

rs888270 5:99532806 Add A 5.56x10-7 0.83 (0.76-0.91) rs2847260 5:99534681 Add C 5.56x10-7 0.83 (0.76-0.91) rs2542147 5:99537356 Add G 5.56x10-7 0.83 (0.76-0.91) rs7237497 5:99556442 Add T 5.56x10-7 0.83 (0.76-0.91) rs2847274 5:99565298 Add T 5.56x10-7 0.83 (0.76-0.91) rs2847278 5:99570547 Add C 5.56x10-7 0.83 (0.76-0.91) rs2542149 5:99646368 Add G 5.56x10-7 0.83 (0.76-0.91) rs2847280 5:99649286 Add A 5.56x10-7 0.83 (0.76-0.91) rs2542150 5:99652649 Add G 5.56x10-7 0.83 (0.76-0.91) rs2542151 5:99656064 Add G 5.56x10-7 0.82 (0.75-0.9) rs1230666 5:99659858 Add A 3.70x10-7 0.83 (0.76-0.91) rs6679677 5:99660694 Add A 1.57x10-10 0.83 (0.76-0.91) rs2476601 5:99664433 Add A 1.46x10-10 0.83 (0.76-0.91) rs10271425 5:99664822 Dom T 3.60x10-2 0.83 (0.76-0.91) rs6780601 5:99666281 Add A 3.59x10-2 0.83 (0.76-0.91)

181

rs1030968 5:111481696 Rec G 3.59x10-2 0.81 (0.74-0.89) rs112361410 5:118154368 Dom G 3.59x10-2 1.55 (1.28-1.87)

rs11811440 5:120626646 Add A 3.59x10-2 1.98 (1.4-2.81)

rs11806703 5:131336105 Add T 3.59x10-2 1.15 (1.08-1.23)

rs76461783 5:131340032 Dom A 3.59x10-2 1.15 (1.08-1.23)

rs77049234 5:131343017 Add A 3.59x10-2 1.15 (1.08-1.23)

rs2266961 5:131347520 Dom G 3.59x10-2 1.16 (1.09-1.24) rs151122832 5:131400433 Dom C 3.59x10-2 1.17 (1.1-1.25)

rs2549798 5:131401845 Dom A 3.58x10-2 1.17 (1.1-1.25)

rs4414739 5:131402738 Dom T 3.58x10-2 1.17 (1.1-1.25)

rs4846819 5:131404093 Dom C 3.57x10-2 1.38 (1.22-1.57)

rs2615132 5:131406433 Dom C 3.57x10-2 1.17 (1.1-1.25)

rs4730235 5:131407493 Add C 3.57x10-2 1.17 (1.1-1.25)

rs5998509 5:131408842 Dom T 3.57x10-2 1.18 (1.09-1.28)

rs6883436 5:131410879 Dom T 3.57x10-2 1.19 (1.1-1.29)

rs3127511 5:131415436 Add G 3.57x10-2 1.19 (1.1-1.29)

182

rs1474654 5:131418948 Add G 3.57x10-2 1.17 (1.1-1.25)

rs6669008 5:131420249 Dom G 3.57x10-2 1.17 (1.1-1.25)

rs9885251 5:131421190 Dom C 3.57x10-2 1.17 (1.1-1.25)

rs1474655 5:131436217 Add C 3.56x10-2 1.17 (1.1-1.24)

rs2850617 5:131436486 Dom A 3.56x10-2 1.16 (1.09-1.24)

rs61820570 5:131462836 Add T 3.56x10-2 1.17 (1.1-1.25)

rs10064534 5:131462918 Dom A 3.56x10-2 1.17 (1.1-1.25) rs117419203 5:131466629 Add A 3.56x10-2 1.18 (1.09-1.27) rs138665726 5:131485383 Dom C 3.56x10-2 1.17 (1.1-1.25)

rs4878809 5:131486284 Dom A 3.56x10-2 1.17 (1.1-1.24)

rs62221570 5:131495729 Add G 3.56x10-2 1.17 (1.1-1.24)

rs7788330 5:131496134 Add T 3.55x10-2 1.17 (1.1-1.24)

rs66611914 5:131496375 Dom A 3.55x10-2 1.18 (1.1-1.25) rs151315185 5:131508017 Dom T 3.55x10-2 1.17 (1.1-1.25)

rs5997641 5:131516531 Add A 3.55x10-2 1.17 (1.1-1.24) rs111262661 5:131521295 Dom A 3.55x10-2 1.17 (1.1-1.24)

183

rs59365894 5:131524299 Dom G 3.75x10-2 1.17 (1.1-1.24) rs9654526 5:131530441 Dom C 3.55x10-2 1.17 (1.1-1.24) rs73065474 5:131534381 Dom T 3.55x10-2 1.17 (1.1-1.24) rs10265270 5:131534499 Dom C 3.55x10-2 1.17 (1.1-1.24) rs12719222 5:131535125 Dom G 3.55x10-2 1.17 (1.1-1.24)

rs256781 5:131536753 Add A 3.55x10-2 1.17 (1.1-1.25) rs62221569 5:131537860 Add A 3.55x10-2 1.17 (1.1-1.24) rs2223582 5:131541363 Dom C 3.53x10-2 1.17 (1.1-1.24) rs73711697 5:131544466 Dom T 3.53x10-2 1.17 (1.1-1.24) rs13437472 5:131545378 Dom A 3.53x10-2 1.17 (1.09-1.24) rs9296324 5:131545387 Rec A 3.53x10-2 1.17 (1.09-1.24) rs1583387 5:131546868 Rec A 3.53x10-2 1.17 (1.1-1.24) rs1930999 5:131547271 Dom A 3.53x10-2 1.17 (1.1-1.24) rs9952058 5:131552385 Rec A 3.53x10-2 1.17 (1.1-1.24) rs62482499 5:131553340 Add G 3.52x10-2 1.17 (1.1-1.24) rs4454230 5:131556174 Dom T 3.75x10-2 1.17 (1.09-1.24)

184

rs2679749 5:131556203 Add T 3.75x10-2 1.16 (1.09-1.24)

rs6582606 5:131570896 Rec A 3.75x10-2 1.27 (1.14-1.42)

rs11853349 5:131573529 Rec G 3.75x10-2 1.27 (1.13-1.41)

rs561 5:131575932 Add A 3.75x10-2 1.27 (1.14-1.42)

rs233909 5:131576737 Dom T 3.75x10-2 1.27 (1.14-1.42)

rs10903119 5:131578637 Dom A 3.74x10-2 1.28 (1.15-1.43)

rs12122588 5:131582356 Rec G 3.74x10-2 1.27 (1.14-1.42) rs114786190 5:131585958 Add C 3.74x10-2 1.28 (1.14-1.42)

rs10908377 5:131586598 Add T 3.73x10-2 1.27 (1.14-1.42)

rs2266963 5:131590387 Dom G 3.73x10-2 1.29 (1.15-1.46)

rs5749502 5:131591725 Dom A 3.73x10-2 1.27 (1.14-1.42)

rs6496489 5:131592405 Rec T 3.73x10-2 1.27 (1.14-1.42)

rs12484550 5:131597005 Dom T 3.72x10-2 1.29 (1.15-1.44)

rs6868302 5:131600187 Dom A 3.72x10-2 1.29 (1.15-1.44)

rs173055 5:131607402 Dom G 3.72x10-2 1.29 (1.15-1.44)

rs76050072 5:131623358 Dom A 3.72x10-2 1.16 (1.09-1.24)

185

rs5749495 5:131638324 Dom G 3.72x10-2 1.16 (1.09-1.24)

rs77300190 5:131652529 Dom G 3.72x10-2 1.16 (1.09-1.23)

rs74416810 5:131672657 Dom A 3.72x10-2 1.17 (1.1-1.25)

rs7714247 5:131676320 Dom T 3.72x10-2 1.17 (1.1-1.25)

rs1581811 5:131677047 Rec G 3.72x10-2 1.16 (1.09-1.24) rs112919320 5:131677642 Dom C 3.72x10-2 1.16 (1.09-1.24)

rs982447 5:131686146 Add C 3.72x10-2 1.16 (1.09-1.24)

rs320359 5:131694077 Rec G 3.72x10-2 1.16 (1.09-1.23) rs111282327 5:131705458 Add C 3.72x10-2 1.29 (1.16-1.44)

rs77523594 5:131707429 Dom A 3.70x10-2 1.29 (1.16-1.43)

rs9548880 5:131708877 Add T 3.70x10-2 1.16 (1.09-1.24)

rs74988433 5:131710399 Dom T 3.70x10-2 1.29 (1.16-1.43)

rs3127513 5:131717050 Add T 3.70x10-2 1.16 (1.09-1.24)

rs3127514 5:131744482 Add A 3.70x10-2 1.27 (1.13-1.43)

rs3127515 5:131770805 Add G 3.70x10-2 1.31 (1.16-1.47)

rs77200985 5:131778452 Dom C 3.70x10-2 1.31 (1.16-1.47)

186

rs78369415 5:131784393 Dom C 3.70x10-2 1.31 (1.16-1.47)

rs613123 5:131785684 Rec C 3.70x10-2 1.31 (1.17-1.48) rs149518322 5:131786595 Rec T 3.70x10-2 1.31 (1.17-1.48)

rs2277350 5:131787137 Rec C 3.70x10-2 1.16 (1.09-1.24)

rs7519937 5:131790616 Dom C 3.52x10-2 0.82 (0.75-0.9)

rs704250 5:131793286 Add T 3.51x10-2 1.3 (1.15-1.46) rs188470344 5:131796163 Dom C 3.51x10-2 1.16 (1.09-1.24)

rs6918708 5:131796809 Dom G 3.51x10-2 1.16 (1.09-1.23)

rs17153981 5:131796922 Add G 3.51x10-2 0.81 (0.74-0.89)

rs62474677 5:131797547 Dom C 3.51x10-2 0.82 (0.74-0.89)

rs4714315 5:131798487 Rec G 3.51x10-2 1.16 (1.09-1.23)

rs6808463 5:131799012 Add T 3.51x10-2 1.34 (1.18-1.53)

rs4587 5:131799961 Add T 3.51x10-2 1.16 (1.09-1.23) rs112657897 5:131800750 Dom A 3.70x10-2 1.16 (1.08-1.23)

rs62482503 5:131801947 Add G 3.75x10-2 1.16 (1.09-1.23)

rs41309367 5:131804347 Add C 3.70x10-2 1.16 (1.09-1.23)

187

rs2278596 5:131811182 Rec T 3.69x10-2 1.16 (1.08-1.23)

rs35963943 5:131813219 Add A 3.69x10-2 0.87 (0.81-0.93)

rs34102671 5:131819921 Dom A 3.69x10-2 0.87 (0.81-0.92)

rs1575763 5:131825842 Rec A 3.69x10-2 0.87 (0.81-0.93)

rs4730220 5:131826322 Add G 3.69x10-2 1.31 (1.16-1.5) rs112149564 5:131826413 Add A 3.69x10-2 1.31 (1.16-1.5)

rs7134838 5:131827775 Rec C 3.69x10-2 0.87 (0.81-0.93) rs192221471 5:131832514 Dom A 3.68x10-2 0.87 (0.81-0.93)

rs11980030 5:157953813 Dom G 3.68x10-2 1.7 (1.32-2.2)

rs1078634 5:157955355 Add T 3.68x10-2 1.72 (1.33-2.21)

rs74463105 5:157958432 Add A 3.68x10-2 1.72 (1.33-2.22)

rs10946885 5:157958760 Add G 3.68x10-2 1.72 (1.33-2.22)

rs12134915 5:158610855 Rec A 3.68x10-2 0.85 (0.78-0.92)

rs2290546 5:158613789 Add C 3.68x10-2 0.85 (0.78-0.92)

rs4436066 5:158625204 Dom G 3.68x10-2 0.85 (0.78-0.92)

rs73166630 5:158637996 Dom A 3.68x10-2 0.84 (0.77-0.91)

188

rs4821116 5:172018540 Dom T 3.68x10-2 1.57 (1.27-1.96)

rs149526 5:175919709 Add C 3.67x10-2 1.4 (1.2-1.63) rs9621715 5:178620316 Dom A 3.67x10-2 3.36 (1.95-5.79) rs5754234 5:180486785 Dom T 3.67x10-2 1.43 (1.23-1.67) rs10052310 6:3711871 Dom T 3.67x10-2 1.44 (1.23-1.69) rs4389662 6:3713222 Dom T 3.67x10-2 1.45 (1.24-1.7)

rs794530 6:3718361 Dom G 3.67x10-2 1.44 (1.23-1.69) rs1575762 6:16814729 Rec C 3.67x10-2 1.22 (1.11-1.34) rs62221572 6:16821679 Add C 3.67x10-2 1.22 (1.11-1.34) rs13224182 6:18511725 Dom T 3.67x10-2 1.25 (1.13-1.38) rs12659105 6:19878461 Dom T 3.67x10-2 0.75 (0.65-0.86) rs1974871 6:23439723 Dom T 3.66x10-2 1.57 (1.2-2.05) rs10057397 6:23634097 Dom C 3.66x10-2 0.75 (0.66-0.85) rs77563005 6:23635503 Dom A 3.66x10-2 0.75 (0.66-0.85) rs10232396 6:23639342 Dom C 3.65x10-2 0.75 (0.66-0.86) rs1444585 6:23645706 Rec A 3.65x10-2 0.73 (0.63-0.84)

189

rs7307585 6:23646647 Rec T 3.65x10-2 0.72 (0.63-0.83) rs7306110 6:23646760 Rec T 3.65x10-2 0.72 (0.63-0.83) rs1444588 6:23648347 Rec T 3.65x10-2 0.73 (0.63-0.84) rs1444587 6:23648392 Rec C 3.65x10-2 0.73 (0.63-0.84) rs1444586 6:26410800 Rec C 3.65x10-2 0.86 (0.81-0.92)

rs717781 6:26415637 Rec C 3.65x10-2 0.86 (0.81-0.92) rs6582608 6:26421392 Rec C 3.65x10-2 0.86 (0.81-0.92)

rs669311 6:26422260 Add T 3.65x10-2 0.86 (0.81-0.92) rs12995923 6:26449219 Add G 3.65x10-2 1.32 (1.17-1.5) rs6569773 6:26455811 Dom C 3.65x10-2 0.86 (0.8-0.92) rs5754166 6:26463321 Dom T 3.65x10-2 0.86 (0.8-0.91) rs13419945 6:26464789 Dom C 3.64x10-2 1.28 (1.18-1.38) rs4274063 6:26470862 Add G 3.64x10-2 1.22 (1.13-1.31) rs7703361 6:26475016 Dom T 3.63x10-2 1.22 (1.13-1.31) rs41295113 6:26478909 Add A 3.63x10-2 1.22 (1.13-1.31) rs34713051 6:26479891 Add G 3.63x10-2 1.21 (1.12-1.31)

190

rs11990686 6:26484330 Dom G 3.63x10-2 1.21 (1.12-1.31)

rs10515294 6:26489006 Dom G 3.63x10-2 1.23 (1.14-1.33)

rs6709270 6:26511805 Add A 3.63x10-2 1.2 (1.11-1.29)

rs3859579 6:26514771 Add A 3.63x10-2 1.19 (1.11-1.29)

rs12148781 6:26520767 Add A 3.62x10-2 1.2 (1.11-1.29)

rs7710010 6:26540683 Dom C 3.62x10-2 1.22 (1.13-1.32)

rs73166619 6:26550288 Dom T 3.62x10-2 1.2 (1.11-1.29)

rs12518193 6:26555289 Dom G 3.61x10-2 1.21 (1.12-1.31) rs139527258 6:26582414 Dom G 3.60x10-2 1.22 (1.12-1.32)

rs7790080 6:26583366 Add A 3.51x10-2 0.86 (0.8-0.91) rs149205336 6:26584526 Dom G 3.51x10-2 0.85 (0.8-0.91)

rs2461213 6:26590249 Add T 3.51x10-2 1.17 (1.1-1.25)

rs1444589 6:26590801 Rec C 3.51x10-2 0.86 (0.8-0.91)

rs6575450 6:26591074 Dom T 3.51x10-2 0.86 (0.8-0.92) rs187950550 6:26592853 Dom T 3.51x10-2 0.86 (0.8-0.91)

rs797014 6:26593471 Dom G 3.51x10-2 0.86 (0.8-0.91)

191

rs11196017 6:26594033 Add A 3.50x10-2 1.19 (1.1-1.28)

rs5754100 6:26595168 Dom C 3.50x10-2 0.86 (0.8-0.91)

rs11830509 6:26595267 Rec C 3.49x10-2 1.17 (1.1-1.25)

rs62008307 6:26595427 Add A 3.48x10-2 0.86 (0.8-0.91)

rs7788271 6:26595446 Add G 3.48x10-2 1.17 (1.1-1.25) rs183009180 6:26597333 Dom T 3.48x10-2 1.17 (1.1-1.25)

rs9326976 6:26597893 Dom A 3.48x10-2 0.86 (0.8-0.91)

rs72682406 6:26597924 Dom C 3.48x10-2 1.17 (1.1-1.25)

rs11634267 6:26598188 Add T 3.47x10-2 0.86 (0.8-0.91)

rs6434435 6:26603259 Add A 3.47x10-2 1.17 (1.09-1.24) rs113575223 6:26603417 Dom C 3.47x10-2 1.17 (1.09-1.24)

rs9383211 6:26604140 Add A 3.47x10-2 1.17 (1.1-1.25)

rs1365469 6:26604650 Dom C 3.47x10-2 0.86 (0.8-0.92)

rs2147926 6:26606512 Rec C 3.47x10-2 1.17 (1.09-1.25)

rs10244223 6:26606579 Dom A 3.46x10-2 1.17 (1.09-1.24)

rs972259 6:26608261 Rec C 3.46x10-2 0.86 (0.8-0.91)

192

rs10167627 6:26608325 Dom A 3.46x10-2 1.17 (1.09-1.25)

rs4747304 6:26614808 Rec A 3.46x10-2 0.86 (0.8-0.91)

rs1217398 6:26614951 Add C 3.45x10-2 1.18 (1.11-1.26)

rs6912933 6:26615223 Add G 3.45x10-2 0.86 (0.8-0.91)

rs12535046 6:26616259 Dom T 3.45x10-2 0.86 (0.8-0.91)

rs12972230 6:26616835 Add G 3.45x10-2 1.16 (1.09-1.24) rs112698206 6:26618276 Dom A 3.45x10-2 1.17 (1.09-1.24)

rs1040509 6:26619041 Dom T 3.45x10-2 0.86 (0.8-0.91)

rs12332175 6:26619226 Dom A 3.45x10-2 0.86 (0.8-0.91)

rs972258 6:26619328 Rec C 3.45x10-2 0.86 (0.8-0.91)

rs16970573 6:26619531 Dom C 3.45x10-2 0.86 (0.8-0.92)

rs56303780 6:26620544 Add C 3.45x10-2 0.86 (0.8-0.91)

rs4714311 6:26620894 Rec T 3.44x10-2 0.86 (0.8-0.91)

rs12706030 6:26621379 Add G 3.44x10-2 1.17 (1.09-1.24)

rs74672251 6:26622055 Dom T 3.44x10-2 1.17 (1.09-1.24)

rs9877192 6:26622734 Add G 3.44x10-2 0.86 (0.8-0.91)

193

rs7529824 6:26622769 Dom A 3.44x10-2 0.86 (0.8-0.91)

rs7777950 6:26622904 Add C 3.44x10-2 0.86 (0.8-0.91)

rs55820401 6:26623511 Dom T 3.44x10-2 0.86 (0.8-0.91)

rs59391722 6:26623996 Dom C 3.43x10-2 1.17 (1.09-1.24)

rs11089620 6:26624822 Dom G 3.43x10-2 0.85 (0.8-0.91)

rs1465883 6:26625651 Rec T 3.43x10-2 0.82 (0.75-0.9)

rs2256609 6:26626036 Dom G 3.43x10-2 0.85 (0.8-0.91) rs147812202 6:26627508 Dom C 3.42x10-2 0.86 (0.8-0.91)

rs813819 6:26628005 Dom C 3.42x10-2 0.86 (0.8-0.91)

rs79789371 6:26629404 Dom T 3.42x10-2 0.85 (0.8-0.91)

rs71409369 6:26630269 Add T 3.42x10-2 1.17 (1.09-1.25)

rs3095407 6:26631306 Add G 3.42x10-2 0.85 (0.8-0.91)

rs1323534 6:26632022 Dom C 3.42x10-2 1.17 (1.09-1.24)

rs159075 6:26632444 Add C 3.42x10-2 0.85 (0.8-0.91) rs142271435 6:26632457 Dom T 3.42x10-2 0.85 (0.8-0.91)

rs75890169 6:26633463 Dom A 3.42x10-2 0.85 (0.8-0.91)

194

rs78435990 6:26634432 Dom C 3.42x10-2 0.85 (0.8-0.91)

rs6892147 6:26639332 Dom A 3.42x10-2 0.86 (0.8-0.91)

rs10071340 6:26639613 Dom A 3.42x10-2 0.85 (0.8-0.91) rs141245069 6:26639777 Dom T 3.42x10-2 0.86 (0.8-0.91)

rs233907 6:26640283 Dom C 3.42x10-2 1.18 (1.11-1.26)

rs74611185 6:26640951 Dom A 3.42x10-2 0.85 (0.8-0.91)

rs6974307 6:26641060 Dom A 3.42x10-2 0.85 (0.8-0.91)

rs62474682 6:26641172 Dom T 3.42x10-2 1.17 (1.09-1.25)

rs935236 6:26641626 Rec C 3.42x10-2 0.85 (0.8-0.91)

rs935235 6:26641627 Rec A 3.42x10-2 0.85 (0.8-0.91)

rs935234 6:26643435 Rec G 3.42x10-2 0.85 (0.8-0.91)

rs11853103 6:26643879 Dom T 3.42x10-2 1.17 (1.09-1.25)

rs78760432 6:26643996 Dom T 3.42x10-2 0.85 (0.8-0.91) rs111706777 6:26644921 Dom G 3.42x10-2 1.17 (1.09-1.25) rs113769809 6:26644925 Dom C 3.42x10-2 1.18 (1.11-1.26)

rs4572972 6:26645100 Dom G 3.42x10-2 1.19 (1.1-1.28)

195

rs72769589 6:26645996 Dom A 3.42x10-2 0.86 (0.8-0.91) rs2147927 6:26646010 Rec C 3.42x10-2 1.17 (1.09-1.25) rs9402702 6:26646579 Add C 3.42x10-2 0.85 (0.8-0.91) rs62482495 6:26646714 Add G 3.42x10-2 0.85 (0.8-0.91) rs7297047 6:26647725 Rec G 3.42x10-2 1.17 (1.09-1.25) rs10880907 6:26648013 Rec T 3.42x10-2 1.17 (1.09-1.25) rs2032931 6:26648334 Add C 3.42x10-2 0.85 (0.8-0.91) rs7801646 6:26649018 Dom T 3.42x10-2 1.17 (1.09-1.25) rs11264096 6:26649421 Add C 3.42x10-2 1.17 (1.09-1.25)

rs159074 6:26650210 Add G 3.42x10-2 0.85 (0.8-0.91) rs4563598 6:26650826 Dom C 3.42x10-2 0.85 (0.8-0.91) rs1025206 6:26651809 Dom G 3.42x10-2 1.17 (1.1-1.25) rs2266959 6:26652703 Dom T 3.42x10-2 1.17 (1.1-1.25) rs1292050 6:26653166 Add C 3.42x10-2 1.19 (1.1-1.29) rs9603610 6:26655594 Dom A 3.42x10-2 1.17 (1.1-1.25) rs1893606 6:26655821 Dom A 3.42x10-2 1.17 (1.09-1.25)

196

rs9603611 6:26656890 Dom A 3.42x10-2 0.85 (0.8-0.91)

rs12595378 6:26657204 Add T 3.41x10-2 1.18 (1.11-1.27)

rs6949634 6:26665451 Add T 3.41x10-2 1.17 (1.1-1.25)

rs974476 6:26665835 Rec C 3.40x10-2 1.17 (1.1-1.25)

rs62474710 6:26670613 Dom T 3.40x10-2 0.85 (0.79-0.91)

rs77944749 6:26670969 Dom T 3.40x10-2 0.85 (0.79-0.91) rs113479298 6:26671135 Dom A 3.40x10-2 0.85 (0.79-0.9)

rs34506003 6:26676083 Add T 3.40x10-2 1.24 (1.13-1.36)

rs573741 6:26682323 Dom C 3.40x10-2 0.86 (0.8-0.92)

rs35025589 6:26705549 Dom G 3.40x10-2 1.14 (1.07-1.22)

rs4714312 6:26706544 Rec C 3.39x10-2 0.86 (0.81-0.92)

rs4351244 6:26903384 Rec C 3.39x10-2 0.87 (0.82-0.93)

rs2250526 6:26922238 Add A 3.39x10-2 0.87 (0.82-0.93)

rs2094085 6:26947474 Rec G 3.39x10-2 0.87 (0.82-0.93)

rs62221568 6:26948174 Add C 3.39x10-2 0.88 (0.82-0.93)

rs794525 6:38468887 Dom T 3.39x10-2 1.34 (1.19-1.51)

197

rs2182186 6:39028606 Rec G 3.39x10-2 3.11 (1.84-5.26) rs74424482 6:39028905 Dom G 3.39x10-2 3.12 (1.85-5.27) rs80133020 6:39030452 Dom C 3.39x10-2 3.04 (1.81-5.11) rs10169196 6:39034095 Dom C 3.39x10-2 2.91 (1.77-4.76) rs77230927 6:40125087 Dom C 3.39x10-2 1.43 (1.22-1.67) rs1000587 6:40125459 Rec G 3.39x10-2 1.4 (1.2-1.64) rs1299514 6:40166385 Add A 3.39x10-2 1.4 (1.21-1.63) rs16875623 6:40171318 Add T 3.38x10-2 1.4 (1.2-1.62) rs5754102 6:40183183 Dom A 3.38x10-2 1.38 (1.19-1.6) rs10785605 6:40184211 Rec G 3.37x10-2 1.38 (1.19-1.61) rs1292049 6:40184894 Add T 3.37x10-2 1.39 (1.2-1.61) rs4821124 6:40185078 Dom C 3.37x10-2 1.39 (1.19-1.61) rs10456103 6:40186239 Rec G 3.37x10-2 1.38 (1.19-1.6) rs2002602 6:40186546 Add C 3.37x10-2 1.38 (1.19-1.61) rs9367047 6:40186636 Rec T 3.37x10-2 1.38 (1.19-1.6) rs1454456 6:40186757 Rec C 3.37x10-2 1.38 (1.19-1.6)

198

rs4895927 6:40187223 Dom C 3.36x10-2 1.38 (1.19-1.6) rs77683665 6:40188351 Dom A 3.36x10-2 1.42 (1.23-1.65) rs7770511 6:40188352 Rec A 3.36x10-2 1.42 (1.23-1.65) rs2526358 6:40188482 Add G 3.36x10-2 1.38 (1.19-1.6) rs7691190 6:40188733 Rec T 3.36x10-2 1.38 (1.19-1.6) rs1568670 6:40189205 Rec C 3.35x10-2 1.35 (1.17-1.56) rs7631995 6:40191338 Add A 3.35x10-2 1.37 (1.18-1.6) rs4605760 6:40191579 Dom A 3.35x10-2 1.37 (1.18-1.6) rs4532340 6:40193032 Dom T 3.35x10-2 1.37 (1.18-1.59)

rs158343 6:40193960 Add G 3.35x10-2 1.36 (1.17-1.58) rs2549142 6:40194547 Dom A 3.35x10-2 1.36 (1.17-1.58) rs4476823 6:40194902 Add C 3.34x10-2 1.36 (1.17-1.58)

rs887098 6:40195566 Add A 3.33x10-2 1.36 (1.17-1.58) rs56305450 6:40195776 Dom A 3.33x10-2 1.36 (1.17-1.58) rs2273758 6:40195932 Add A 3.33x10-2 1.36 (1.17-1.58) rs10192357 6:40195954 Dom T 3.33x10-2 1.36 (1.17-1.58)

199

rs4677869 6:40196306 Dom T 3.33x10-2 1.36 (1.17-1.58)

rs705376 6:40196518 Rec A 3.33x10-2 1.36 (1.17-1.58) rs11788070 6:40196582 Rec C 3.33x10-2 1.36 (1.17-1.58) rs41295071 6:40196698 Add T 3.33x10-2 1.36 (1.17-1.58)

rs154225 6:40198529 Add T 3.32x10-2 1.36 (1.17-1.58) rs2549781 6:40198930 Dom G 3.32x10-2 1.35 (1.16-1.57) rs7005431 6:40199229 Dom A 3.32x10-2 1.36 (1.17-1.58) rs12763519 6:40200774 Add T 3.32x10-2 1.36 (1.17-1.58) rs10998340 6:40200846 Add G 3.32x10-2 1.36 (1.17-1.58) rs28379898 6:40201477 Dom G 3.31x10-2 1.36 (1.17-1.58) rs2614279 6:40202195 Add A 3.31x10-2 1.36 (1.17-1.58) rs7786966 6:40202353 Dom A 3.31x10-2 1.36 (1.17-1.58) rs7197188 6:40202503 Add C 3.30x10-2 1.36 (1.17-1.58) rs10785602 6:40202513 Rec T 3.30x10-2 1.36 (1.17-1.57) rs4768678 6:40202524 Rec C 3.30x10-2 1.36 (1.17-1.58) rs1444584 6:40202585 Rec C 3.30x10-2 1.36 (1.17-1.58)

200

rs10785604 6:40203437 Rec G 3.30x10-2 1.36 (1.17-1.57) rs72684575 6:40204685 Add A 3.30x10-2 1.35 (1.17-1.57) rs36022132 6:40205434 Add G 3.30x10-2 1.35 (1.16-1.57) rs12595382 6:40205609 Dom G 3.29x10-2 1.35 (1.17-1.57) rs79112356 6:40205686 Add A 3.29x10-2 1.35 (1.17-1.57) rs72769591 6:40205890 Dom G 3.29x10-2 1.35 (1.17-1.57) rs1230715 6:40206623 Add A 3.29x10-2 1.35 (1.16-1.57) rs11711354 6:40207153 Add C 3.29x10-2 1.35 (1.16-1.57) rs10880908 6:40209466 Rec C 3.29x10-2 1.35 (1.16-1.57) rs11855677 6:40209859 Dom A 3.28x10-2 1.35 (1.16-1.57) rs76159595 6:40210296 Add C 3.28x10-2 1.36 (1.17-1.58) rs10785603 6:40210321 Rec C 3.28x10-2 1.36 (1.17-1.58)

rs158642 6:40210341 Add G 3.28x10-2 1.36 (1.17-1.57) rs11183317 6:40210387 Rec T 3.28x10-2 1.36 (1.17-1.58) rs1550736 6:40226347 Rec C 3.28x10-2 1.36 (1.17-1.58) rs35170982 6:40227984 Add G 3.28x10-2 1.35 (1.16-1.56)

201

rs10872430 6:40233877 Add C 3.28x10-2 1.35 (1.16-1.58)

rs191318 6:40235515 Add A 3.27x10-2 1.36 (1.16-1.59) rs66614747 6:40236430 Add A 3.27x10-2 1.57 (1.28-1.93) rs2370261 6:40236613 Dom G 3.27x10-2 1.54 (1.26-1.88)

rs929294 6:44477114 Rec G 3.27x10-2 1.17 (1.09-1.26) rs9960632 6:70860725 Rec A 3.27x10-2 1.32 (1.16-1.52)

rs382082 6:81385896 Add T 3.27x10-2 0.61 (0.49-0.77) rs16970618 6:94950647 Add T 3.27x10-2 0.88 (0.82-0.94) rs72771014 6:94967014 Dom C 3.27x10-2 0.88 (0.82-0.94) rs41295081 6:94968592 Add T 3.27x10-2 0.88 (0.82-0.94) rs4260464 6:94975832 Add A 3.24x10-2 0.88 (0.82-0.94)

rs794982 6:127964225 Dom C 3.24x10-2 1.24 (1.12-1.36) rs62221567 6:127978792 Add T 3.24x10-2 1.23 (1.12-1.36) rs7782030 6:127979601 Dom C 3.24x10-2 1.23 (1.12-1.36) rs4699192 6:132299373 Add A 3.24x10-2 1.29 (1.14-1.45)

rs256780 6:132303216 Add A 3.51x10-2 1.23 (1.12-1.35)

202

rs10064647 6:132307750 Dom G 3.24x10-2 1.23 (1.11-1.35) rs8085810 6:132308229 Dom T 3.23x10-2 1.23 (1.11-1.35) rs11584465 6:132309046 Add T 3.23x10-2 1.22 (1.11-1.34)

rs166309 6:132310138 Add C 3.22x10-2 1.22 (1.11-1.35) rs10152663 6:132310410 Rec A 3.22x10-2 1.22 (1.11-1.35)

rs158345 6:132311109 Add G 3.51x10-2 1.22 (1.11-1.35) rs1820149 6:132311694 Dom A 3.51x10-2 1.22 (1.11-1.35) rs12716486 6:132319245 Dom G 3.51x10-2 1.22 (1.11-1.35) rs10078007 6:132325398 Dom A 3.51x10-2 1.23 (1.11-1.35) rs2134904 6:132330862 Dom G 3.51x10-2 1.21 (1.1-1.33) rs9357320 6:132350493 Rec C 3.51x10-2 1.22 (1.11-1.34) rs12672451 6:132352569 Add G 3.51x10-2 1.22 (1.11-1.34) rs75617662 6:132357057 Add A 3.51x10-2 1.22 (1.11-1.34) rs4267967 6:132358591 Add G 2.50x10-2 1.22 (1.11-1.35) rs9955736 6:132359178 Add C 2.50x10-2 1.22 (1.11-1.34) rs10880901 6:132359614 Rec A 2.48x10-2 1.21 (1.1-1.33)

203

rs8181861 6:132360385 Rec T 2.48x10-2 1.21 (1.1-1.33)

rs17771304 6:132360576 Add C 2.48x10-2 1.21 (1.1-1.33)

rs873233 6:132361316 Rec G 2.48x10-2 1.21 (1.1-1.33)

rs4838648 6:132361812 Add C 2.48x10-2 1.21 (1.1-1.33) rs115726191 6:132362265 Dom G 2.48x10-2 1.21 (1.1-1.33)

rs1981846 6:132362412 Dom A 2.48x10-2 1.21 (1.1-1.33)

rs726786 6:132363507 Add G 2.48x10-2 1.21 (1.1-1.33)

rs11853392 6:132364235 Rec T 2.48x10-2 1.21 (1.1-1.33)

rs12970557 6:132375483 Dom A 2.48x10-2 1.22 (1.11-1.34)

rs8083450 6:132377908 Add A 2.48x10-2 1.21 (1.11-1.33)

rs11984075 6:132380078 Dom G 2.47x10-2 1.21 (1.1-1.33) rs147957176 6:132380404 Add A 2.47x10-2 1.21 (1.1-1.33)

rs12565904 6:132405059 Rec A 2.47x10-2 1.21 (1.1-1.33)

rs10261857 6:132409903 Dom G 2.47x10-2 1.21 (1.1-1.32)

rs1370428 6:132417092 Rec A 2.47x10-2 1.21 (1.1-1.33)

rs4472368 6:132418809 Add G 2.47x10-2 1.21 (1.1-1.33)

204

rs6425124 6:132426945 Add G 2.47x10-2 1.21 (1.1-1.33)

rs27397 6:135265617 Dom T 2.47x10-2 1.14 (1.07-1.22)

rs4646868 6:135268142 Add G 2.47x10-2 1.14 (1.07-1.22)

rs3103969 6:135271946 Dom A 2.47x10-2 1.15 (1.08-1.23)

rs1322143 6:135272477 Dom T 2.47x10-2 1.15 (1.08-1.23)

rs77649404 6:135274232 Add G 2.47x10-2 1.15 (1.08-1.23)

rs78473634 6:135276696 Add G 2.47x10-2 1.15 (1.08-1.23)

rs17771736 6:135280519 Add T 2.47x10-2 1.16 (1.08-1.23)

rs10421099 6:135281795 Rec G 2.47x10-2 1.15 (1.08-1.23)

rs35786810 6:135282656 Add A 2.47x10-2 1.16 (1.09-1.23)

rs9610682 6:135624811 Dom C 2.46x10-2 1.17 (1.1-1.25)

rs73029206 6:135626348 Rec G 2.46x10-2 1.15 (1.08-1.23) rs112605625 6:135627369 Dom T 2.46x10-2 1.17 (1.1-1.25)

rs79302626 6:135627534 Dom T 2.46x10-2 1.14 (1.07-1.21)

rs1216568 6:135632625 Dom G 2.46x10-2 1.17 (1.09-1.24)

rs10931480 6:135632649 Add G 2.45x10-2 1.17 (1.09-1.24)

205

rs6498184 6:135634006 Add T 2.45x10-2 0.86 (0.8-0.92) rs10061936 6:135635100 Dom C 2.44x10-2 1.17 (1.1-1.25) rs10069361 6:135635549 Dom A 2.44x10-2 1.16 (1.09-1.24) rs12746609 6:135639644 Dom G 2.43x10-2 1.17 (1.1-1.25) rs28450989 6:135640965 Add C 2.43x10-2 1.14 (1.07-1.22) rs62482493 6:135641369 Add C 2.43x10-2 1.16 (1.08-1.23) rs61886860 6:135641417 Dom A 2.43x10-2 1.16 (1.09-1.24) rs61817579 6:135642756 Dom A 2.43x10-2 1.16 (1.09-1.24) rs10888542 6:135645203 Rec A 2.43x10-2 1.16 (1.09-1.24) rs10203807 6:135645447 Dom A 2.42x10-2 1.16 (1.09-1.24) rs2101752 6:135646235 Dom T 2.42x10-2 1.17 (1.1-1.25) rs77935513 6:135649013 Add C 2.42x10-2 1.14 (1.07-1.22) rs2940738 6:135649816 Add T 2.42x10-2 1.16 (1.09-1.23) rs6902837 6:135650266 Rec T 2.42x10-2 1.14 (1.07-1.21) rs2100028 6:135651721 Add A 2.41x10-2 1.16 (1.09-1.24) rs12901447 6:135653357 Rec G 2.39x10-2 1.15 (1.08-1.22)

206

rs742090 6:135653398 Add A 2.38x10-2 1.16 (1.09-1.23)

rs16970636 6:135653855 Add A 2.38x10-2 1.13 (1.06-1.21)

rs2591604 6:135654994 Add G 2.38x10-2 1.14 (1.07-1.21) rs141754474 6:135656252 Add A 2.37x10-2 1.18 (1.11-1.26)

rs863901 6:135658514 Rec G 2.37x10-2 1.17 (1.1-1.25)

rs6793201 6:135659194 Add C 2.37x10-2 1.17 (1.09-1.24)

rs61819423 6:135661629 Dom T 2.36x10-2 1.16 (1.09-1.23)

rs12031202 6:135662372 Add T 2.36x10-2 1.17 (1.1-1.25)

rs72695953 6:135662821 Dom G 2.35x10-2 1.14 (1.07-1.21)

rs75104221 6:135663581 Dom T 2.34x10-2 1.14 (1.07-1.21)

rs4699198 6:135664365 Add A 2.34x10-2 1.16 (1.09-1.23)

rs1885454 6:135666432 Dom G 2.33x10-2 1.16 (1.09-1.23)

rs12723023 6:135669097 Dom G 2.33x10-2 1.16 (1.09-1.23)

rs12739970 6:135673284 Dom A 2.33x10-2 1.16 (1.09-1.24)

rs5754177 6:135673292 Dom T 2.32x10-2 1.16 (1.09-1.23)

rs17462614 6:135676404 Dom T 2.32x10-2 1.18 (1.1-1.25)

207

rs10058655 6:135677202 Rec T 2.31x10-2 1.16 (1.09-1.24) rs1345880 6:135677252 Add T 2.31x10-2 1.16 (1.09-1.24) rs2940704 6:135681704 Add A 2.31x10-2 1.17 (1.1-1.25) rs6820671 6:135684623 Add G 2.31x10-2 1.16 (1.09-1.24) rs2161657 6:135687201 Dom C 2.30x10-2 1.15 (1.08-1.23) rs1983613 6:135688062 Rec T 2.29x10-2 1.16 (1.09-1.24) rs56381014 6:135689835 Add A 2.29x10-2 1.16 (1.09-1.24) rs2031611 6:135691516 Add G 2.29x10-2 1.17 (1.1-1.25) rs10166084 6:135691792 Add G 2.29x10-2 1.17 (1.09-1.25) rs12753075 6:135692671 Dom T 2.29x10-2 1.16 (1.09-1.24) rs2548529 6:135692847 Dom T 2.29x10-2 1.17 (1.1-1.25) rs4705950 6:135696597 Rec T 2.29x10-2 1.17 (1.1-1.25) rs10809042 6:135700705 Add G 2.29x10-2 1.17 (1.1-1.25) rs2498399 6:135704092 Add C 2.29x10-2 0.87 (0.82-0.93) rs2031613 6:135709760 Add C 2.28x10-2 1.17 (1.1-1.25) rs17778154 6:135710694 Add T 2.27x10-2 1.17 (1.09-1.24)

208

rs12758546 6:135715375 Dom T 2.27x10-2 1.18 (1.1-1.27) rs10422616 6:135716532 Rec C 2.26x10-2 1.18 (1.1-1.25) rs7722694 6:135718068 Dom C 2.26x10-2 1.18 (1.1-1.25) rs4440481 6:135719500 Add C 2.25x10-2 1.17 (1.09-1.24) rs2549787 6:135726613 Dom G 2.25x10-2 1.18 (1.1-1.26) rs3849750 6:135734310 Dom G 2.24x10-2 1.17 (1.09-1.26) rs2928401 6:135767554 Add G 2.24x10-2 1.16 (1.08-1.25) rs3789595 6:135776478 Dom A 2.23x10-2 1.16 (1.08-1.25) rs28498756 6:135818897 Dom A 2.23x10-2 1.16 (1.08-1.24) rs12927773 6:135827673 Add T 2.23x10-2 1.16 (1.09-1.24) rs12670688 6:148728790 Add A 2.23x10-2 1.2 (1.1-1.31) rs4940648 6:148729351 Add G 2.23x10-2 1.2 (1.1-1.31) rs2548593 6:154471682 Add G 2.23x10-2 1.15 (1.08-1.23)

rs251342 6:155534464 Dom C 2.23x10-2 1.22 (1.11-1.33) rs4142369 6:157206716 Add C 2.22x10-2 4.61 (2.36-9.03) rs4142370 7:1778225 Add C 2.22x10-2 3.1 (1.93-4.96)

209

rs1796520 7:13096591 Add C 2.22x10-2 0.74 (0.64-0.85) rs62221586 7:13110383 Add G 2.21x10-2 0.74 (0.65-0.86)

rs743564 7:13112229 Add C 2.20x10-2 0.75 (0.66-0.86) rs75602061 7:13112572 Dom T 2.19x10-2 0.77 (0.67-0.87) rs7802652 7:13116330 Dom G 2.19x10-2 0.79 (0.71-0.87) rs7860123 7:13117827 Add C 2.19x10-2 0.76 (0.66-0.86) rs4275951 7:13118225 Rec T 2.18x10-2 0.76 (0.66-0.86) rs11996310 7:13137142 Dom T 2.18x10-2 0.76 (0.66-0.87) rs4324248 7:13142485 Rec G 2.18x10-2 0.76 (0.66-0.86) rs12494675 7:22798080 Dom C 2.18x10-2 1.15 (1.08-1.23) rs2910787 7:22798531 Dom T 2.18x10-2 1.16 (1.08-1.23) rs3852206 7:22800314 Add A 2.18x10-2 1.16 (1.08-1.23) rs10421283 7:22803861 Rec G 2.18x10-2 1.14 (1.07-1.22) rs10422113 7:22805072 Rec T 2.18x10-2 1.14 (1.07-1.21) rs10423310 7:22809160 Rec C 2.18x10-2 1.16 (1.09-1.24) rs1206721 7:22809490 Dom G 3.20x10-2 1.16 (1.09-1.24)

210

rs72769593 7:22810569 Dom A 3.20x10-2 1.16 (1.09-1.24) rs72769595 7:28141220 Dom C 3.20x10-2 1.3 (1.15-1.47) rs12902285 7:29344681 Add T 3.19x10-2 2.12 (1.42-3.16) rs34725611 7:37407510 Add G 3.18x10-2 1.27 (1.13-1.43) rs72769561 7:37407555 Dom A 3.18x10-2 1.27 (1.13-1.43) rs6958096 7:37407606 Dom T 3.17x10-2 1.27 (1.13-1.43) rs2179780 7:37407849 Add G 3.17x10-2 1.27 (1.13-1.43) rs10259888 7:37408401 Dom C 3.17x10-2 1.27 (1.13-1.43) rs2089855 7:37408654 Rec G 3.17x10-2 1.27 (1.13-1.43) rs10853455 7:37408769 Dom T 3.16x10-2 1.27 (1.13-1.43) rs13197384 7:37408774 Add A 3.16x10-2 1.27 (1.13-1.43) rs2018365 7:37412964 Add A 3.16x10-2 1.27 (1.13-1.42) rs4532339 7:37418454 Dom T 3.16x10-2 1.27 (1.13-1.42) rs2757635 7:37421401 Add T 3.16x10-2 1.27 (1.13-1.42) rs11085727 7:37421584 Add T 3.16x10-2 1.27 (1.13-1.42) rs72769582 7:37423642 Dom C 3.15x10-2 1.27 (1.13-1.42)

211

rs72771008 7:37427289 Dom C 3.15x10-2 1.28 (1.14-1.43)

rs62482507 7:37427351 Add G 3.15x10-2 1.27 (1.14-1.43)

rs61543586 7:37431317 Dom A 3.15x10-2 1.28 (1.15-1.44)

rs2614255 7:37431559 Add C 3.15x10-2 1.28 (1.14-1.44)

rs12212302 7:37433537 Add G 3.15x10-2 1.28 (1.14-1.43)

rs1206719 7:37436695 Dom C 3.15x10-2 1.28 (1.14-1.43)

rs6978038 7:37436854 Add C 3.15x10-2 1.27 (1.14-1.43)

rs9429730 7:37437617 Add T 3.15x10-2 1.29 (1.15-1.45)

rs12624116 7:39511845 Dom T 3.15x10-2 1.26 (1.12-1.42)

rs58434222 7:78103655 Dom A 3.15x10-2 2.02 (1.48-2.76)

rs606890 7:86706725 Add G 3.15x10-2 1.89 (1.35-2.64) rs114892137 7:94906798 Dom T 3.15x10-2 3.28 (1.91-5.64)

rs6535900 7:106763218 Rec G 3.15x10-2 1.35 (1.19-1.53)

rs12676374 7:106796537 Dom T 3.15x10-2 0.85 (0.79-0.92)

rs7710027 7:106809056 Add T 3.14x10-2 0.87 (0.81-0.93) rs144289994 7:106812246 Dom T 3.14x10-2 0.84 (0.78-0.9)

212

rs140105036 7:106817901 Dom A 3.14x10-2 0.84 (0.78-0.91)

rs12624110 7:106821016 Dom T 3.14x10-2 0.85 (0.79-0.92)

rs771759 7:106824580 Add G 3.14x10-2 0.85 (0.79-0.92)

rs6928977 7:106835410 Add T 3.13x10-2 0.85 (0.79-0.92)

rs10239114 7:106836242 Dom G 3.13x10-2 0.85 (0.79-0.92)

rs6442038 7:106837866 Add A 3.13x10-2 0.8 (0.73-0.88)

rs79385886 7:106847492 Add G 3.13x10-2 0.85 (0.79-0.92)

rs771755 7:106853817 Add A 3.13x10-2 0.86 (0.79-0.92)

rs77024710 7:106856002 Dom T 3.13x10-2 0.86 (0.79-0.92)

rs9462597 7:106862963 Rec A 3.12x10-2 0.86 (0.8-0.92)

rs12540739 7:106863123 Dom G 3.12x10-2 0.86 (0.8-0.92)

rs7989997 7:106866178 Dom G 3.12x10-2 0.86 (0.8-0.92)

rs6062486 7:106866498 Add G 3.12x10-2 0.86 (0.8-0.92)

rs77395658 7:106897500 Add A 3.12x10-2 0.86 (0.79-0.92)

rs1581810 7:106899685 Rec G 3.11x10-2 0.86 (0.79-0.92)

rs4476937 7:106900214 Add C 3.11x10-2 0.85 (0.79-0.92)

213

rs28843793 7:106901741 Dom C 3.11x10-2 0.85 (0.79-0.92)

rs67602218 7:106906998 Add A 3.11x10-2 0.86 (0.79-0.92) rs113602630 7:106909172 Dom C 3.11x10-2 0.86 (0.79-0.92)

rs1841851 7:106922106 Dom G 3.10x10-2 0.86 (0.8-0.92)

rs7801078 7:106934246 Add A 3.10x10-2 0.85 (0.79-0.92)

rs7804814 7:106940098 Add A 3.10x10-2 0.86 (0.79-0.92)

rs1092464 7:106951579 Add T 3.10x10-2 0.85 (0.79-0.92)

rs2488456 7:106964433 Add T 3.10x10-2 0.76 (0.67-0.87)

rs4445269 7:106965009 Add T 3.10x10-2 0.86 (0.8-0.92)

rs10074490 7:106973534 Add T 3.10x10-2 0.86 (0.8-0.92)

rs2467080 7:106975059 Rec A 3.09x10-2 0.86 (0.8-0.92) rs111531441 7:106984684 Dom C 3.09x10-2 0.86 (0.8-0.92)

rs13144652 7:106985648 Add A 3.09x10-2 0.86 (0.8-0.92)

rs158348 7:106985873 Add A 3.09x10-2 0.86 (0.8-0.92)

rs32516 7:106987988 Add T 3.09x10-2 0.86 (0.8-0.92)

rs233935 7:107000651 Dom G 3.09x10-2 0.86 (0.79-0.92)

214

rs73065468 7:107004672 Dom T 3.09x10-2 0.86 (0.8-0.92)

rs61659105 7:107005246 Add T 3.09x10-2 0.86 (0.8-0.93)

rs10466272 7:107022506 Rec T 3.09x10-2 0.86 (0.8-0.92)

rs66899264 7:107024488 Add C 3.09x10-2 0.86 (0.79-0.92)

rs9603617 7:107030439 Rec G 3.09x10-2 0.86 (0.8-0.92) rs140466070 7:107031322 Dom A 3.09x10-2 0.86 (0.8-0.92)

rs6062298 7:114959247 Add G 3.09x10-2 0.8 (0.71-0.89)

rs75899512 7:114960443 Dom A 3.09x10-2 0.78 (0.69-0.88)

rs6594905 7:114963568 Dom T 3.09x10-2 0.86 (0.8-0.94)

rs9389286 7:114965505 Add G 3.09x10-2 0.8 (0.72-0.9)

rs9969194 7:114968881 Dom T 3.09x10-2 0.81 (0.72-0.9)

rs4591421 7:114969699 Add A 3.09x10-2 0.85 (0.78-0.92)

rs56655904 7:114970213 Add T 3.09x10-2 0.85 (0.78-0.92)

rs80138149 7:114970238 Dom G 3.08x10-2 0.8 (0.72-0.9) rs191000115 7:114970446 Dom C 3.08x10-2 0.85 (0.78-0.92)

rs2283869 7:114971787 Add T 3.08x10-2 0.85 (0.78-0.92)

215

rs10165261 7:114971825 Dom T 3.08x10-2 0.8 (0.72-0.9)

rs17260006 7:114973194 Add G 3.08x10-2 0.86 (0.8-0.94)

rs158342 7:114973225 Add G 3.07x10-2 0.85 (0.78-0.92)

rs7270776 7:114974327 Add C 3.07x10-2 0.8 (0.71-0.9)

rs10785601 7:114974695 Rec A 3.07x10-2 0.86 (0.8-0.94)

rs1348569 7:114975392 Rec G 3.07x10-2 0.81 (0.72-0.9)

rs4358499 7:114975759 Dom G 3.06x10-2 0.81 (0.72-0.9)

rs2433192 7:114981828 Rec G 3.06x10-2 0.85 (0.78-0.92)

rs10880904 7:114981944 Rec G 3.06x10-2 0.85 (0.78-0.92)

rs10515293 7:114995159 Dom T 3.06x10-2 0.81 (0.72-0.9)

rs34832141 7:114995700 Add G 3.06x10-2 0.8 (0.72-0.9)

rs72659492 7:114997176 Add C 3.05x10-2 0.85 (0.79-0.93)

rs3095422 7:115001358 Add G 3.05x10-2 0.8 (0.72-0.9) rs115978073 7:115005049 Dom C 3.05x10-2 0.8 (0.72-0.9)

rs159076 7:115005335 Add T 3.05x10-2 0.8 (0.72-0.9)

rs1407534 7:115010623 Add T 3.05x10-2 0.8 (0.72-0.9)

216

rs7772688 7:115010823 Rec C 3.05x10-2 0.8 (0.72-0.9) rs2157934 7:115018516 Add T 3.05x10-2 0.8 (0.72-0.9) rs5997629 7:115019527 Add G 3.05x10-2 0.8 (0.72-0.9) rs58267504 7:115024856 Dom G 3.05x10-2 0.8 (0.72-0.9) rs13092972 7:115025907 Add A 3.05x10-2 0.8 (0.72-0.9) rs79265471 7:115032255 Dom C 3.05x10-2 0.81 (0.72-0.9) rs1594873 7:115035099 Dom A 3.05x10-2 0.8 (0.72-0.9) rs2304256 7:115035504 Add A 3.05x10-2 0.8 (0.72-0.9) rs2018514 7:115036212 Add T 3.05x10-2 0.8 (0.72-0.9) rs10427847 7:115037927 Rec A 3.05x10-2 0.8 (0.72-0.9) rs13230144 7:115038988 Add C 3.04x10-2 0.8 (0.72-0.9) rs1426692 7:115044851 Add A 3.04x10-2 0.8 (0.72-0.9) rs4594848 7:119205742 Rec A 3.04x10-2 1.22 (1.11-1.34) rs4653327 7:119205987 Add G 3.04x10-2 1.23 (1.12-1.36) rs1581808 7:119206096 Rec T 3.04x10-2 1.24 (1.12-1.36) rs2107317 7:119207620 Add C 3.04x10-2 1.22 (1.11-1.35)

217

rs6689879 7:119207800 Add C 3.04x10-2 1.23 (1.11-1.35) rs113136521 7:119208489 Dom T 3.04x10-2 1.24 (1.12-1.36)

rs2663053 7:119208693 Add C 3.04x10-2 1.22 (1.11-1.35)

rs1550737 7:119209352 Rec G 3.04x10-2 1.23 (1.11-1.36)

rs1550735 7:119209707 Rec T 3.04x10-2 1.23 (1.11-1.35)

rs4554958 7:119211325 Rec C 3.04x10-2 1.24 (1.12-1.36)

rs62402006 7:119211514 Add G 3.03x10-2 1.24 (1.12-1.36)

rs80168506 7:119212131 Dom G 3.03x10-2 1.24 (1.12-1.36)

rs2347247 7:119213503 Dom C 3.03x10-2 1.24 (1.12-1.36)

rs2099983 7:119213998 Rec T 3.03x10-2 1.24 (1.12-1.36) rs113112402 7:119214879 Dom T 3.03x10-2 1.24 (1.12-1.36) rs116385512 7:119214897 Dom C 3.02x10-2 1.22 (1.11-1.35)

rs76151962 7:119216180 Dom A 3.02x10-2 1.22 (1.11-1.35)

rs75803718 7:119217124 Dom C 3.02x10-2 1.24 (1.12-1.36)

rs4487258 7:119217251 Add G 3.02x10-2 1.22 (1.11-1.35)

rs1426694 7:119219473 Dom A 3.02x10-2 1.22 (1.11-1.35)

218

rs142340032 7:119221169 Add T 3.02x10-2 1.22 (1.11-1.35)

rs80043323 7:119222610 Add T 3.01x10-2 1.23 (1.11-1.35)

rs1555799 7:119223204 Rec G 3.01x10-2 1.24 (1.12-1.36)

rs1365470 7:119226397 Dom C 3.01x10-2 1.24 (1.12-1.36)

rs12967828 7:119228877 Dom A 3.01x10-2 1.22 (1.11-1.34)

rs9954090 7:119232476 Dom C 3.01x10-2 1.22 (1.1-1.34) rs111854164 7:119233696 Dom A 3.01x10-2 1.23 (1.12-1.36)

rs13436226 7:119235090 Dom A 3.01x10-2 1.21 (1.1-1.34)

rs56091270 7:119236139 Dom A 3.00x10-2 1.22 (1.1-1.34)

rs11949055 7:119236659 Rec C 2.99x10-2 1.22 (1.1-1.34)

rs6863213 7:119237090 Rec T 2.99x10-2 1.23 (1.12-1.36)

rs1087423 7:119237322 Dom T 2.98x10-2 1.23 (1.12-1.36)

rs2548525 7:119243687 Dom C 2.98x10-2 1.23 (1.12-1.36)

rs2549799 7:119244067 Dom C 2.98x10-2 1.22 (1.1-1.34)

rs12518666 7:119244284 Dom T 2.98x10-2 1.22 (1.1-1.34)

rs2237665 7:119247500 Add C 2.97x10-2 1.24 (1.12-1.36)

219

rs113428748 7:119247600 Dom A 2.96x10-2 1.22 (1.1-1.34)

rs251344 7:119248801 Dom C 2.96x10-2 1.23 (1.12-1.36)

rs12716677 7:119251779 Dom T 2.96x10-2 1.22 (1.1-1.34)

rs17036102 7:119251847 Add C 2.96x10-2 1.22 (1.1-1.34)

rs62483641 7:119252903 Add C 2.96x10-2 1.22 (1.11-1.34)

rs7127214 7:119255678 Add G 2.96x10-2 1.24 (1.12-1.36)

rs2395869 7:119255954 Add A 2.96x10-2 1.22 (1.11-1.34)

rs233936 7:119256362 Dom T 2.96x10-2 1.22 (1.1-1.34)

rs7917467 7:119258312 Add T 2.96x10-2 1.24 (1.12-1.36)

rs1893662 7:119258557 Dom G 2.96x10-2 1.22 (1.1-1.34)

rs12043639 7:119258671 Add A 2.96x10-2 1.22 (1.1-1.34)

rs1217402 7:119260423 Add C 2.95x10-2 1.22 (1.1-1.34)

rs7772681 7:119260501 Add C 2.95x10-2 1.23 (1.12-1.36)

rs6435760 7:119261199 Dom A 2.94x10-2 1.23 (1.12-1.36)

rs6435761 7:119261782 Dom C 2.93x10-2 1.21 (1.1-1.34)

rs59659604 7:119261874 Dom G 2.93x10-2 1.23 (1.12-1.36)

220

rs79651842 7:119262116 Dom G 2.93x10-2 1.24 (1.12-1.36)

rs7577080 7:119264961 Dom A 2.93x10-2 1.22 (1.11-1.34)

rs7599177 7:119266253 Dom C 2.93x10-2 1.23 (1.12-1.36)

rs57007662 7:119266354 Dom T 2.93x10-2 1.22 (1.1-1.34)

rs59438872 7:119266825 Dom A 2.93x10-2 1.22 (1.1-1.34)

rs73989820 7:119268273 Dom A 2.93x10-2 1.22 (1.1-1.34)

rs13031598 7:119269803 Add T 2.93x10-2 1.23 (1.12-1.36)

rs7573888 7:119270056 Dom A 2.93x10-2 1.22 (1.1-1.34)

rs7591133 7:119270368 Dom C 2.93x10-2 1.22 (1.1-1.34)

rs73989818 7:119270386 Dom A 2.93x10-2 1.23 (1.12-1.36)

rs73989819 7:119271024 Dom G 2.93x10-2 1.24 (1.12-1.36)

rs72727827 7:119272639 Rec T 2.93x10-2 1.22 (1.1-1.34)

rs7588822 7:119272851 Dom C 2.93x10-2 1.23 (1.12-1.36)

rs2112974 7:119276154 Dom A 2.93x10-2 1.24 (1.12-1.36)

rs10768207 7:119276476 Add A 2.92x10-2 1.23 (1.12-1.36) rs142221769 7:119277285 Dom G 2.92x10-2 1.23 (1.12-1.35)

221

rs1893663 7:119280807 Dom A 2.92x10-2 1.23 (1.12-1.36)

rs17516457 7:119284745 Rec C 2.92x10-2 1.26 (1.14-1.39)

rs4799485 7:119288657 Dom T 2.91x10-2 1.22 (1.11-1.35)

rs10836534 7:119289545 Add A 2.91x10-2 1.24 (1.12-1.36)

rs7803151 7:119291725 Add A 2.91x10-2 1.22 (1.11-1.35)

rs12889006 7:123739439 Dom C 2.91x10-2 3.73 (2.12-6.57)

rs6704188 8:13277856 Add A 2.91x10-2 3.4 (1.88-6.16) rs111922546 8:29363220 Dom T 2.91x10-2 1.15 (1.08-1.23)

rs2395868 8:29365363 Add C 2.91x10-2 1.15 (1.08-1.23)

rs7917086 8:29371314 Add T 2.91x10-2 1.15 (1.08-1.23)

rs2072157 8:29371374 Add T 2.91x10-2 1.15 (1.08-1.23)

rs11135485 8:29371726 Dom G 2.90x10-2 1.15 (1.08-1.23)

rs1562324 8:29371763 Rec G 2.89x10-2 1.15 (1.08-1.23)

rs55878237 8:29373273 Dom T 2.89x10-2 1.15 (1.08-1.23)

rs38041 8:29373610 Dom A 2.89x10-2 1.15 (1.08-1.23)

rs27305 8:43013936 Dom G 2.88x10-2 0.45 (0.31-0.65)

222

rs1322142 8:75026234 Add G 2.87x10-2 1.29 (1.15-1.43)

rs1056893 8:75026885 Dom C 2.87x10-2 1.3 (1.17-1.45)

rs1834650 8:75028337 Dom T 2.87x10-2 1.28 (1.15-1.42)

rs12752932 8:75033766 Dom A 2.86x10-2 1.27 (1.14-1.42)

rs2120716 8:75034158 Rec A 2.86x10-2 1.27 (1.14-1.42)

rs6711890 8:75035040 Dom G 2.86x10-2 1.28 (1.15-1.42)

rs9815758 8:75035349 Add C 2.85x10-2 1.27 (1.14-1.42)

rs1080307 8:80516672 Dom G 2.85x10-2 0.76 (0.67-0.86) rs112397486 8:103531728 Dom C 2.84x10-2 1.29 (1.16-1.42)

rs72744954 8:103815498 Add T 2.84x10-2 0.78 (0.7-0.87)

rs889648 8:103817106 Add C 2.84x10-2 0.8 (0.73-0.89)

rs11795353 8:103818770 Rec C 2.83x10-2 0.81 (0.73-0.89)

rs2965152 8:103830395 Rec A 2.83x10-2 0.83 (0.75-0.91)

rs73987886 8:103831754 Dom C 2.82x10-2 0.88 (0.83-0.94) rs111821651 8:103836253 Dom C 2.82x10-2 0.88 (0.83-0.94)

rs62221564 8:103837912 Add A 2.82x10-2 0.88 (0.83-0.94)

223

rs7431213 8:103843032 Rec C 2.82x10-2 0.88 (0.83-0.94) rs10809037 8:103844702 Add T 2.82x10-2 0.88 (0.83-0.94) rs3825568 8:103848263 Dom T 2.81x10-2 0.88 (0.83-0.94) rs9383692 8:103850232 Add A 2.81x10-2 0.88 (0.83-0.94) rs13300585 8:103852407 Dom G 2.81x10-2 0.88 (0.83-0.94) rs10756010 8:103852409 Add G 2.81x10-2 0.88 (0.83-0.94) rs4838998 8:103855011 Add C 2.81x10-2 0.88 (0.83-0.94) rs56305841 8:103858488 Dom G 2.81x10-2 0.88 (0.83-0.94)

rs38042 8:103861040 Dom C 2.81x10-2 0.88 (0.83-0.94) rs7971826 8:103861436 Rec G 2.80x10-2 0.88 (0.83-0.94) rs17274634 8:103864473 Dom C 2.80x10-2 0.88 (0.83-0.94) rs6879764 8:103868000 Dom A 2.79x10-2 0.88 (0.83-0.94) rs79942247 8:103868910 Dom C 2.79x10-2 0.88 (0.83-0.94) rs2052469 8:103870469 Rec T 2.79x10-2 0.83 (0.75-0.91)

rs38037 8:103870818 Dom C 2.78x10-2 0.83 (0.75-0.91) rs16970664 8:119837151 Add A 2.78x10-2 0.81 (0.74-0.89)

224

rs1292042 8:119858126 Dom G 2.78x10-2 0.8 (0.73-0.88) rs10753026 8:119859169 Add G 2.77x10-2 0.8 (0.73-0.88) rs75290411 8:119859675 Dom A 2.77x10-2 0.81 (0.74-0.89) rs11741255 8:119859803 Add A 2.77x10-2 0.81 (0.74-0.89) rs12679976 8:120014632 Add A 2.77x10-2 0.78 (0.71-0.87) rs10887879 8:120030933 Add A 2.77x10-2 0.79 (0.71-0.87) rs13122213 8:131117885 Add C 2.76x10-2 1.4 (1.21-1.62) rs1217394 8:131118180 Add G 2.76x10-2 1.41 (1.21-1.63) rs2548539 8:131146844 Dom C 2.76x10-2 1.39 (1.2-1.61) rs12257092 8:131240989 Add T 2.76x10-2 1.42 (1.23-1.64) rs7625376 8:131326131 Add A 2.76x10-2 1.43 (1.23-1.65) rs12956072 8:131388642 Dom G 2.75x10-2 1.37 (1.19-1.58) rs76563384 8:131390017 Dom G 2.75x10-2 1.36 (1.18-1.56)

rs797013 8:131396318 Dom G 2.75x10-2 1.37 (1.19-1.57) rs10501149 8:131399834 Add A 2.75x10-2 1.36 (1.18-1.57) rs77233592 8:131422367 Dom A 2.74x10-2 1.47 (1.23-1.75)

225

rs723278 8:135415212 Dom T 2.74x10-2 1.3 (1.15-1.46)

rs7866028 8:135418567 Add G 2.74x10-2 1.31 (1.16-1.48)

rs38040 8:135422909 Dom A 2.74x10-2 1.34 (1.18-1.52)

rs42983 8:135426026 Dom G 2.74x10-2 1.33 (1.17-1.52)

rs6872737 8:135426793 Dom T 2.74x10-2 1.33 (1.17-1.52)

rs9425669 9:8415071 Add A 2.74x10-2 0.45 (0.3-0.66)

rs4658559 9:8417182 Rec T 2.74x10-2 0.45 (0.3-0.66)

rs576816 9:10224568 Rec A 2.74x10-2 0.86 (0.81-0.92)

rs1418957 9:10225027 Add A 2.74x10-2 0.86 (0.81-0.92)

rs12712263 9:10225500 Add A 2.74x10-2 0.87 (0.81-0.92)

rs11917784 9:10226432 Dom C 2.74x10-2 0.86 (0.81-0.92) rs144486808 9:10227464 Add G 2.74x10-2 0.87 (0.81-0.92)

rs158347 9:10229902 Add A 2.74x10-2 1.17 (1.09-1.26)

rs27613 9:10231300 Dom T 2.74x10-2 0.87 (0.81-0.92)

rs10246901 9:10231667 Dom C 2.74x10-2 0.87 (0.81-0.92)

rs9789859 9:10233361 Add A 2.74x10-2 0.87 (0.81-0.92)

226

rs12040742 9:10234839 Add G 2.73x10-2 0.86 (0.81-0.92) rs61819424 9:10235458 Dom G 2.72x10-2 0.87 (0.81-0.92) rs10958965 9:10236063 Add T 2.72x10-2 1.27 (1.14-1.42) rs11793308 9:10236246 Rec C 2.72x10-2 0.87 (0.81-0.92) rs7720230 9:10237264 Rec G 2.72x10-2 0.79 (0.71-0.87) rs3844312 9:10237682 Rec T 2.71x10-2 0.79 (0.71-0.87) rs10738156 9:10238353 Dom G 2.71x10-2 0.79 (0.72-0.88) rs66796078 9:10238391 Dom T 2.70x10-2 0.79 (0.71-0.88) rs35879464 9:10238675 Dom A 2.69x10-2 0.78 (0.71-0.87) rs73719952 9:10240686 Dom T 2.69x10-2 0.79 (0.71-0.87) rs2887606 9:10240823 Dom T 2.69x10-2 0.78 (0.71-0.87) rs12353282 9:10243703 Dom A 2.68x10-2 0.79 (0.72-0.88) rs7170048 9:10255540 Rec A 2.68x10-2 0.8 (0.72-0.88) rs10054432 9:10258159 Add C 2.67x10-2 0.78 (0.71-0.86) rs62483640 9:33257447 Add G 2.67x10-2 4.6 (2.44-8.67) rs12731010 9:33259501 Dom G 2.67x10-2 3.64 (2.01-6.61)

227

rs3761931 9:34397545 Dom A 2.67x10-2 1.25 (1.12-1.39)

rs505304 9:34400581 Rec C 2.67x10-2 1.26 (1.13-1.4)

rs62483619 9:34414339 Add T 2.66x10-2 1.26 (1.13-1.4) rs112537099 9:34415648 Rec G 2.66x10-2 1.25 (1.12-1.4)

rs17695904 9:38405834 Dom A 2.65x10-2 0.81 (0.73-0.9)

rs61817586 9:89351232 Dom C 2.65x10-2 0.79 (0.7-0.89)

rs34530460 9:94118921 Add A 2.65x10-2 2.45 (1.61-3.72)

rs1539438 9:96494541 Add C 2.65x10-2 0.88 (0.82-0.93)

rs527583 9:117493017 Rec C 2.64x10-2 1.18 (1.1-1.27)

rs1230381 9:117494365 Dom G 2.64x10-2 1.18 (1.1-1.27)

rs2237659 9:124972352 Add G 2.64x10-2 1.26 (1.13-1.41)

rs2113050 9:134042835 Dom G 2.64x10-2 3.53 (1.9-6.55)

rs10958962 10:6069561 Add C 2.64x10-2 0.77 (0.69-0.86)

rs6879678 10:6070276 Dom C 2.64x10-2 0.77 (0.69-0.86)

rs2919842 10:6071347 Rec C 2.64x10-2 0.77 (0.69-0.86)

rs11082093 10:6078553 Add A 2.63x10-2 0.77 (0.69-0.86)

228

rs2472928 10:6088743 Add C 2.63x10-2 0.77 (0.69-0.85)

rs9803891 10:6089841 Dom G 2.63x10-2 0.77 (0.69-0.85) rs150449635 10:6092444 Dom C 2.63x10-2 1.16 (1.08-1.25)

rs2965147 10:6094697 Rec G 2.63x10-2 0.75 (0.67-0.84)

rs2965145 10:6096667 Rec G 2.63x10-2 0.77 (0.69-0.86)

rs2919843 10:6097283 Rec G 2.62x10-2 0.77 (0.69-0.86)

rs57450080 10:6098824 Dom G 2.62x10-2 0.87 (0.82-0.93)

rs13374352 10:6098949 Dom A 2.62x10-2 1.19 (1.12-1.27)

rs12022838 10:6099045 Rec A 2.62x10-2 0.65 (0.54-0.77)

rs3095425 10:6100725 Add T 2.62x10-2 1.22 (1.14-1.31)

rs75443678 10:6101129 Dom A 2.62x10-2 1.22 (1.14-1.31)

rs1230382 10:6101713 Dom A 2.62x10-2 1.19 (1.11-1.27)

rs1019503 10:6102725 Dom A 2.62x10-2 1.2 (1.13-1.29)

rs10096995 10:6102757 Add C 2.62x10-2 1.22 (1.14-1.31) rs117155251 10:6106266 Dom A 2.62x10-2 1.19 (1.11-1.26)

rs2706403 10:6106552 Rec A 2.61x10-2 1.18 (1.11-1.26)

229

rs9943140 10:6106638 Add A 2.61x10-2 1.18 (1.11-1.26)

rs32487 10:6107007 Add G 2.61x10-2 1.2 (1.13-1.29)

rs10489936 10:6108340 Dom G 2.60x10-2 1.19 (1.11-1.26)

rs2746431 10:6108439 Add C 2.60x10-2 1.2 (1.13-1.29)

rs6674848 10:6109676 Dom C 2.60x10-2 0.76 (0.68-0.85)

rs9425671 10:6111993 Add C 2.60x10-2 0.76 (0.68-0.85)

rs35012149 10:6112605 Add G 2.60x10-2 1.18 (1.09-1.29)

rs9425670 10:6114660 Add T 2.60x10-2 0.75 (0.67-0.84)

rs9922935 10:6114856 Add G 2.60x10-2 1.25 (1.12-1.39)

rs13281383 10:6115171 Add A 2.59x10-2 1.19 (1.09-1.29)

rs12127544 10:6115204 Rec G 2.59x10-2 0.76 (0.67-0.85)

rs38036 10:6115639 Dom G 2.59x10-2 0.75 (0.67-0.84)

rs12753351 10:6116975 Dom A 2.59x10-2 0.76 (0.68-0.85)

rs3747998 10:6118111 Dom C 2.59x10-2 0.79 (0.71-0.88)

rs17359302 10:6119234 Dom G 2.59x10-2 0.79 (0.71-0.88) rs144663046 10:6122382 Add A 2.59x10-2 0.78 (0.71-0.86)

230

rs140541988 10:6123113 Add C 2.59x10-2 0.78 (0.7-0.86)

rs10186633 10:6123329 Dom C 2.59x10-2 0.79 (0.71-0.88)

rs2168443 10:6123495 Dom T 2.59x10-2 0.78 (0.71-0.86)

rs744790 10:6123716 Add T 2.59x10-2 0.79 (0.72-0.88)

rs6870825 10:17367299 Dom T 2.59x10-2 0.74 (0.64-0.85)

rs10958964 10:17371332 Add G 2.59x10-2 0.75 (0.65-0.86)

rs2965146 10:17373617 Rec C 2.59x10-2 0.74 (0.65-0.86)

rs12124156 10:18711996 Rec A 2.58x10-2 1.96 (1.46-2.63)

rs2548522 10:18716084 Dom G 2.58x10-2 1.95 (1.45-2.62) rs139008840 10:27605646 Dom C 2.58x10-2 1.59 (1.29-1.96)

rs17274550 10:49984053 Dom G 2.58x10-2 1.19 (1.1-1.3)

rs2359174 10:49984538 Dom G 2.58x10-2 1.21 (1.07-1.37)

rs2359173 10:49984690 Dom G 2.58x10-2 1.24 (1.14-1.36)

rs2663035 10:49987303 Add C 2.58x10-2 1.26 (1.15-1.37)

rs12518643 10:49989419 Dom G 2.58x10-2 1.16 (1.08-1.24)

rs34049619 10:49989792 Add A 2.58x10-2 1.26 (1.15-1.38)

231

rs75791290 10:49992689 Dom T 2.58x10-2 1.16 (1.08-1.24) rs13252461 10:49998569 Add T 2.58x10-2 1.16 (1.08-1.24) rs2216763 10:50000908 Add A 2.58x10-2 1.16 (1.08-1.24) rs61820162 10:50001532 Dom T 2.57x10-2 1.16 (1.08-1.24) rs35342456 10:50002557 Add C 2.57x10-2 1.16 (1.08-1.24) rs72922276 10:50003435 Dom A 2.57x10-2 1.16 (1.08-1.24) rs35836713 10:50010214 Dom T 2.57x10-2 1.16 (1.09-1.25) rs12127520 10:50013402 Rec G 2.57x10-2 1.16 (1.09-1.25) rs17274620 10:50013594 Dom T 2.57x10-2 1.17 (1.09-1.25) rs10088728 10:50013840 Add C 2.57x10-2 1.27 (1.16-1.39) rs9610683 10:62452564 Dom C 2.56x10-2 1.33 (1.15-1.53) rs1910024 10:70380077 Add T 2.56x10-2 1.22 (1.11-1.34) rs35320278 10:70381342 Dom T 2.56x10-2 1.22 (1.11-1.35) rs3748003 10:70381954 Dom C 2.56x10-2 1.22 (1.11-1.35) rs56182724 10:70383593 Dom G 2.56x10-2 1.22 (1.11-1.34) rs7751650 10:70387847 Rec G 2.56x10-2 1.23 (1.12-1.35)

232

rs9532439 10:70387992 Rec T 2.56x10-2 1.23 (1.12-1.35) rs12734625 10:70388379 Dom A 2.56x10-2 1.22 (1.11-1.35)

rs32497 10:70389037 Add T 2.56x10-2 1.23 (1.12-1.35) rs6558121 10:70389895 Add A 2.56x10-2 1.23 (1.12-1.35) rs7901839 10:70390134 Rec C 2.56x10-2 1.23 (1.12-1.35) rs6488242 10:70394649 Dom G 2.56x10-2 1.23 (1.12-1.36) rs1030966 10:70608349 Rec C 2.56x10-2 1.25 (1.12-1.39) rs1030967 10:70608612 Rec A 2.56x10-2 1.33 (1.17-1.51) rs2256126 10:70610714 Rec G 2.55x10-2 1.25 (1.12-1.41) rs2549796 10:70611616 Dom C 2.55x10-2 1.26 (1.12-1.41) rs2042385 10:70616199 Dom A 2.55x10-2 1.26 (1.12-1.41) rs4902643 10:90766924 Dom A 2.55x10-2 1.2 (1.1-1.3) rs35866703 10:90767395 Add T 2.55x10-2 1.2 (1.1-1.3) rs7846730 10:90770852 Add C 2.55x10-2 1.16 (1.08-1.24) rs7750586 10:90771829 Add G 2.54x10-2 1.16 (1.08-1.24) rs2120737 10:90776396 Rec G 2.54x10-2 1.16 (1.08-1.24)

233

rs193994 10:90777111 Dom C 2.54x10-2 1.2 (1.1-1.31) rs12716547 10:90777850 Add T 2.54x10-2 1.2 (1.1-1.31) rs2928393 10:90778656 Add G 2.54x10-2 1.2 (1.1-1.31) rs7913880 10:90779318 Add T 2.54x10-2 1.16 (1.08-1.24)

rs38035 10:90781976 Dom T 2.52x10-2 1.16 (1.08-1.24) rs74830391 10:90782827 Dom T 2.52x10-2 1.16 (1.08-1.24) rs9349142 10:112032958 Rec T 2.52x10-2 0.78 (0.69-0.87) rs76393576 10:112928036 Add G 2.52x10-2 2.04 (1.51-2.77) rs2224988 10:114359653 Rec C 2.51x10-2 1.26 (1.13-1.41) rs6460998 10:114371443 Dom G 2.51x10-2 1.26 (1.13-1.4) rs4727895 10:114378293 Dom T 2.51x10-2 1.24 (1.11-1.38) rs75351767 10:123793368 Dom C 2.51x10-2 0.87 (0.81-0.93) rs55752638 11:36329290 Add A 1.80x10-2 0.8 (0.72-0.89) rs8117412 11:36336464 Add C 1.79x10-2 0.85 (0.79-0.92) rs4705928 11:36336788 Rec T 1.79x10-2 0.85 (0.79-0.92) rs4714310 11:36338370 Rec T 1.77x10-2 0.75 (0.67-0.84)

234

rs11969625 11:36339673 Rec A 1.77x10-2 1.27 (1.13-1.42)

rs77354199 11:36341743 Add T 1.76x10-2 0.85 (0.79-0.91)

rs2614258 11:36343693 Add A 1.76x10-2 0.85 (0.79-0.92)

rs10742370 11:36344442 Rec C 1.76x10-2 0.79 (0.71-0.88)

rs12928822 11:36346859 Add T 1.76x10-2 1.28 (1.14-1.43)

rs10228248 11:36347625 Dom T 1.76x10-2 1.28 (1.14-1.43)

rs4934435 11:36348120 Add A 1.75x10-2 0.8 (0.72-0.88)

rs6703387 11:36348498 Dom C 1.74x10-2 1.28 (1.14-1.43)

rs10478257 11:36352698 Dom C 1.74x10-2 0.8 (0.72-0.88)

rs2614265 11:36355092 Add C 1.74x10-2 1.28 (1.14-1.43) rs113949610 11:36356259 Dom C 1.74x10-2 0.8 (0.72-0.88)

rs453169 11:36357037 Add A 1.74x10-2 1.26 (1.13-1.41)

rs9576892 11:36357257 Add T 1.74x10-2 0.8 (0.73-0.88)

rs6955486 11:36357871 Dom C 1.74x10-2 1.27 (1.13-1.41)

rs35307035 11:36358876 Add A 1.73x10-2 0.77 (0.69-0.86)

rs228960 11:36360366 Add A 1.73x10-2 1.26 (1.12-1.41)

235

rs12924957 11:36360598 Add T 1.73x10-2 0.78 (0.69-0.87) rs9349140 11:36361607 Rec T 1.72x10-2 0.74 (0.66-0.83) rs3789609 11:36361616 Dom T 1.71x10-2 0.74 (0.66-0.83) rs17699323 11:36363575 Add C 1.71x10-2 0.8 (0.73-0.88) rs10224524 11:36365253 Add T 1.71x10-2 0.81 (0.74-0.88) rs6874656 11:36368153 Dom C 1.69x10-2 1.26 (1.12-1.41) rs6859160 11:36368327 Dom T 1.69x10-2 1.26 (1.12-1.41) rs6873441 11:36371634 Dom G 1.68x10-2 0.84 (0.78-0.91) rs7117002 11:36376021 Dom A 1.68x10-2 0.84 (0.78-0.91) rs12928968 11:63512565 Add T 1.67x10-2 0.8 (0.73-0.88) rs59733414 11:63957104 Add T 1.67x10-2 0.81 (0.73-0.89) rs4621357 11:64124622 Dom C 1.67x10-2 0.8 (0.72-0.88) rs9548884 11:64125680 Add T 1.67x10-2 0.81 (0.74-0.89) rs9548916 11:87950191 Add C 1.67x10-2 0.8 (0.71-0.89)

rs500694 11:87950306 Rec C 1.66x10-2 0.79 (0.71-0.89) rs75630613 11:121264079 Dom A 1.66x10-2 0.82 (0.75-0.9)

236

rs10809045 12:10120831 Dom T 1.66x10-2 0.79 (0.71-0.88)

rs8135343 12:10120840 Dom A 1.66x10-2 0.79 (0.71-0.88) rs114406434 12:10153190 Add T 1.66x10-2 1.27 (1.13-1.44)

rs13129806 12:26554780 Add G 1.65x10-2 1.5 (1.23-1.82)

rs12162021 12:46458819 Add A 1.65x10-2 0.78 (0.7-0.87)

rs78708639 12:46459642 Dom G 1.64x10-2 0.79 (0.71-0.88)

rs55734227 12:46462036 Add G 1.64x10-2 0.79 (0.71-0.88)

rs1373346 12:46463406 Add T 1.64x10-2 0.79 (0.71-0.88)

rs10494298 12:46464417 Rec A 1.63x10-2 0.79 (0.71-0.88)

rs12598646 12:46464451 Add T 1.63x10-2 0.79 (0.71-0.88)

rs1325558 12:46464689 Rec A 1.63x10-2 0.79 (0.71-0.88)

rs4730924 12:46465283 Dom C 1.63x10-2 0.79 (0.71-0.88)

rs3134087 12:46466490 Dom G 1.63x10-2 0.79 (0.71-0.88)

rs1325557 12:46466593 Rec T 1.63x10-2 0.79 (0.71-0.88)

rs7617634 12:46468097 Add C 1.62x10-2 0.79 (0.71-0.88)

rs9548917 12:46468949 Add T 1.62x10-2 0.79 (0.71-0.88)

237

rs9548918 12:46469052 Add T 1.62x10-2 0.79 (0.71-0.88) rs9548919 12:46470948 Add A 1.62x10-2 0.79 (0.71-0.88) rs9548920 12:46471047 Add G 1.62x10-2 0.79 (0.71-0.88) rs7998641 12:46471433 Add T 1.62x10-2 0.79 (0.71-0.88) rs4508817 12:46472696 Dom A 1.61x10-2 0.79 (0.71-0.88) rs1796524 12:46474450 Add A 1.60x10-2 0.79 (0.71-0.88) rs9932855 12:46474887 Add C 1.60x10-2 0.79 (0.71-0.88) rs9367046 12:46475127 Rec T 1.58x10-2 0.79 (0.71-0.88) rs12935137 12:46475193 Add C 1.58x10-2 0.79 (0.71-0.88) rs72769521 12:46475533 Dom A 1.58x10-2 0.79 (0.71-0.88) rs10065787 12:46475579 Add T 1.58x10-2 0.79 (0.71-0.88) rs4705938 12:46476036 Add C 1.56x10-2 0.79 (0.71-0.88) rs1476659 12:46476201 Add A 1.56x10-2 0.79 (0.71-0.88) rs1252785 12:46477664 Dom A 1.54x10-2 0.79 (0.71-0.88) rs79167231 12:46477776 Dom C 1.54x10-2 0.79 (0.71-0.88) rs2548998 12:46479015 Add G 1.54x10-2 0.79 (0.71-0.88)

238

rs379723 12:46479056 Add T 1.54x10-2 0.79 (0.71-0.88) rs1608549 12:46480908 Rec C 1.54x10-2 0.79 (0.71-0.88) rs2188962 12:46481089 Rec T 1.53x10-2 0.79 (0.71-0.88) rs4486113 12:46481178 Dom G 1.53x10-2 0.79 (0.71-0.88) rs28893249 12:46481573 Dom T 1.53x10-2 0.79 (0.71-0.88) rs10267600 12:58609584 Dom A 1.53x10-2 0.43 (0.29-0.64) rs6466700 12:58612809 Dom T 1.53x10-2 0.43 (0.29-0.64) rs2070721 12:58623023 Add G 1.53x10-2 0.43 (0.29-0.64) rs10281676 12:58624856 Dom G 1.53x10-2 0.43 (0.29-0.64) rs10268082 12:58625612 Dom C 1.53x10-2 0.43 (0.29-0.64) rs73483305 12:58637020 Dom C 1.53x10-2 0.43 (0.29-0.64) rs10250138 12:58641894 Dom T 1.53x10-2 0.43 (0.29-0.64) rs4551909 12:58643380 Add C 1.53x10-2 0.43 (0.29-0.64) rs9969193 12:58669612 Dom T 1.52x10-2 0.42 (0.28-0.63) rs12106618 12:58677249 Add A 1.52x10-2 0.42 (0.28-0.63) rs7555634 12:82340358 Add C 1.50x10-2 1.35 (1.16-1.57)

239

rs7292744 12:94664421 Add C 1.50x10-2 2.19 (1.58-3.02) rs4943688 12:94664423 Add A 1.50x10-2 2.19 (1.58-3.02) rs4943689 12:112486818 Add T 1.50x10-2 1.16 (1.09-1.24) rs7999758 12:112591686 Add G 1.50x10-2 1.17 (1.09-1.27) rs28523826 12:112883476 Add A 1.50x10-2 1.17 (1.08-1.27) rs4705862 13:31854617 Add T 1.50x10-2 2.83 (1.61-4.97) rs4492929 13:40218220 Add G 1.50x10-2 0.79 (0.71-0.88) rs12729708 13:40225467 Dom C 1.50x10-2 1.16 (1.09-1.24) rs34214074 13:40225469 Dom G 1.50x10-2 1.16 (1.09-1.24) rs2617434 13:40233404 Dom G 1.50x10-2 0.85 (0.8-0.91) rs9295689 13:40233691 Add C 1.50x10-2 0.85 (0.8-0.91) rs10227191 13:40233966 Dom G 1.50x10-2 0.85 (0.8-0.91) rs2127590 13:40235373 Add T 1.50x10-2 0.85 (0.8-0.91) rs4636783 13:40236390 Add C 1.50x10-2 0.85 (0.8-0.92) rs4566029 13:40236505 Add T 1.50x10-2 0.85 (0.8-0.92) rs4275735 13:40236601 Add A 1.50x10-2 0.85 (0.8-0.92)

240

rs4277227 13:40237911 Add A 1.50x10-2 0.85 (0.8-0.92) rs4569133 13:40238162 Add T 1.50x10-2 0.85 (0.8-0.92) rs7991151 13:40238387 Add G 1.50x10-2 0.85 (0.8-0.92) rs7998582 13:40238481 Add A 1.50x10-2 0.85 (0.8-0.91) rs6563738 13:40238483 Add G 1.50x10-2 0.85 (0.8-0.91) rs6563739 13:40238492 Add G 1.50x10-2 0.85 (0.8-0.91) rs4941940 13:40238649 Add A 1.49x10-2 0.85 (0.8-0.92) rs4129475 13:40238841 Dom T 1.49x10-2 0.85 (0.8-0.92) rs2919844 13:40238899 Rec T 2.17x10-2 0.85 (0.8-0.92) rs12504088 13:40239044 Add G 2.17x10-2 0.85 (0.8-0.92) rs3096168 13:40239139 Dom G 2.17x10-2 0.85 (0.8-0.92) rs10066308 13:40239618 Dom A 2.16x10-2 0.85 (0.8-0.92) rs66718203 13:40239764 Add G 2.16x10-2 0.85 (0.8-0.92) rs10127930 13:40239785 Dom C 2.16x10-2 0.85 (0.8-0.92) rs12511885 13:40241873 Add A 2.16x10-2 0.85 (0.8-0.92) rs1796521 13:40242097 Add T 2.16x10-2 0.85 (0.8-0.92)

241

rs10809044 13:40245500 Dom C 2.16x10-2 0.85 (0.8-0.92)

rs4683301 13:40247557 Dom A 2.16x10-2 0.85 (0.8-0.92)

rs2548520 13:40251422 Dom G 2.16x10-2 0.85 (0.8-0.92)

rs2548521 13:40251851 Dom G 2.15x10-2 0.8 (0.72-0.89) rs149961585 13:40253901 Add T 2.15x10-2 0.85 (0.8-0.92)

rs11585095 13:40257420 Rec A 2.15x10-2 0.85 (0.8-0.92)

rs6709484 13:40258085 Dom C 2.15x10-2 0.85 (0.8-0.92)

rs6814280 13:40262246 Add G 2.15x10-2 1.15 (1.08-1.23)

rs4705908 13:40262760 Add A 2.15x10-2 0.86 (0.8-0.92)

rs4941342 13:40266064 Add C 2.15x10-2 0.86 (0.8-0.92)

rs6668829 13:40280589 Dom T 2.15x10-2 0.81 (0.72-0.9)

rs74945236 13:40289070 Dom C 2.15x10-2 1.15 (1.08-1.23)

rs77047725 13:40293686 Dom G 2.15x10-2 0.8 (0.72-0.9)

rs2549795 13:40295068 Dom A 2.15x10-2 1.15 (1.08-1.23)

rs7808122 13:40299252 Add T 2.15x10-2 1.16 (1.08-1.23)

rs3801966 13:40300328 Add A 2.15x10-2 0.8 (0.72-0.88)

242

rs10241088 13:40302410 Dom C 2.15x10-2 0.77 (0.68-0.87) rs7696836 13:40303160 Add A 2.15x10-2 1.16 (1.09-1.24) rs2549801 13:40303194 Dom C 2.14x10-2 1.17 (1.09-1.24) rs7334651 13:40307537 Add C 2.14x10-2 1.16 (1.09-1.24) rs3801964 13:40308117 Add C 2.14x10-2 1.16 (1.09-1.24) rs4391362 13:40308307 Dom T 2.14x10-2 0.85 (0.79-0.9) rs7659526 13:40311300 Add C 2.13x10-2 1.16 (1.09-1.24) rs34341173 13:40318819 Dom A 2.12x10-2 0.84 (0.79-0.9) rs2218565 13:40319225 Add T 2.11x10-2 0.84 (0.78-0.9) rs34649199 13:40319257 Dom C 2.11x10-2 1.17 (1.09-1.24) rs6556943 13:40319954 Dom G 2.11x10-2 0.84 (0.78-0.9) rs17509390 13:40322095 Dom C 2.11x10-2 1.16 (1.09-1.24) rs2255637 13:40323238 Dom A 2.11x10-2 1.16 (1.09-1.24) rs7701414 13:40323443 Rec G 2.11x10-2 1.16 (1.09-1.24) rs2255634 13:40323451 Dom T 2.11x10-2 1.16 (1.09-1.24) rs2255633 13:40325310 Dom G 2.11x10-2 1.17 (1.09-1.25)

243

rs12039224 13:40326282 Add G 2.11x10-2 0.84 (0.79-0.9) rs12021513 13:40327460 Add T 2.11x10-2 1.16 (1.09-1.24) rs1363977 13:40327895 Dom G 2.11x10-2 1.16 (1.09-1.24) rs1363975 13:40329032 Dom A 2.11x10-2 1.17 (1.09-1.25) rs2255546 13:40330050 Dom C 2.11x10-2 0.77 (0.68-0.87) rs7092857 13:40330105 Add C 2.11x10-2 0.77 (0.68-0.87) rs2548526 13:40333369 Dom T 2.11x10-2 0.85 (0.79-0.91) rs2113191 13:40333767 Dom T 2.11x10-2 1.17 (1.09-1.24) rs2548524 13:40334309 Dom A 2.11x10-2 1.17 (1.1-1.25) rs2548523 13:40342557 Dom G 2.11x10-2 0.84 (0.79-0.9) rs34042871 13:40345356 Dom G 2.11x10-2 0.84 (0.79-0.9) rs61817617 13:40345466 Dom T 2.11x10-2 0.85 (0.79-0.9) rs10067427 13:40349357 Dom G 2.10x10-2 1.16 (1.09-1.24) rs4459999 13:40350912 Add C 2.10x10-2 0.84 (0.79-0.9) rs3789607 13:40351064 Dom C 2.10x10-2 0.78 (0.71-0.85) rs74483807 13:40351094 Dom T 2.10x10-2 0.84 (0.79-0.9)

244

rs1590264 13:40351341 Add C 2.10x10-2 0.84 (0.78-0.9)

rs1423846 13:40352602 Add G 2.10x10-2 1.16 (1.09-1.24) rs142866816 13:40352671 Dom T 2.10x10-2 0.84 (0.78-0.9)

rs12735104 13:40353230 Dom A 2.09x10-2 0.84 (0.78-0.9)

rs10227401 13:40354200 Dom T 2.08x10-2 0.84 (0.79-0.9)

rs3824946 13:40355913 Add A 2.08x10-2 0.84 (0.79-0.9)

rs12730735 13:40357677 Dom C 2.08x10-2 1.16 (1.09-1.24)

rs10236510 13:40362229 Dom A 2.08x10-2 0.85 (0.79-0.91)

rs1135205 13:40365765 Add T 2.08x10-2 1.16 (1.09-1.24)

rs4727894 13:40368069 Dom G 2.07x10-2 0.84 (0.79-0.9)

rs7555354 13:40368444 Dom A 2.07x10-2 0.84 (0.79-0.9)

rs7533605 13:40368601 Dom T 2.07x10-2 0.84 (0.79-0.9)

rs36115604 13:40369683 Dom A 2.07x10-2 1.34 (1.18-1.52)

rs71662845 13:40370177 Dom A 2.07x10-2 1.34 (1.18-1.53)

rs2549797 13:40370391 Dom A 2.07x10-2 1.34 (1.17-1.52)

rs12600282 13:44005235 Add T 2.07x10-2 0.83 (0.76-0.91)

245

rs28391170 13:44006926 Add C 2.07x10-2 0.83 (0.76-0.91)

rs1600034 13:44007861 Dom A 2.07x10-2 0.83 (0.76-0.91)

rs9603603 13:44010917 Dom G 2.07x10-2 0.83 (0.76-0.91)

rs12748727 13:44011766 Dom A 2.07x10-2 0.83 (0.76-0.91)

rs12760457 13:44012078 Dom T 2.07x10-2 0.83 (0.76-0.91)

rs1796522 13:44013457 Add G 2.07x10-2 0.83 (0.76-0.91)

rs1329096 13:44013673 Rec C 2.06x10-2 0.83 (0.76-0.91)

rs17087165 13:44014393 Dom C 2.06x10-2 0.83 (0.76-0.91)

rs2548527 13:44015107 Dom A 2.06x10-2 0.83 (0.76-0.91) rs113558521 13:44015580 Dom G 2.06x10-2 0.83 (0.76-0.91)

rs33934033 13:70732939 Dom G 2.06x10-2 1.35 (1.17-1.57)

rs2283038 13:70733844 Add T 2.05x10-2 1.35 (1.16-1.56) rs147950045 13:72774354 Dom A 2.05x10-2 1.23 (1.11-1.37) rs115584284 13:72774592 Dom G 2.04x10-2 1.29 (1.14-1.45)

rs11102658 13:96917144 Add C 2.04x10-2 3.36 (1.89-5.96)

rs11586275 13:96956056 Rec A 2.04x10-2 3.52 (1.97-6.26)

246

rs4617096 13:96968273 Dom C 2.04x10-2 3.52 (1.97-6.27) rs11033552 14:42107623 Dom A 2.04x10-2 1.4 (1.2-1.62) rs9594356 14:69135753 Dom T 2.04x10-2 0.76 (0.68-0.86) rs10466394 14:69222144 Dom C 2.02x10-2 0.82 (0.75-0.9) rs11690012 14:69250891 Rec C 2.02x10-2 0.81 (0.73-0.89) rs1216565 14:69253343 Dom A 2.02x10-2 0.81 (0.73-0.89) rs11033559 14:69253364 Dom A 2.02x10-2 0.81 (0.73-0.89) rs1216569 14:69254191 Dom T 2.02x10-2 0.81 (0.73-0.89) rs2549789 14:69260563 Dom A 2.02x10-2 0.81 (0.74-0.9) rs35779989 14:69260588 Add A 2.02x10-2 0.81 (0.74-0.89) rs9548881 14:69271784 Add T 2.02x10-2 1.24 (1.11-1.37) rs4722177 14:94444482 Add T 2.01x10-2 3.05 (1.8-5.16) rs10274137 14:95106873 Dom T 2.01x10-2 0.8 (0.72-0.89) rs4902647 14:102215101 Dom T 2.01x10-2 4.53 (2.45-8.38) rs4941341 15:34962405 Add C 2.01x10-2 0.82 (0.74-0.9) rs8086560 15:34962535 Add T 2.01x10-2 0.81 (0.74-0.9)

247

rs2548528 15:45970676 Dom G 2.01x10-2 1.24 (1.13-1.37) rs36072192 15:45971130 Dom C 2.01x10-2 1.24 (1.12-1.36) rs13132308 15:56899523 Add G 2.00x10-2 1.22 (1.11-1.34) rs1216570 15:56902021 Dom C 2.00x10-2 1.21 (1.11-1.32) rs12539982 15:56902429 Dom A 2.00x10-2 1.21 (1.11-1.32) rs10238927 15:56903390 Dom A 1.98x10-2 1.21 (1.1-1.32) rs12922090 15:56941323 Add T 1.98x10-2 1.2 (1.1-1.3) rs9394666 15:56949316 Rec C 1.98x10-2 1.2 (1.1-1.3) rs1900337 15:56949333 Rec G 1.98x10-2 1.2 (1.1-1.3) rs34877889 15:56950346 Dom A 1.98x10-2 1.19 (1.1-1.3) rs7697619 15:56950376 Add C 1.98x10-2 1.2 (1.1-1.31) rs11205250 15:56950402 Rec T 1.97x10-2 1.2 (1.1-1.3) rs10239176 15:56951278 Dom T 1.97x10-2 1.2 (1.11-1.31) rs13163165 15:61465666 Dom G 1.96x10-2 1.31 (1.15-1.48) rs1363976 15:61466208 Dom T 1.96x10-2 1.31 (1.15-1.48) rs9394665 15:61466475 Rec C 1.96x10-2 1.3 (1.15-1.48)

248

rs9649962 15:61467308 Dom A 1.96x10-2 1.29 (1.14-1.45) rs9857771 15:61467353 Dom A 1.96x10-2 1.29 (1.14-1.46) rs2549790 15:61468345 Dom T 1.96x10-2 1.28 (1.13-1.45) rs6866614 15:67090391 Add A 1.96x10-2 0.8 (0.71-0.89) rs9349141 15:87394092 Rec G 1.96x10-2 1.27 (1.15-1.4) rs73483374 15:87395749 Dom C 1.95x10-2 1.27 (1.14-1.4) rs10267793 15:89043063 Dom A 1.95x10-2 1.33 (1.16-1.52) rs10266505 15:89044880 Dom A 1.95x10-2 1.33 (1.16-1.52) rs11158763 15:89045066 Dom T 1.95x10-2 1.33 (1.16-1.52) rs12434551 15:89045112 Dom T 1.95x10-2 1.39 (1.19-1.62) rs12918017 15:89045724 Add A 1.95x10-2 1.33 (1.16-1.52) rs12922409 15:89045938 Add T 1.95x10-2 1.33 (1.16-1.52) rs2910688 15:89046783 Dom C 2.18x10-2 1.32 (1.16-1.52) rs10421796 15:89046895 Rec G 2.18x10-2 1.33 (1.17-1.53) rs2549782 15:89046989 Dom G 1.94x10-2 1.33 (1.16-1.52) rs12917839 15:89047168 Add T 1.94x10-2 1.33 (1.16-1.52)

249

rs2522057 15:89047338 Add G 1.94x10-2 1.33 (1.16-1.52)

rs2548536 15:89048183 Dom T 1.93x10-2 1.35 (1.18-1.54)

rs11202927 15:89048184 Add G 1.93x10-2 1.35 (1.18-1.54) rs140470930 15:89048198 Add A 1.93x10-2 1.34 (1.17-1.53)

rs34947566 15:89048298 Add A 1.93x10-2 1.33 (1.16-1.53)

rs2549784 15:89048442 Dom G 1.93x10-2 1.33 (1.16-1.52)

rs2549788 15:89049243 Dom A 1.93x10-2 1.33 (1.17-1.53)

rs2758383 15:89049490 Add G 1.92x10-2 1.33 (1.17-1.53)

rs4290197 15:89049516 Rec C 1.92x10-2 1.33 (1.16-1.53)

rs2548538 15:89050628 Dom T 1.92x10-2 1.34 (1.17-1.53)

rs2548537 15:89050834 Dom G 1.92x10-2 1.34 (1.17-1.53)

rs2549785 15:91482198 Dom C 1.92x10-2 1.33 (1.16-1.52)

rs2548535 15:91482524 Dom A 1.91x10-2 1.33 (1.16-1.52)

rs2548533 15:91482719 Dom A 1.91x10-2 1.33 (1.16-1.52)

rs2549800 15:91484033 Dom A 1.91x10-2 1.34 (1.17-1.54)

rs72797306 15:91484717 Add C 1.91x10-2 1.34 (1.17-1.54)

250

rs73425525 15:91484923 Dom C 1.91x10-2 1.34 (1.17-1.54) rs2113189 15:91485582 Dom T 1.91x10-2 1.34 (1.17-1.53) rs2548534 15:91505447 Dom G 1.90x10-2 1.33 (1.16-1.52) rs2248116 15:91508028 Add C 1.90x10-2 1.33 (1.16-1.52) rs2548540 15:91513674 Dom G 1.90x10-2 1.32 (1.16-1.52) rs1810764 15:91516737 Add T 1.90x10-2 1.32 (1.16-1.52) rs2161658 15:91517796 Dom G 1.89x10-2 1.32 (1.16-1.52) rs2042383 15:91520150 Dom C 1.89x10-2 1.32 (1.15-1.51)

rs193993 15:91520805 Dom T 1.89x10-2 1.34 (1.17-1.54) rs72797303 15:91528823 Add C 1.89x10-2 1.32 (1.15-1.51) rs1423568 15:91790302 Dom A 1.87x10-2 1.26 (1.13-1.41) rs2248374 15:91793114 Dom A 1.87x10-2 1.28 (1.15-1.43) rs1853817 15:91794183 Rec A 1.87x10-2 1.33 (1.18-1.49) rs9376072 15:93885108 Add C 1.87x10-2 0.84 (0.78-0.91) rs6570001 15:99074963 Add G 1.87x10-2 1.24 (1.13-1.36) rs2234978 15:99078262 Add T 1.87x10-2 1.25 (1.14-1.37)

251

rs17699806 15:99079241 Add C 1.87x10-2 1.24 (1.13-1.36) rs74257707 15:100820034 Add G 1.87x10-2 0.74 (0.65-0.85) rs2113190 15:100821426 Dom G 1.87x10-2 0.71 (0.6-0.83)

rs475625 16:1080100 Rec T 1.87x10-2 0.7 (0.59-0.82) rs1926188 16:1080554 Add T 1.87x10-2 0.66 (0.55-0.79)

rs226936 16:1081188 Add A 1.87x10-2 0.69 (0.59-0.82) rs1329095 16:1083660 Rec G 1.86x10-2 0.69 (0.59-0.82)

rs187265 16:1084440 Dom C 1.86x10-2 0.69 (0.59-0.82) rs2706396 16:1086120 Add A 1.86x10-2 0.69 (0.59-0.81) rs1407242 16:1092871 Rec G 1.86x10-2 0.69 (0.59-0.81) rs2287988 16:5625681 Dom G 1.86x10-2 1.26 (1.14-1.38)

rs171647 16:11400900 Dom C 1.86x10-2 0.82 (0.75-0.89) rs2522052 16:11401503 Add C 1.86x10-2 0.82 (0.75-0.89) rs2706336 16:11401866 Add T 1.85x10-2 0.81 (0.75-0.89) rs6466704 16:11402350 Dom A 1.85x10-2 0.81 (0.74-0.89) rs2620903 16:11402908 Add G 1.85x10-2 0.81 (0.74-0.89)

252

rs111044 16:11403013 Add C 1.85x10-2 0.81 (0.74-0.89) rs1571020 16:11403766 Add C 1.85x10-2 0.81 (0.74-0.89) rs4941340 16:11403893 Add G 1.85x10-2 0.81 (0.74-0.89) rs73485181 16:11403963 Dom T 1.84x10-2 0.82 (0.75-0.89)

rs190129 16:11404428 Add G 1.84x10-2 0.82 (0.75-0.89) rs10982385 16:11404857 Add T 1.84x10-2 0.82 (0.75-0.89) rs12435329 16:11406519 Dom C 1.83x10-2 0.81 (0.74-0.89) rs34294744 16:11406544 Add G 1.83x10-2 0.81 (0.74-0.89) rs2170132 16:11406792 Add C 1.83x10-2 0.81 (0.74-0.89) rs3096167 16:11407623 Dom G 1.83x10-2 0.81 (0.74-0.89) rs72773819 16:11409493 Add A 1.82x10-2 0.81 (0.74-0.89) rs1078904 16:11412167 Add G 1.82x10-2 0.81 (0.75-0.89) rs35978977 16:11412926 Add T 1.81x10-2 0.81 (0.75-0.89) rs2395732 16:11414758 Rec A 1.81x10-2 0.81 (0.75-0.89) rs9394664 16:11415289 Rec T 1.80x10-2 0.81 (0.75-0.89) rs4235415 16:11418478 Add G 1.80x10-2 0.81 (0.74-0.89)

253

rs2549792 16:11422015 Dom G 1.80x10-2 0.81 (0.74-0.89)

rs2436865 16:11428643 Dom T 1.80x10-2 0.82 (0.75-0.89)

rs10742369 16:11430375 Dom T 1.80x10-2 0.82 (0.75-0.89)

rs73390209 16:11435990 Add A 1.80x10-2 0.82 (0.75-0.89)

rs2549791 16:11438021 Dom G 1.80x10-2 0.82 (0.75-0.89)

rs9548900 16:11443424 Add C 1.80x10-2 0.83 (0.77-0.91)

rs9576891 16:11444469 Add T 1.80x10-2 0.83 (0.77-0.91)

rs10217805 16:11455816 Dom A 1.80x10-2 0.83 (0.76-0.9)

rs61839680 16:17189438 Add T 1.32x10-2 4.01 (2.1-7.64) rs116962260 16:54984588 Dom G 1.31x10-2 1.23 (1.12-1.36)

rs510023 16:62699115 Rec C 1.31x10-2 1.23 (1.11-1.35)

rs7109880 16:82874082 Rec A 1.31x10-2 1.45 (1.23-1.71)

rs2070729 16:82876386 Add A 1.30x10-2 1.45 (1.23-1.71)

rs3821236 16:83721952 Add A 1.30x10-2 1.18 (1.1-1.27)

rs12515180 16:87240148 Rec T 1.30x10-2 1.32 (1.15-1.51)

rs11951091 17:2711764 Rec A 1.30x10-2 1.21 (1.1-1.33)

254

rs1539437 17:26075070 Add C 1.30x10-2 0.77 (0.68-0.87) rs8050084 17:26133177 Add G 1.29x10-2 0.81 (0.74-0.89)

rs447883 17:26201218 Add C 1.29x10-2 0.83 (0.76-0.9) rs12254050 17:57934995 Add G 1.29x10-2 1.22 (1.11-1.34) rs7733502 17:57942585 Add C 1.29x10-2 1.18 (1.09-1.28) rs10479000 17:57951973 Rec C 1.29x10-2 1.18 (1.09-1.28) rs1310182 17:57953082 Add A 1.27x10-2 1.18 (1.09-1.28)

rs757660 17:57957888 Add A 1.26x10-2 1.17 (1.08-1.27) rs2884704 17:57960436 Add C 1.24x10-2 1.17 (1.08-1.27) rs3018952 17:57965169 Dom C 1.24x10-2 1.18 (1.09-1.28) rs7735891 17:57965731 Rec T 1.23x10-2 1.17 (1.08-1.27) rs11950562 17:57966230 Add C 1.23x10-2 1.18 (1.09-1.27) rs13132245 17:57966233 Add G 1.23x10-2 1.17 (1.08-1.27) rs10060615 17:57967268 Add C 1.23x10-2 1.18 (1.09-1.27) rs13357280 17:58046246 Rec G 1.22x10-2 1.18 (1.09-1.28) rs1217378 17:59923491 Add C 1.22x10-2 1.89 (1.39-2.57)

255

rs3789600 17:66796719 Add C 1.21x10-2 1.44 (1.2-1.72) rs12528142 18:12770851 Add T 1.21x10-2 1.32 (1.19-1.46) rs9548871 18:12774326 Add T 1.21x10-2 1.37 (1.25-1.49) rs9548872 18:12774894 Add G 1.21x10-2 1.37 (1.26-1.5) rs4833833 18:12775591 Add T 1.21x10-2 1.37 (1.25-1.49) rs13119723 18:12775851 Add G 1.20x10-2 1.37 (1.25-1.49) rs6672018 18:12777325 Add T 1.20x10-2 1.37 (1.25-1.49) rs13137072 18:12777573 Add A 1.20x10-2 1.37 (1.25-1.49) rs2246852 18:12777603 Add G 1.20x10-2 1.37 (1.25-1.49)

rs974404 18:12778715 Add G 1.19x10-2 1.37 (1.25-1.49) rs9321500 18:12779018 Add T 1.19x10-2 1.37 (1.25-1.49) rs12465689 18:12779342 Add T 1.19x10-2 1.37 (1.25-1.49) rs5753116 18:12779763 Add G 1.19x10-2 1.37 (1.25-1.49) rs1217406 18:12779947 Add A 1.19x10-2 1.36 (1.25-1.49) rs35505357 18:12782448 Rec G 1.19x10-2 1.39 (1.23-1.57) rs1217404 18:12783086 Add T 1.18x10-2 1.39 (1.24-1.57)

256

rs13122932 18:12789556 Add G 1.18x10-2 1.35 (1.24-1.48) rs4670838 18:12792736 Add G 1.18x10-2 1.35 (1.24-1.48) rs1217405 18:12795420 Add A 1.17x10-2 1.35 (1.23-1.47) rs2488458 18:12797694 Add T 1.16x10-2 1.22 (1.14-1.3) rs34453863 18:12808140 Add C 1.15x10-2 1.39 (1.24-1.57) rs7793125 18:12809340 Add A 1.14x10-2 1.39 (1.24-1.57) rs77841697 18:12818922 Add G 1.14x10-2 1.37 (1.21-1.56) rs2631360 18:12820900 Rec G 1.13x10-2 0.82 (0.77-0.88) rs1217420 18:12821593 Add A 1.13x10-2 0.82 (0.77-0.88) rs6537798 18:12821903 Add C 1.12x10-2 1.3 (1.19-1.42) rs16833214 18:12822314 Add G 1.11x10-2 0.83 (0.78-0.89) rs3734540 18:12823402 Add C 1.10x10-2 1.3 (1.19-1.42) rs13207371 18:12824930 Add A 1.10x10-2 0.84 (0.78-0.89) rs2614276 18:12826385 Add T 1.09x10-2 1.3 (1.19-1.41) rs9548926 18:12829065 Add C 1.07x10-2 0.83 (0.78-0.89) rs2283868 18:12830538 Add T 1.07x10-2 0.82 (0.77-0.88)

257

rs1230686 18:12832842 Add G 1.06x10-2 0.83 (0.78-0.89) rs2494695 18:12834359 Add T 1.06x10-2 0.84 (0.78-0.89) rs7705189 18:12835976 Add G 1.05x10-2 0.83 (0.78-0.89) rs17591266 18:12841176 Add G 1.05x10-2 0.83 (0.77-0.88) rs34303787 18:12842480 Dom C 1.04x10-2 1.33 (1.21-1.47) rs1230682 18:12842567 Add G 1.03x10-2 1.33 (1.21-1.47) rs13140970 18:12842681 Add G 1.03x10-2 1.33 (1.21-1.47) rs6946509 18:12843137 Add T 1.03x10-2 1.32 (1.21-1.43) rs7529353 18:12843263 Add A 1.03x10-2 0.82 (0.77-0.88) rs2797414 18:12847136 Add G 1.03x10-2 1.31 (1.2-1.43) rs2494708 18:12848349 Add T 1.02x10-2 0.82 (0.77-0.88) rs2746430 18:12850211 Add A 1.02x10-2 1.31 (1.2-1.43) rs10463196 18:12853458 Rec T 1.01x10-2 1.31 (1.2-1.43) rs1217418 18:12854072 Add A 1.01x10-2 1.3 (1.2-1.42) rs12173982 18:12855440 Add C 1.01x10-2 1.31 (1.2-1.42) rs6892698 18:12855864 Rec C 1.00x10-2 1.34 (1.22-1.48)

258

rs80156335 18:12856908 Add T 1.00x10-2 0.83 (0.77-0.88)

rs228963 18:12857335 Add G 1.00x10-2 1.31 (1.2-1.42) rs9532432 18:12858610 Add A 9.98x10-3 1.31 (1.21-1.43) rs17622208 18:12860934 Add A 9.92x10-3 1.31 (1.2-1.43) rs7325068 18:12863840 Add A 9.91x10-3 1.34 (1.21-1.47) rs11102691 18:12864762 Add T 9.87x10-3 1.34 (1.21-1.47) rs1217419 18:12865822 Add T 9.82x10-3 1.34 (1.22-1.48) rs11208540 18:12868506 Add G 9.68x10-3 1.32 (1.21-1.44) rs6596070 18:12870499 Add C 9.61x10-3 1.36 (1.19-1.55) rs9548901 18:12871972 Add T 9.61x10-3 1.34 (1.22-1.47) rs9548930 18:12872424 Add T 9.58x10-3 1.34 (1.22-1.47) rs1217409 18:12875975 Add C 9.58x10-3 1.32 (1.21-1.44) rs2614278 18:12877060 Add G 9.56x10-3 1.32 (1.21-1.43) rs4820010 18:12878582 Add A 9.54x10-3 1.34 (1.22-1.48) rs17696736 18:12879466 Add G 9.52x10-3 1.34 (1.22-1.48) rs13136827 18:12880206 Add C 9.52x10-3 1.31 (1.2-1.42)

259

rs11893432 18:12881361 Dom G 9.49x10-3 1.32 (1.21-1.44) rs3807028 18:12882359 Add A 9.49x10-3 0.83 (0.77-0.88) rs72795121 18:12884343 Add A 9.45x10-3 0.83 (0.77-0.88) rs1027203 18:12885577 Add C 9.40x10-3 1.35 (1.22-1.48) rs2172007 18:12886441 Add C 9.40x10-3 1.35 (1.23-1.49) rs5753117 18:36125658 Add G 9.38x10-3 1.21 (1.1-1.32) rs35026134 18:36125898 Add G 9.37x10-3 1.21 (1.11-1.33)

rs200838 18:36125986 Rec A 9.35x10-3 1.2 (1.1-1.32) rs6894249 18:36126923 Dom G 9.31x10-3 1.22 (1.11-1.33) rs2746427 18:36127494 Add T 9.16x10-3 1.23 (1.11-1.35) rs10858016 18:36129154 Add A 9.12x10-3 1.22 (1.11-1.33) rs61839672 18:36129451 Add A 9.10x10-3 1.22 (1.11-1.33) rs2074732 18:36129657 Add A 9.00x10-3 1.22 (1.11-1.33) rs9532436 18:36129761 Add A 8.98x10-3 1.22 (1.11-1.33) rs1428638 18:36130729 Dom T 8.98x10-3 1.22 (1.11-1.33) rs4408422 18:36131429 Add G 8.95x10-3 1.22 (1.11-1.34)

260

rs13151961 18:36131552 Add G 8.93x10-3 1.22 (1.11-1.33)

rs11242109 18:36131557 Add T 8.88x10-3 1.22 (1.11-1.33)

rs2451717 18:36132354 Add G 8.83x10-3 1.22 (1.11-1.35)

rs5997605 18:36139407 Add A 8.81x10-3 1.22 (1.11-1.33)

rs12525810 18:36140233 Add A 8.77x10-3 1.23 (1.11-1.35) rs117356590 18:36141662 Dom T 8.69x10-3 1.24 (1.12-1.37)

rs2179779 18:36142795 Add A 8.68x10-3 1.22 (1.11-1.34)

rs58811396 18:36142887 Rec A 8.57x10-3 1.22 (1.12-1.34)

rs59913349 18:36145004 Rec G 8.57x10-3 1.24 (1.12-1.37)

rs2243471 18:36146449 Add G 8.51x10-3 1.24 (1.12-1.37)

rs2746421 18:36149849 Add T 8.51x10-3 1.24 (1.12-1.37)

rs7765920 18:36149906 Add C 8.40x10-3 1.22 (1.12-1.34)

rs2746425 18:36152042 Add T 8.40x10-3 1.24 (1.13-1.38)

rs3789598 18:36153493 Add A 8.40x10-3 1.24 (1.14-1.36)

rs2746426 18:36156508 Add T 8.35x10-3 1.23 (1.12-1.35)

rs3024859 18:36159926 Add T 8.32x10-3 1.24 (1.14-1.36)

261

rs2104286 18:36160294 Rec C 8.25x10-3 1.25 (1.14-1.37) rs10518402 18:36161213 Add C 8.22x10-3 1.25 (1.14-1.37) rs10058074 18:36161584 Add A 8.17x10-3 1.25 (1.14-1.37) rs4820003 18:36162582 Add T 8.14x10-3 1.25 (1.13-1.38) rs67434056 18:42366648 Dom G 8.07x10-3 2.48 (1.62-3.79) rs6456738 18:44887089 Add T 8.05x10-3 0.59 (0.46-0.75) rs2240422 18:44895906 Add T 8.05x10-3 0.6 (0.47-0.76) rs2101582 18:44899325 Add T 7.88x10-3 0.6 (0.47-0.76) rs2494709 18:44902098 Add C 7.84x10-3 0.59 (0.46-0.75) rs7556622 18:63140423 Add C 7.84x10-3 1.19 (1.1-1.29) rs11102671 18:63141908 Add T 7.81x10-3 1.19 (1.1-1.29) rs6912292 18:63144954 Add C 7.81x10-3 1.19 (1.1-1.29)

rs388373 18:63146018 Add T 7.81x10-3 1.19 (1.1-1.29) rs13426947 18:63146247 Add A 7.81x10-3 1.19 (1.1-1.29) rs9461276 18:63150470 Add C 7.81x10-3 1.19 (1.1-1.29) rs3800303 18:63154900 Add G 7.80x10-3 1.19 (1.1-1.29)

262

rs7767847 18:63156868 Add T 7.77x10-3 1.19 (1.1-1.29) rs6840978 18:63161923 Add T 7.76x10-3 1.2 (1.1-1.3) rs10075801 18:63177860 Add G 7.76x10-3 1.21 (1.11-1.31) rs2451732 18:63186922 Add A 7.76x10-3 1.2 (1.1-1.3) rs2494696 18:63187229 Add G 7.72x10-3 1.2 (1.1-1.3) rs2146019 18:63189058 Add C 7.72x10-3 1.2 (1.1-1.3) rs34135604 18:63189066 Add A 7.72x10-3 1.2 (1.1-1.3) rs1544777 18:63189455 Dom G 7.72x10-3 1.2 (1.1-1.3) rs6466702 18:63190772 Dom C 1.48x10-2 1.2 (1.11-1.31) rs10228518 18:63191276 Dom G 1.48x10-2 1.2 (1.11-1.31) rs7945962 18:63191367 Dom A 1.48x10-2 1.2 (1.1-1.3) rs10258423 18:63192879 Dom A 1.48x10-2 1.2 (1.11-1.31) rs4611851 18:63193528 Dom C 1.48x10-2 1.2 (1.11-1.31) rs4432137 18:63195218 Add G 1.48x10-2 1.2 (1.1-1.3) rs4334152 18:63195942 Add G 1.48x10-2 1.2 (1.1-1.3) rs9532417 18:63196665 Add G 1.48x10-2 1.2 (1.1-1.3)

263

rs34014736 18:77256620 Dom T 1.48x10-2 0.84 (0.78-0.91) rs4514547 18:77264539 Add C 1.49x10-2 0.84 (0.78-0.91) rs9548877 18:77264649 Add T 1.47x10-2 0.84 (0.78-0.91) rs76570161 18:77268510 Dom G 1.47x10-2 0.84 (0.78-0.91) rs41525648 18:77268694 Add A 1.46x10-2 0.84 (0.78-0.91) rs1217411 18:77273646 Add A 1.44x10-2 0.84 (0.78-0.91) rs12521868 19:8368142 Rec T 1.43x10-2 0.83 (0.77-0.9) rs4485233 19:8369504 Add A 1.43x10-2 0.83 (0.76-0.9) rs2797416 19:8376431 Add T 1.43x10-2 0.83 (0.77-0.9) rs2476600 19:8388940 Add A 1.43x10-2 0.83 (0.77-0.91) rs11961563 19:8393126 Add C 1.43x10-2 0.83 (0.77-0.9) rs6563740 19:8395043 Add G 1.43x10-2 0.83 (0.77-0.91) rs7325354 19:9197528 Add C 1.43x10-2 1.16 (1.08-1.24) rs73529419 19:9198245 Add A 1.43x10-2 1.16 (1.08-1.24) rs3024886 19:9202286 Add A 1.42x10-2 1.15 (1.08-1.23) rs13101493 19:10466123 Add C 1.42x10-2 0.8 (0.73-0.89)

264

rs6563737 19:10475652 Add C 1.42x10-2 0.81 (0.74-0.89) rs7047097 19:10477067 Add C 1.41x10-2 0.81 (0.73-0.89) rs9548876 19:40366716 Add G 1.41x10-2 1.88 (1.39-2.53) rs7124910 19:42100825 Rec C 1.40x10-2 1.63 (1.31-2.03) rs12043386 19:45189000 Rec G 1.40x10-2 1.25 (1.12-1.4) rs7330515 19:45189191 Add T 1.40x10-2 1.26 (1.13-1.4) rs4598779 19:45189332 Add C 1.38x10-2 1.25 (1.12-1.4) rs1900334 19:45189451 Rec C 1.37x10-2 1.25 (1.12-1.4) rs17622378 19:45189493 Rec G 1.36x10-2 1.26 (1.13-1.4)

rs706779 19:45189611 Add C 1.35x10-2 1.26 (1.13-1.4) rs6822844 19:45189627 Add T 1.35x10-2 1.26 (1.13-1.4) rs2422247 19:45190163 Rec T 1.35x10-2 1.26 (1.13-1.4) rs7330016 19:45190526 Add C 1.35x10-2 1.26 (1.13-1.4) rs9548873 19:45190608 Add C 1.35x10-2 1.26 (1.13-1.4) rs1900333 19:45190982 Rec A 1.34x10-2 1.25 (1.12-1.4) rs62394558 19:45190985 Add A 1.33x10-2 1.25 (1.12-1.4)

265

rs66782936 19:45191010 Add G 1.32x10-2 1.25 (1.12-1.4) rs1217379 19:45191041 Add C 1.32x10-2 1.25 (1.12-1.4) rs4991898 19:45191186 Add T 1.32x10-2 1.25 (1.12-1.4) rs2069803 20:258820 Add C 7.56x10-3 1.24 (1.12-1.37) rs10168266 20:259513 Add T 7.54x10-3 1.22 (1.1-1.34) rs2504540 20:10364376 Add G 7.48x10-3 1.56 (1.28-1.9) rs79447522 20:10656087 Add T 7.48x10-3 1.28 (1.14-1.44) rs10111354 20:10681095 Add T 7.38x10-3 1.31 (1.15-1.48)

rs38032 20:10684218 Dom C 7.34x10-3 1.32 (1.16-1.49) rs2451750 20:10686700 Add T 7.34x10-3 1.31 (1.16-1.48) rs2451751 20:10691496 Add C 7.32x10-3 1.31 (1.16-1.48) rs9855938 20:10698303 Add G 7.25x10-3 1.31 (1.16-1.49) rs17013326 20:10701291 Add A 7.14x10-3 1.31 (1.16-1.48) rs13139130 20:52414486 Add G 7.14x10-3 0.77 (0.68-0.88)

rs228954 20:52415871 Add C 7.14x10-3 0.76 (0.67-0.86) rs9467805 20:56252485 Add T 7.14x10-3 1.79 (1.35-2.39)

266

rs2504600 20:62301970 Add A 7.13x10-3 0.86 (0.8-0.92) rs12566340 20:62302539 Add T 7.08x10-3 0.86 (0.8-0.92) rs9295701 20:62309554 Add C 7.04x10-3 0.86 (0.8-0.92)

rs27306 20:62310806 Dom G 6.99x10-3 0.86 (0.8-0.92) rs2614286 21:33140589 Add C 6.99x10-3 1.4 (1.2-1.63) rs2101581 21:33142383 Add T 6.99x10-3 1.4 (1.2-1.63) rs2451736 21:33144504 Add A 6.97x10-3 1.39 (1.19-1.63) rs2451741 21:33146205 Add G 6.97x10-3 1.39 (1.19-1.62) rs2130657 21:33147228 Add T 6.97x10-3 1.39 (1.19-1.62)

rs228953 21:33149127 Add A 6.97x10-3 1.39 (1.19-1.62) rs2451737 21:33149501 Add C 6.97x10-3 1.39 (1.19-1.62) rs2494693 21:33149658 Add C 6.97x10-3 1.39 (1.19-1.62) rs2494694 21:33151096 Add T 6.97x10-3 1.38 (1.19-1.62) rs4800030 21:33151738 Dom G 6.97x10-3 1.38 (1.19-1.62) rs2494713 21:33153368 Add T 6.95x10-3 1.38 (1.18-1.62) rs35452333 21:33168078 Dom T 6.94x10-3 1.4 (1.2-1.64)

267

rs4755449 21:33169880 Dom T 6.94x10-3 1.4 (1.2-1.64) rs1775754 22:21916166 Add C 6.89x10-3 1.24 (1.12-1.36) rs13122573 22:21916272 Add T 6.89x10-3 1.24 (1.13-1.36) rs1535275 22:21917450 Add G 6.89x10-3 1.22 (1.12-1.34) rs2451731 22:21917479 Add C 6.89x10-3 1.23 (1.12-1.35) rs2504571 22:21917859 Add T 6.88x10-3 1.23 (1.12-1.35) rs1111695 22:21920817 Add C 6.86x10-3 1.23 (1.12-1.35)

rs38039 22:21922904 Dom C 7.72x10-3 1.23 (1.12-1.35) rs2504565 22:21925017 Add A 6.78x10-3 1.23 (1.12-1.35) rs34258372 22:21928597 Dom G 6.74x10-3 1.23 (1.12-1.35) rs55855422 22:21930093 Dom A 6.71x10-3 1.23 (1.12-1.35) rs7227126 22:21930777 Dom A 6.71x10-3 1.23 (1.12-1.35) rs12730675 22:21933428 Dom G 6.70x10-3 1.24 (1.13-1.37) rs2631367 22:21940310 Rec C 7.72x10-3 1.23 (1.12-1.35) rs9461275 22:21941915 Add T 7.72x10-3 1.23 (1.12-1.35) rs6925087 22:21942007 Add A 7.72x10-3 1.23 (1.12-1.35)

268

rs4368798 22:21942978 Add G 7.72x10-3 1.23 (1.12-1.35) rs1490488 22:21945096 Add C 7.72x10-3 1.23 (1.12-1.35) rs2494692 22:21945978 Add A 7.72x10-3 1.23 (1.12-1.35) rs2451740 22:21947467 Add T 7.72x10-3 1.23 (1.12-1.35) rs4245396 22:21950405 Add T 7.72x10-3 1.23 (1.12-1.35) rs4943694 22:21963786 Add T 7.72x10-3 1.23 (1.12-1.35) rs61464017 22:21970810 Dom G 7.72x10-3 1.23 (1.12-1.35)

rs737302 22:21973319 Rec G 7.70x10-3 1.23 (1.12-1.35) rs12722522 22:21979289 Add A 7.67x10-3 1.23 (1.12-1.36) rs17508163 22:30685560 Dom G 7.66x10-3 1.18 (1.1-1.27)

rs228958 22:30700924 Add C 7.66x10-3 1.17 (1.09-1.26) rs9467810 22:30705279 Add C 7.61x10-3 1.17 (1.09-1.26) rs61927163 22:30711624 Dom C 7.59x10-3 1.17 (1.09-1.26) rs61927164 22:30736147 Dom T 7.59x10-3 1.17 (1.09-1.26) rs11154799 22:30744444 Add C 6.65x10-3 1.18 (1.1-1.26) rs9467813 22:30750907 Add G 6.57x10-3 1.18 (1.1-1.27)

269

rs11154798 22:30755168 Add A 6.57x10-3 1.18 (1.1-1.27) rs2614259 22:30755172 Add C 6.56x10-3 1.18 (1.1-1.27) rs2614285 22:30773731 Add G 6.42x10-3 1.18 (1.1-1.27) rs9321501 22:30774490 Add C 6.40x10-3 1.18 (1.1-1.27) rs7748148 22:30776419 Add T 6.38x10-3 1.18 (1.1-1.27) rs6696784 22:30777888 Add G 6.31x10-3 1.19 (1.11-1.28) rs4581284 22:30780724 Dom A 6.30x10-3 1.17 (1.09-1.25) rs12722558 22:30780889 Add T 6.21x10-3 1.17 (1.09-1.25) rs12740234 22:30781182 Rec A 6.18x10-3 1.17 (1.09-1.25) rs3856863 22:30781512 Dom A 6.18x10-3 1.17 (1.09-1.25) rs2494700 22:30782089 Add T 6.18x10-3 1.16 (1.08-1.24) rs1021372 22:30783525 Add C 6.18x10-3 1.17 (1.09-1.25) rs1021373 22:30783551 Add A 6.18x10-3 1.17 (1.09-1.26) rs2451744 22:30790807 Add T 6.18x10-3 1.17 (1.09-1.26) rs2494701 22:30793137 Add T 6.18x10-3 1.17 (1.09-1.25) rs1027204 22:30793270 Add C 6.18x10-3 1.16 (1.08-1.25)

270

rs2504592 22:30797590 Add G 6.18x10-3 1.16 (1.09-1.25) rs2064431 22:30799720 Add G 6.18x10-3 1.17 (1.09-1.26) rs2614284 22:30800305 Add G 6.18x10-3 1.16 (1.09-1.25) rs2504599 22:30802444 Add T 6.18x10-3 1.17 (1.09-1.25) rs12722563 22:30803289 Add A 5.97x10-3 1.16 (1.08-1.24) rs10076758 22:30809342 Add G 5.92x10-3 1.16 (1.08-1.25) rs11745587 22:30864269 Dom A 5.92x10-3 1.28 (1.14-1.44) rs2185971 22:34533197 Add G 5.90x10-3 4.21 (2.15-8.22) rs6918097 22:34544645 Add A 6.18x10-3 4.28 (2.19-8.36) rs34021916 22:37531436 Add G 6.14x10-3 0.84 (0.78-0.9) rs12653783 22:37532665 Add G 6.11x10-3 0.84 (0.78-0.9) rs12657965 22:37533786 Add G 6.11x10-3 0.84 (0.78-0.9) rs2498380 22:37533795 Add C 6.11x10-3 0.84 (0.79-0.91) rs13224682 22:37534947 Add G 6.11x10-3 0.85 (0.79-0.91) rs2223803 22:37535948 Add T 6.09x10-3 0.84 (0.78-0.91) rs2746429 22:37627234 Add C 6.69x10-3 0.78 (0.7-0.88)

271

rs2947344 22:37627246 Dom G 6.66x10-3 0.79 (0.7-0.88)

rs9295696 22:37627845 Add C 6.02x10-3 0.78 (0.69-0.87)

rs12967678 22:37633851 Add A 6.02x10-3 0.79 (0.71-0.89)

rs4705916 22:45196994 Add A 6.01x10-3 2.88 (1.75-4.72) aCoordinates are based on the GRCh37 assembly

Add=Additive, Dom=Dominant, Rec=Recessive, FDR=False Discovery Rate, OR=Odds Ratio, CI=Confidence Interval

272

Supplemental Table 4. Histone modificationsa at SNP positions in the nine regions with genetic association with oligoarticular and polyarticular RF negative JIA (P < 1x10-6)

273

274

Supplemental Table 5. Oligoarticular and RF negative polyarticular JIA association results for genome-wide significant SNPs associated with rheumatoid arthritis (RA)a

JIA Reference RA JIA RAF JIA P- JIA JIA OR (95% SNPb Gene Region RAF Powerc Allele OR Controlsb value Model CI) Casesb -1 rs187786174 MMEL1 A 1.10 0.32 0.32 5.83x10 Add 0.99 (0.92-1.06) 0.361

-1 rs227163 UTS2 C 1.00 0.41 0.42 1.43x10 Rec 0.92 (0.82-1.04) 0.000

-2 rs28411352 MTF1 T 1.10 0.26 0.24 1.17x10 Add 1.10 (1.02-1.19) 0.273

rs12140275 MIR3659 T 1.11 0.24 0.24 1.61x10-1 Add 0.95 (0.89-1.03) 0.371

-17 rs2476601 PTPN22 A 1.80 0.14 0.10 3.11x10 Add 1.52 (1.38-1.69) 0.990

rs624988 MIR320B1_CD2 T 1.09 0.40 0.40 3.76x10-1 Dom 0.95 (0.84-1.08) 0.087

-4 rs2228145 IL6R C 1.07 0.38 0.40 3.40x10 Add 0.90 (0.85-0.96) 0.125

rs2317230 FCRL3_FCRL2 T 1.06 0.42 0.42 2.27x10-1 Rec 0.94 (0.84-1.06) 0.073

rs72717009 C1orf192_FCGR2A T 1.12 0.11 0.13 4.79x10-2 Dom 0.80 (0.63-1.00) 0.225

-3 rs2105325 LOC100506023 A 1.12 0.24 0.26 2.08x10 Add 0.88 (0.82-0.95) 0.511

-1 rs17668708 PTPRC T 1.12 0.10 0.11 2.61x10 Add 0.88 (0.71-1.10) 0.010

rs10175798 YPEL5 G 1.09 0.38 0.39 4.45x10-1 Dom 0.95 (0.86-1.04) 0.295

-1 rs34695944 REL C 1.13 0.28 0.31 2.16x10 Rec 1.10 (0.94-1.30) 0.689

275

rs13385025 B3GNT2 A 1.08 0.11 0.11 6.47x10-1 Add 1.04 (0.93-1.15) 0.040

-2 rs1858037 SPRED2 A 1.09 0.36 0.34 8.20x10 Add 1.06 (0.99-1.13) 0.270

-3 rs9653442 BC105019 C 1.12 0.49 0.46 1.53x10 Add 1.09 (1.03-1.17) 0.671

-2 rs6732565 ACOXL G 1.10 0.37 0.37 1.31x10 Dom 0.87 (0.79-0.95) 0.518

-10 rs11889341 STAT4 T 1.12 0.26 0.22 1.26x10 Add 1.27 (1.17-1.36) 0.438

-1 rs6715284 ALS2CR12 G 1.15 0.11 0.10 1.42x10 Dom 1.08 (0.96-1.21) 0.323

rs1980422 CD28_CTLA4 C 1.13 0.25 0.24 3.37x10-2 Add 1.09 (1.01-1.17) 0.584

rs3087243 CTLA4_ICOS A 1.15 0.43 0.44 1.02x10-2 Dom 0.88 (0.08-0.97) 0.905

-1 rs4452313 PLCL2 T 1.11 0.30 0.30 6.58x10 Rec 0.95 (0.81-1.11) 0.454

rs3806624 EOMES G 1.08 0.47 0.46 3.32x10-1 Rec 1.12 (0.89-1.39) 0.012

-3 rs73081554 RPP14 T 1.18 0.08 0.06 8.38x10 Add 1.30 (1.07-1.57) 0.148

-2 rs9826828 STAG1 A 1.44 0.02 0.02 9.07x10 Dom 1.20 (0.94-1.53) 0.269 rs11933540 RBPJ C 1.15 0.32 0.31 1.05x10-1 Rec 1.11 (0.95-1.29) 0.856

-1 rs2664035 TEC A 1.08 0.41 0.40 5.43x10 Dom 1.04 (0.93-1.17) 0.201

-1 rs10028001 ANXA3 T 1.02 0.38 0.38 2.44x10 Rec 1.08 (0.92-1.27) 0.003 rs45475795 IL2_IL21 G 1.14 0.08 0.07 6.89x10-3 Add 1.19 (1.04-1.36) 0.144

276

R -1 rs2561477 C5orf30 A 1.11 0.31 0.31 2.24x10 Rec 0.91 (0.78-1.06) 0.465

rs657075 SnoZ6_P4HA2 A 1.07 0.09 0.10 1.68x10-2 Add 0.88 (0.79-0.98) 0.022

rs74984480 RNF182_CD83 T 1.10 0.05 0.05 2.18x10-1 Dom 0.91 (0.79-1.06) 0.024 rs116633882 Chr6q32 G 2.47 0.32 0.44 9.33x10-14 Dom 0.49 (0.41-0.59) 0.990

rs2234067 ETV7_PXT1 A 1.14 0.14 0.13 6.54x10-2 Dom 1.08 (0.98-1.21) 0.373

rs2233424 NFKBIE_TMEM151B T 1.33 0.04 0.05 1.93x10-1 Dom 0.79 (0.56-1.12) 0.079

-1 rs9372120 ATG5 G 1.10 0.20 0.20 1.44x10 Dom 1.08 (0.98-1.18) 0.219

rs17264332 AK124173 G 1.17 0.23 0.21 1.78x10-3 Add 1.13 (1.05-1.22) 0.857

rs7752903 TNFAIP3 G 1.41 0.03 0.03 4.20x10-2 Dom 1.20 (0.99-1.45) 0.842

-1 rs9373594 PPIL4 C 1.07 0.15 0.15 6.32x10 Add 0.98 (0.90-1.07) 0.040

rs2451258 TAGAP_FNDC1 C 1.10 0.36 0.35 2.24x10-1 Dom 1.06 (0.97-1.17) 0.385

-1 rs1571878 CCR6 C 1.13 0.45 0.44 1.31x10 Rec 1.08 (0.97-1.21) 0.770

-1 rs67250450 JAZF1 C 1.11 0.22 0.21 2.67x10 Dom 1.05 (0.95-1.15) 0.320

-1 rs4272 CDK6 G 1.10 0.21 0.21 6.90x10 Rec 1.04 (0.84-1.29) 0.233

-1 rs3778753 IRF5 G 1.12 0.46 0.45 3.15x10 Add 1.05 (0.96-1.15) 0.251

rs2736337 FAM167A_BLK C 1.09 0.27 0.25 5.78x10-2 Dom 1.10 (0.98-1.23) 0.108

277

rs998731 TPD52 T 1.09 0.46 0.46 4.21x10-1 Dom 0.96 (0.86-1.07) 0.171

rs678347 AK291701_GRHL2 G 1.10 0.28 0.28 2.29x10-1 Rec 0.90 (0.76-1.06) 0.321

rs1516971 Chr8q130 C 1.16 0.12 0.13 2.95x10-3 Add 0.87 (0.79-0.96) 0.541

-4 rs10985070 PHF19 C 1.09 0.46 0.43 1.80x10 Dom 1.21 (1.10-1.34) 0.308

-8 rs706778 IL2RA T 1.12 0.45 0.41 6.48x10 Add 1.19 (1.12-1.27) 0.658

rs947474 LOC399715_PRKCQ G 1.12 0.19 0.19 5.34x10-1 Dom 0.96 (0.88-1.06) 0.374

-1 rs3824660 GATA3 C 1.10 0.39 0.40 6.95x10 Add 0.97 (0.85-1.11) 0.023

rs793108 ZNF438_AK296146 T 1.07 0.50 0.49 1.02x10-1 Add 1.05 (0.99-1.12) 0.132

-2 rs2671692 WDFY4 G 1.06 0.38 0.37 2.51x10 Dom 1.11 (1.01-1.22) 0.067

-1 rs6479800 ZNF365 C 1.08 0.23 0.23 2.17x10 Add 0.96 (0.89-1.03) 0.118

-1 rs726288 SFTPD T 0.96 0.03 0.03 3.03x10 Dom 1.15 (0.94-1.41) 0.002

rs331463 PRR5L_TRAF6 A 1.12 0.15 0.15 2.24x10-1 Rec 1.24 (0.89-1.73) 0.277

-1 rs508970 VPS37C A 1.07 0.49 0.48 4.18x10 Add 1.03 (0.97-1.10) 0.132

-1 rs968567 FADS2 T 1.12 0.16 0.17 5.53x10 Add 0.97 (0.89-1.06) 0.326

-1 rs11605042 ARAP1 A 1.05 0.49 0.48 1.33x10 Dom 1.09 (0.99-1.21) 0.039

rs4409785 FAM76B C 1.12 0.18 0.17 1.22x10-1 Add 1.09 (0.98-1.22) 0.096

278

-1 rs138193887 CUL5 G 1.21 0.07 0.07 1.15x10 Rec 1.84 (0.86-3.93) 0.316 rs10790268 DDX6_CXCR5 A 1.17 0.20 0.20 2.01x10-1 Rec 1.15 (0.91-1.47) 0.839

-4 rs1633360 OS9 C 1.08 0.39 0.41 8.59x10 Rec 0.82 (0.72-0.92) 0.203 rs9603616 COG6 T 1.11 0.30 0.34 4.77x10-7 Add 0.84 (0.79-0.90) 0.495

-1 rs3783782 PRKCH A 1.12 0.01 0.01 4.10x10 Dom 0.87 (0.63-1.19) 0.004

-1 rs1950897 RAD51B C 1.09 0.29 0.29 3.46x10 Rec 1.14 (0.93-1.40) 0.128

-1 rs2582532 PLD4 T 0.93 0.01 0.01 7.82x10 Dom 0.97 (0.73-1.29) 0.002

-1 rs8032939 RASGRP1 C 1.13 0.26 0.26 4.45x10 Add 1.03 (0.96-1.11) 0.619

rs8026898 AK097902 A 1.15 0.27 0.27 2.40x10-2 Rec 1.21 (1.01-1.43) 0.815

-1 rs72634030 Nup88 A 1.12 0.07 0.07 1.30x10 Dom 1.11 (0.97-1.27) 0.082

rs1877030 CDK12_NUEROD2 T 1.09 0.16 0.16 1.52x10-1 Dom 0.94 (0.85-1.04) 0.110

-3 rs59716545 ZPBP2 G 1.09 0.47 0.44 4.51x10 Rec 1.22 (1.06-1.40) 0.311

-10 rs8083786 PTPN2 G 1.12 0.19 0.16 1.35x10 Add 1.32 (1.21-1.44) 0.302

-2 rs2469434 CD226 C 1.05 0.43 0.41 5.25x10 Add 1.09 (1.00-1.19) 0.012

-3 rs34536443 TYK2 C 1.46 0.03 0.05 1.69x10 Dom 0.57 (0.41-0.81) 0.244

-1 rs147622113 ILF3 T 1.47 0.02 0.03 2.50x10 Dom 0.78 (0.51-1.19) 0.108

279

-1 rs4239702 CD40 T 1.14 0.28 0.28 6.56x10 Dom 1.01 (0.92-1.11) 0.747

rs73194058 IFNAR1_IFNGR2 A 1.13 0.12 0.12 4.10x10-1 Rec 0.85 (0.56-1.28) 0.263

-3 rs147868091 RCAN1 T 1.12 0.13 0.12 3.17x10 Rec 1.96 (1.24-3.08) 0.200

-3 rs8133843 RUNX1 G 1.09 0.35 0.38 1.36x10 Dom 0.81 (0.71-0.92) 0.057

-1 rs1893592 UBASH3A C 1.11 0.25 0.27 2.60x10 Add 0.93 (0.82-1.06) 0.029

-5 rs2236668 ICOSLG T 1.07 0.27 0.29 9.05x10 Dom 0.81 (0.72-0.90) 0.051

rs11089637 UBE2L3_YDJC C 1.10 0.18 0.17 2.16x10-2 Add 1.12 (1.02-1.23) 0.092

-1 rs3218251 IL2RB A 1.08 0.29 0.28 1.35x10 Dom 1.13 (0.96-1.32) 0.015

-1 rs909685 SYNGR1 A 1.11 0.30 0.30 4.71x10 Dom 0.96 (0.88-1.06) 0.454

Power Total = 25.902 aList of included RA SNPs was derived from the 101 loci reported in Okada et al., Nature 2014 bCase n=2,751, Control n=15,886; the following SNPs did not pass QC in all cohorts: case-control numbers for rs73081554, rs2664035, rs10028001, rs2736337, rs1950897, rs59716545, and rs2236668 are 1,937 and 12,828, respectively; case-control numbers for rs998731, rs138193887, and rs11089637 are 1,871 and 14,901, respectively; case-control numbers for rs624988, rs3778753, rs4409785, and rs2469434 are 1,694 and 4,043, respectively; case-control numbers for rs11203202 are 1,057 and 11,843, respectively; case-control numbers for rs72717009, rs17668708, rs3806624, rs116633882, rs2233424, rs3824660, rs34536443, and rs147622113 are 880 and 985, respectively; case-control numbers for rs1893592 and rs3218251 are 814 and 3,058, respectively

280

cPower analysis was calculated based on the OR reported for RA, the allele frequency in the JIA controls, the JIA sample size, and the type I error rate defined by the Bonferroni correction p < 5.8x10-4

Add = Additive, Dom = Dominant, Rec = Recessive, RAF = Reference Allele Frequency, OR = Odds Ratio, CI = Confidence Interval

281

Supplemental Table 6. Oligoarticular and RF negative polyarticular JIA association results for genome-wide significant SNPs associated with type 1 diabetes (T1D)a

JIA Reference T1D JIA RAF JIA P- JIA JIA OR SNPb Gene Region RAF Powerc Allele OR Controlsb value Model (95% CI) Casesb -7 rs2476601 PTPN22 A 1.89 0.14 0.10 3.11x10 Add 1.52 (1.38-1.69) 1.000

-2 rs6691977 CAMSAP2 C 1.13 0.19 0.20 3.03x10 Dom 0.90 (0.82-0.99) 0.580

rs3024505 MAPKAPK2_IL10 A 0.86 0.16 0.16 3.21x10-1 Rec 1.22 (0.84-1.77) 0.275

rs13415583 AFF3_BC105019 G 0.90 0.33 0.36 2.95x10-3 Add 0.91 (0.85-0.98) 0.583

-1 rs4849135 ACOXL T 0.89 0.29 0.28 4.37x10 Dom 1.04 (0.95-1.14) 0.619

rs3087243 CTLA4_ICOS A 0.84 0.43 0.44 1.02x10-2 Dom 0.88 (0.80-0.97) 0.996 rs113010081 CCRL2_LTF C 0.85 0.09 0.11 1.22x10-3 Dom 0.79 (0.69-0.91) 0.350

rs2611215 HH932813 A 1.18 0.17 0.16 2.56x10-1 Dom 1.05 (0.95-1.16) 0.859

rs11954020 IL7R_CAPSL G 1.11 0.42 0.40 6.20x10-3 Add 1.09 (1.02-1.17) 0.618

-1 rs1538171 AK127472 G 1.12 0.47 0.46 1.72x10 Rec 1.09 (0.97-1.21) 0.744

-1 rs62447205 IKZF1 G 0.89 0.26 0.27 3.67x10 Dom 0.95 (0.85-1.06) 0.393

-1 rs6476839 GLIS3 T 1.12 0.41 0.41 8.05x10 Dom 1.00 (0.91-1.10) 0.732

-7 rs61839660 IL2RA T 0.62 0.07 0.10 4.80x10 Add 0.75 (0.67-0.84) 1.000

282

rs10795791 IL2RA_RBM17 G 1.16 0.45 0.41 1.29x10-7 Add 1.19 (1.11-1.26) 0.965

-1 rs12416116 RNLS A 0.85 0.28 0.28 7.51x10 Rec 1.05 (0.86-1.29) 0.820

-1 rs917911 CD69 C 1.10 0.37 0.37 2.79x10 Rec 1.07 (0.93-1.22) 0.481

rs705705 IKZF4_RPS26 C 1.25 0.33 0.33 1.22x10-1 Rec 1.12 (0.97-1.29) 1.000

-4 rs653178 ATXN2 C 1.30 0.53 0.49 3.08x10 Add 1.16 (1.07-1.27) 0.999 rs9585056 MIR548AN_AK123584 C 1.12 0.23 0.24 4.09x10-2 Rec 0.83 (0.68-1.02) 0.561 rs1456988 C14orf64 G 1.12 0.28 0.28 3.29x10-1 Add 1.04 (0.97-1.12) 0.624

-2 rs72727394 RASGRP1 T 1.15 0.21 0.20 9.90x10 Add 1.08 (1.00-1.17) 0.760

-1 rs12927355 CLEC16A T 0.82 0.32 0.33 1.63x10 Dom 0.95 (0.86-1.03) 0.999

-1 rs193778 RMI2 G 1.14 0.25 0.24 1.60x10 Dom 1.07 (0.98-1.18) 0.755 rs8056814 CTRB2_CTRB1 A 1.32 0.09 0.09 3.86x10-1 Add 1.05 (0.94-1.18) 0.995 rs12453507 ZPBP2_GSDMB C 0.90 0.49 0.50 1.61x10-2 Dom 0.88 (0.79-0.97) 0.650

rs757411 CCR7_SMARCE1 C 0.90 0.38 0.38 1.83x10-1 Add 0.95 (0.89-1.02) 0.600

-8 rs1893217 PTPN2 G 1.21 0.19 0.16 5.37x10 Dom 1.39 (1.24-1.57) 0.840

-9 rs12971201 PTPN2 A 0.89 0.37 0.41 7.82x10 Add 0.82 (0.77-0.88) 0.750 rs1615504 CD226 T 1.13 0.51 0.48 1.58x10-2 Dom 1.19 (1.03-1.36) 0.407

283

-3 rs12720356 TYK2 C 0.82 0.07 0.09 3.25x10 Add 0.79 (0.68-0.93) 0.283

-1 rs402072 PRKD2 C 0.87 0.15 0.15 3.90x10 Add 0.96 (0.87-1.05) 0.533

-1 rs516246 FUT2 T 0.87 0.49 0.47 1.87x10 Rec 1.08 (0.95-1.22) 0.787

-2 rs6043409 AK093519 A 0.88 0.33 0.34 3.42x10 Rec 0.86 (0.72-1.02) 0.597

rs6518350 C21orf33_ICOSLG G 0.88 0.17 0.19 2.27x10-2 Add 0.90 (0.81-1.00) 0.351

-1 rs4820830 HORMAD2 C 1.14 0.38 0.38 1.22x10 Dom 0.93 (0.85-1.02) 0.880

-3 rs229533 C1QTNF6 C 1.11 0.45 0.42 1.48x10 Add 1.12 (1.05-1.19) 0.626

rs2111485 FAP_IFIH1 A 0.85 0.38 0.39 4.57x10-1 Dom 0.93 (0.77-1.12) 0.204

rs10277986 GRB10_COBL T 0.76 0.04 0.03 6.60x10-1 Add 0.95 (0.74-1.21) 0.397

-1 rs11203202 UBASH3A G 1.16 0.34 0.34 3.00x10 Dom 1.07 (0.94-1.22) 0.468

Power Total = 26.080 aList of included T1D SNPs was derived from Onengut-Gumuscu et al., Nat Genet 2015 bCase n=2,751, Control n=15,886; the following SNPs did not pass QC in all cohorts: case-control numbers for rs113010081, rs62447205, rs12416116, rs1893217, rs516246, rs6043409, and rs6518350 are 1,937 and 12,828, respectively; case-control numbers for rs3024505, rs653178, rs1615504, and rs12720356 are 1,694 and 4,043, respectively; case-control numbers for rs11203202 are

1,057 and 11,843, respectively; case-controls numbers for rs2111485 are 880 and 985, respectively

284

cPower analysis was calculated based on the OR reported for T1D, the allele frequency in the JIA controls, the JIA sample size, and the type I error rate defined by the Bonferroni correction p < 1.2x10-3

Add = Additive, Dom = Dominant, Rec = Recessive, RAF = Reference Allele Frequency, OR = Odds Ratio, CI = Confidence Interval

285

Chapter 3: Whole exome trio sequencing implicates DOCK2 in juvenile idiopathic arthritis

286

ABSTRACT

Objective: Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease of childhood and has a fundamental genetic component. Genome-wide association studies have been the primary method for understanding genetic risk in complex diseases, including JIA, but they do not fully explain disease inheritance. This study focuses on identifying de novo mutations (DNMs) among sporadic oligoarticular and rheumatoid factor-negative (RF-) polyarticular JIA patients that may contribute to disease pathogenesis.

Methods: Whole exome sequencing (WES) and downstream bioinformatic analyses were used to identify rare, nonsynonymous DNMs among 10 oligoarticular or RF- polyarticular JIA patient- parent trios. Subsequent analysis of these mutations suggested a role for DOCK2 in JIA. The impact of DOCK2 genetic deficiency in C57BL/6 mice on arthritis development and progression was evaluated using the autoantibody-induced, K/BxN serum-transfer model.

Results: Sanger sequencing confirmed 15 nonsynonymous, DNMs identified by WES among 8

JIA trios. One DNM was located in DOCK2, whose gene product complexes with the gene products of two JIA-associated loci identified by association testing. In mice, DOCK2 deficiency resulted in decreased clinical measures of disease, while also reducing histopathological features in the forepaws, metacarpophalangeal joints, and knee joints induced by the K/BxN serum-transfer model. DOCK2 expression drives neutrophil infiltration into the hindpaws that can further exacerbate disease.

Conclusions: DOCK2 is a molecular determinant of autoantibody-induced arthritis that augments disease severity and pathology through a potential mechanism driving neutrophil infiltration. Furthermore, this study demonstrates the value of rare variant detection in understanding the genetic architecture of JIA.

287

Introduction

Juvenile idiopathic arthritis (JIA) is a complex genetic disease distinguished by inflammation of the joints and associated tissues that lasts for a minimum of six weeks with onset before the age of

16. It has a prevalence of approximately 1 in 1,000 children, making it the most common rheumatic disease of childhood [1]. The International League of Associations for Rheumatology categorizes

JIA into seven mutually exclusive subtypes [2]. The two most common subtypes, oligoarticular and rheumatoid factor (RF)-negative polyarthritis (poly RF-), are the focus of this study. These two disease categories share HLA associations and are differentiated primarily by the number of involved joints within the first six months of disease.

The approach to dissect the genetic basis of complex diseases and traits, including JIA, has been mostly focused on the “common disease-common variant” hypothesis with the use of genome- wide association studies (GWAS). There are concrete data supporting JIA’s genetic component, as evidenced by numerous established susceptibility loci [3-8], a sibling recurrence risk ratio of

11.6 [9], and a 25-40% monozygotic twin concordance rate [10]. However, it is estimated that the fraction of JIA risk attributable to the common SNP variation elucidated by large-scale association studies only accounts for about one-third of JIA heritability [4, 5]. Therefore, there is a need to explore other genetic sources of variability contributing to disease risk.

Germline de novo mutations (DNMs) are such sources of variability that are undetectable by large- scale studies, but can be identified by whole exome/genome sequencing (WES/WGS). These rare

DNA mutations are found in the genome of an individual, but neither parent, and can vary from a single base pair change to large (>50kbp) duplications, deletions, or rearrangements. It is estimated

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that each person possesses between 40-80 germline DNMs [11, 12], which is correlated with the father’s age at the time of conception [13]. Notably, DNMs contributing to risk have been reported in individuals with autism spectrum disorders [14], systemic lupus erythematosus [15], and early- onset sarcoidosis [16]. These studies have convincingly elucidated a path to gene discovery, which we extend to oligoarticular and poly RF- JIA to further delineate its genetic architecture. We hypothesize that DNMs will be unique to families, but located in genes related to known biological pathways associated with disease.

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Materials and Methods

Subjects. Ten trios (JIA patient, biological father, and biological mother) of European ancestry were selected for inclusion in this study. JIA subtypes were limited to oligoarthritis and RF- negative polyarthritis (poly RF-). Trios were recruited at Cincinnati Children’s Hospital Medical

Center (CCHMC) and Toledo Children’s Hospital. All cases met either the ILAR or American

College of Rheumatology (ACR) classification for JIA. DNA collections were approved and collected under the Institutional Review Board at CCHMC. Parents of participants provided written consent prior to enrollment in this study.

Whole exome sequencing and analyses. Trios were sequenced in three groups. The first and second groups contained 4 and 2 trios, respectively, and whole exome sequencing (WES) was performed at the CCHMC DNA Sequencing and Genotyping Facility using the Illumina HiSeq

2000 with the Illumina TruSeq DNA Library Prep. The third group contained 4 trios and WES was completed at PerkinElmer (Branford, CT) using the Illumina HiSeq 2000 with the Agilent

SureSelect Human All Exon V4. Sequence data were analyzed as previously described [17].

Briefly, the University of California, Santa Cruz (UCSC) reference human genome assembly 37 was used to align resulting reads using Burrows-Wheeler Aligner (BWA) [18] and variants were called by the Broad Institute’s Genome Analysis Tool Kit (GATK) [19]. VCF files generated by

GATK were analyzed with Golden Helix SNP and Variation Suite Software version 7.7.8

(Bozeman, MT).

De novo mutation validation. Polymerase chain reaction (PCR) primers were designed to amplify the region surrounding each candidate de novo mutation (DNM). DNA of each member of the trio

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was PCR amplified for the suspected DNM identified in the JIA proband. Samples were Sanger sequenced by GenScript (Piscataway, NJ). Resulting electropherograms were used to confirm the presence/absence of DNMs using SeqMan Pro (Lasergene, Madison, WI).

Mice. The C57BL/6 DOCK2 knockout (DOCK2-/-) mice have previously been described [20].

PCR primers to confirm DOCK2 genotype were: 1) 5’-GGAAAGACTAGCCCAGGAGAG-3’,

2) 5’-CCCAGCAGGTCTAAAGCAGATT-3’, 3) 5’-AGGATCTCCTGTCATCTCACCTTGCT

CCTG-3’, and 4) 5’-AAGAACTCGTCAAGAAGGCGATAGAAGGCG-3’. Briefly, primers 1 and 2 confirmed the presence of the wildtype (WT) allele and primers 3 and 4 confirmed the presence of a neomycin cassette. Animals were housed, bred, and maintained under specific pathogen-free conditions in the animal housing facility at CCHMC. Murine study protocols were approved by the Cincinnati Children’s Hospital Institutional Animal Care and Use Committee.

K/BxN serum-transfer model. Sera were pooled from adult KRNxNOD F1 mice that spontaneously developed arthritis [21]. Age-matched, female wildtype (WT) and DOCK2-/- mice, both on the C57BL/6 background, were injected intraperitoneally with 300μl of sera at day 0 of disease.

Clinical evaluation of arthritis. Arthritis development was monitored daily for 14 days. Calipers were used to measure mouse hindpaw thickness and ankle thickness. Ankle thickness was calculated using two measurements for elliptical area, which included an intermalleolar measurement and a measurement for the distance between the dorsal talus and calcaneus. These measurements are depicted in Figure S1. Macroscopic arthritis was evaluated using an arthritis

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index scoring system ranging from 0 to 4 for each paw (0 = no evidence of arthritis, 1 = swelling of paw or one digit, 2 = two joints involved, 3 = three joints involved, 4 = severe arthritis of the paw and digits).

Flow cytometry. For analysis of joint-derived cells, mice were sacrificed at day 9 and hindpaws were removed just above the ankle joint. Following skin dissection, the remaining tissue was put in 0.5ml of RPMI. Tissue was removed from the bones and joints using a number 10 scalpel and subsequently disaggregated, as described previously [22]. Joint cell suspensions were strained through a 100 micron filter, counted, and 2.5x105 cells were stained in FACS buffer (1X PBS, 1%

BSA) containing 2.4G2 (American Type Culture Collection) hybridoma supernatant. Splenocyte suspensions at day 14 following arthritis induction were strained through a 70 micron filter, counted, and 2.5x105 cells were stained in FACS buffer. The following antibody panel was used to assess joint-derived cells and splenocytes from K/BxN serum treated mice: FITC conjugated anti-CD4 (clone GK1.5, BioLegend, San Diego, CA), PerCP/Cy5.5 conjugated anti-CD11b (clone

M1/70, BioLegend), PE/Cy7 conjugated anti-CD19 (clone 6D5, BioLegend), APC conjugated anti-Ly6G (clone 1A8, BioLegend), APC/Cy7 conjugated anti-CD8 (clone 53-6.7, BioLegend), and V500 conjugated anti-CD3 (clone 500A2, Becton Dickinson (BD) Horizon, San Jose, CA).

Cells were acquired using FACSCanto or LSRFortessa (BD, Franklin Lakes, NJ) analytical cytometers and analyzed using FlowJo PC version 10.4.1 (Ashland, OR).

Histological analysis. Mouse tissues were fixed in formalin, decalcified in EDTA, and embedded in paraffin. Sectioned tissues were stained with hematoxylin and eosin (H&E). Forepaw, metacarpophalangeal joint, and knee joint sections were evaluated by two investigators, blinded

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to mouse genotype, by the following parameters: inflammation (scale of 0-3), synovial hyperplasia

(scale of 0-3), edema (scale of 0-3), pannus (scale of 0-1), and bone/cartilage erosion (scale of 0-

3). The scores for each metacarpophalangeal and knee joint of each mouse were summed (scale of

0-12) to calculate a total histopathology index. An additional score for overall forepaw inflammation (scale of 0-3) was included for forepaw sections only. Sections were imaged using a Nikon Eclipse Ti2 inverted microscope (Nikon Instruments Inc., USA).

Statistical analysis. GraphPad Prism version 7.04 (San Diego, CA) was used for statistical analysis. Mann Whitney U tests were used for group comparisons of unpaired, nonparametric data.

Descriptive statistics, as reported by median + interquartile range (IQR) are also reported.

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Results

Demographics

Inclusion criteria for trios first required a diagnosis of oligoarthritis (persistent or extended) or poly RF- in order to reduce heterogeneity. Patients with extreme phenotypes (age at onset ≤ 2 years old) were prioritized for inclusion to minimize environmental influences and maximize discovery, based on the assumption that stronger effects lead to early onset. Young age at onset might correlate to stronger genetics. Additionally, probands were selected that lacked JIA-associated

HLA-DRB1 risk alleles (DRB1*0801, *1103, *1104, and *1301) [23] and possessed minimal alleles for JIA risk loci with the strongest reported odds ratios (PTPN2, PTPN22, STAT4, and IL-

2/IL-21) [4]. This was meant to enrich for patients whose common variants were not likely to explain disease, and thus, the potential of discovering alternate genetic architecture. Of the included patients, six were diagnosed with oligoarticular JIA and four with poly RF- JIA. Overall, there were one male and nine female JIA cases. The mean age at disease onset was 1.38 years, which is considerably young when compared to the mean age at onset of our JIA cohort in a

GWAS, which was 5.53 years [3]. Three patients did not possess any of the selected associated risk alleles, while one patient had one risk allele and six patients possessed two risk alleles.

Notably, two patients possessed the protective HLA-DRB1 allele, *1501 [23]. Details are provided in Table S1.

Discovery of DNMs in oligoarticular and poly RF- JIA patients

A total of 26 nonsynonymous DNMs representing 25 genes were identified among the 10 trios using whole exome sequencing and downstream bioinformatic analyses. Of these, Sanger sequencing confirmed 15 nonsynonymous DNMs present in 8 of the 10 oligoarticular or poly RF-

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JIA probands. These validated DNMs are shown in Table 1. The DNMs were unique to individual patients and did not overlap with reported JIA-associated loci. Of the DNMs described in Table 1, four identical variants were found in the Exome Aggregation Consortium (ExAC) database [24]:

ZNF485, ARFGEF1, CELSR3, and C10orf12.

Validated DNMs were then analyzed relative to the known molecular pathways likely to function in disease pathogenesis. Interestingly, upon activation, DOCK2 forms a ternary complex with

ELMO1 and RAC molecules. A genetic locus that includes the ELMO1 gene has recently been reported to associate with oligoarticular and poly RF- JIA patients in a GWAS (P = 5.87x10-6 [3]), and single nucleotide polymorphisms (SNPs) in the intronic region of RAC2 reach genome-wide significance (P < 5x10-8; data not published, Juvenile Arthritis Consortium for Immunochip

(JACI)). Since independent lines of genetic evidence supports a role for each component of the ternary complex in oligoarticular and poly RF- JIA, this implicates the DOCK2 complex in JIA disease pathogenesis. Thus, we sought to determine the role of DOCK2 in a mouse model of arthritis.

Loss of DOCK2 diminishes autoantibody-induced arthritis

To determine the role of DOCK2 in the pathogenesis of autoantibody-induced arthritis, the progression of disease was evaluated in wildtype (WT) and DOCK2 deficient (DOCK2-/-) female mice on the C57BL/6 background using the K/BxN serum-transfer arthritis model [25]. Mice challenged with this sera were monitored for 14 days following injection. Disease was penetrant in 100% of WT and DOCK2-/- mice. As shown in Figure 1A, the overall disease score was significantly reduced in DOCK2-/- mice compared to WT mice. These data are consistent with

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DOCK2 deficient mice exhibiting decreased measures of hindpaw thickness (Figure 1B) and ankle thickness (Figure 1C), which is illustrated in Figure 1D. This suggests that DOCK2 contributes to the pathogenesis of autoantibody-induced arthritis.

DOCK2 deficiency is protective against K/BxN serum-transfer arthritis-induced histological pathologies

The forepaws and knees of WT and DOCK2-/- mice were examined for histopathological evidence of inflammation and arthritis by hematoxylin and eosin (H&E) staining at day 14 following sera administration. Importantly, DOCK2 deficiency did not alter forepaw, metacarpophalangeal joint, or knee joint architecture (Figures 2A, 2C, and 3A) in unchallenged mice. Inflammation was noticeably present in forepaw sections of arthritic WT mice, whereas DOCK2-/- mice showed little to no cellular influx (Figure 2A). Quantitative scoring of forepaw inflammation revealed significantly decreased cellular inflammatory infiltrate in DOCK2 deficient mice compared to WT mice (Figure 2B). Furthermore, the pattern of decreased joint disease (i.e. clinical index scoring) in DOCK2 deficient mice was consistent with diminished pathology in the metacarpophalangeal joints of the forepaw (Figure 2C). Microscopic evaluation of pathological features in the metacarpophalangeal joints revealed that inflammation, synovial hyperplasia, and cartilage/bone erosion were considerably reduced in DOCK2-/- mice (Figure 2D). This resulted in an overall decrease in the cumulative histopathological index score relative to WT mice (P < 0.05, Figure

2E).

Consistent with the joints in the forepaws, DOCK2 deficiency had no impact on normal knee histopathology in unchallenged mice, but following arthritis induction, resulted in markedly

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decreased disease severity in the knees compared to WT mice (Figure 3A). Quantitative analyses of histopathologic disease confirmed decreased inflammation and synovial hyperplasia in

DOCK2-/- mice (Figure 3B), leading to an overall significant reduction in the cumulative histopathology index score compared to WT mice (median + IQR: WT = 0 + 7.438, DOCK2-/- =

0 + 0; P = 0.039). The histopathological data from the forepaws, metacarpophalangeal joints, and knee joints suggests that DOCK2 is a regulator of arthritis by driving pathological aspects of disease.

DOCK2-/- mice have reduced hindpaw neutrophil infiltration in autoantibody-induced arthritis

Given the essential role for neutrophils in the development of K/BxN serum-transfer arthritis [26,

27] and the observation that neutrophils are the most abundant cell population in the synovial fluid of JIA patients [28], it was important to determine whether neutrophil infiltration into the joint was altered with DOCK2 deficiency. At day nine following the administration of sera in the K/BxN serum-transfer arthritis model, WT and DOCK2-/- mice were sacrificed and the hindpaws of individual mice were harvested. Resulting single cell suspensions were stained for neutrophil markers, CD11b and Ly6G. Figure 4A shows representative flow cytometry plots for neutrophils in the hindpaws of WT and DOCK2 deficient mice. Analysis of the joint cells showed a significant decrease in both the percentage and total number of neutrophils upon arthritis induction by sera treatment in the DOCK2-/- mice relative to the WT mice. This suggests that the expression of

DOCK2 is important to the progression and severity of arthritis by impacting the infiltration of neutrophils into the joint where disease is active.

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Due to the fact that neutrophil populations were decreased at local disease sites in DOCK2 deficient mice, we examined whether this was a defect in migration or if neutrophil populations are affected by genetic loss of DOCK2. Thus, we examined cells from the spleens of challenged

WT and DOCK2-/- mice. Neutrophil, B cell, and T cell (CD4+ and CD8+) populations in WT and

DOCK2-/- mice were analyzed in the spleen using markers for CD3, CD4, CD8, CD19, CD11b, and Ly6G. At day 14 following sera injection, mice were sacrificed and single cell suspensions were obtained from the spleen of each mouse. Representative plots for each cell type are provided in Figure S2A. Arthritic DOCK2 deficient mice had significantly decreased total numbers of T

(CD4+ and CD8+) and B cells, while there was no difference in the total number of neutrophils

(Figure S2B). Therefore, when compared to the site-specific joint infiltration, splenic levels of neutrophils were unaffected, which is consistent with an inflammatory process rather than a global defect in neutrophil numbers.

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DISCUSSION

This study used a WES strategy to investigate and identify rare, nonsynonymous DNMs in oligoarticular and poly RF- JIA patient-parent trios (Table 1). Our approach was designed to provide a better understanding of the genetic architecture of JIA by identifying novel genes related to known pathways that influence disease susceptibility. This limited variation detection to coding regions only, as mutations located in the promoter and intronic regions that might affect transcription were not evaluated. Validated DNMs were located in genes that were unique to each individual patient and were not found in any established JIA risk loci. It is interesting to note that validated DNMs were found in two DOCK family proteins (DOCK2 and DOCK11) in our study of 10 JIA trios, suggesting a role for this family of proteins in JIA pathogenesis. The DOCK proteins are a family of 11 evolutionarily conserved guanine exchange factors (GEFs) for the Rho family of GTPases (RHO, RAC, and CDC42) that are differentiated by their sequence homology and substrate specificity [29]. DOCK2 warranted further investigation given the independent lines of genetic evidence (discussed below) for each component of the DOCK2-ELMO1-RAC complex.

DOCK2 is a GEF expressed in hematopoietic cells that specifically activates RAC molecules, which act as molecular switches to initiate actin polymerization and cytoskeletal reorganization for necessary processes, such as cellular migration [20, 30]. DOCK2 is highly conserved across the phylogenetic tree and binds to the adaptor protein, ELMO1 [31]. In unstimulated conditions, both DOCK2 and ELMO1 are self-inhibited and in inactive states. The ability of DOCK2 to activate RAC molecules is enhanced when DOCK2 is complexed with ELMO1 [32], and point mutations in DOCK2 have been shown to affect binding to ELMO1 [33]. Intriguingly, the

Ile101Val DOCK2 DNM reported here, which appears to be a private mutation as it was not

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detected in any individual of a JIA case-control cohort (n = 1,873) that we genotyped, is directly adjacent to a mutation affecting ELMO1 binding at position Trp102 [32]. Despite the fact that

SIFT and PolyPhen2 predict the nonsynonymous mutation to be benign or tolerated, sequence- based prediction of propensity for secondary structure elements and conformational flexibility

(upon an Ile to Val substitution) suggest that the Ile101Val DOCK2 mutation may allosterically disrupt DOCK2 autoinhibition and/or alter ELMO1 binding, both of which would cause aberrations in RAC activation. As a whole, DOCK2 activation is the initiating event in the formation of this DOCK2-ELMO1-RAC complex that enables downstream cellular events. The discovery of a DOCK2 DNM is interesting in the context of JIA genetic association findings.

Specifically, we recently reported an association with a locus that includes the ELMO1 gene (P =

5.87x10-6) with oligoarticular and poly RF- JIA patients of European ancestry [3], and have new association findings among patients of the same ethnic background for intronic RAC2 SNPs that reach genome-wide levels of significance (data not published, JACI). The fact that genetic findings support a role for each component of this complex in disease suggested that variations in DOCK2 may also influence arthritis.

Given that JIA is an autoimmune disease, it is important to consider the role of DOCK2 in immune functions. DOCK2 deficient lymphocytes (T and B cells) do not respond chemotactically when stimulated with chemokines CCL21, CXCL12, and CXCL13. This has been shown to be due to failed RAC activation and subsequent actin polymerization for cellular migration [20]. Similar defects in chemotaxis are found in DOCK2-/- plasmacytoid dendritic cells (in response to CXCL12 and CXCL9) and neutrophils (in response to fMLP (N-Formylmethionyl-leucyl-phenylalanine),

C5a, and PMA (phorbol myristate acetate)) [34, 35]. In addition to migratory defects, loss of

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DOCK2 also impacts immune cell effector function. For example, loss of DOCK2 in CD4+ T cells impairs cellular proliferation [36] and skews differentiation toward a T helper (Th) type 2 response

[37]. Furthermore, DOCK2 deficient neutrophils have inhibited superoxide production and extracellular trap formation [38], while natural killer cells have reduced cytotoxicity [39]. Thus, the ability of cells in the immune system to expand and secrete mediators is impaired with DOCK2 deficiency. These findings are meaningful when considered in the context of the disease process in JIA, and future work to dissect these features that impact neutrophils, and other cell types, in an inflammatory model of arthritis is necessary. JIA is characterized by an infiltration of activated immune cells into the synovium that subsequently proliferate. Infiltrating cells are predominantly neutrophils, but also include populations such as macrophages, autoantibody-secreting B cells, and autoreactive CD4+ T cells enriched for the Th1 phenotype [28, 40]. These cells secrete pro- inflammatory cytokines and mediators, such as TNF-α, IL-1β, IL-6, IL-12, and IFN-γ that contribute to joint pathology [40]. DOCK2 deficiency has been shown to reduce adipose tissue inflammation in a mouse model of obesity [41] and transplant rejection in a cardiac allograft model

[42]; therefore, arguing for the impact of the key migratory molecule, DOCK2, in an inflammatory mouse model of arthritis, and by translation, in JIA.

Subsequent studies were designed to determine the effect of DOCK2 deficiency in the autoantibody-mediated, K/BxN serum-transfer arthritis model that recapitulates the effector phase of arthritic disease. Our results indicate that DOCK2 deficiency impedes the progression of arthritis, as measured by reduced joint involvement and disease severity (Figure 1A-C).

Furthermore, histopathological analysis of the forepaws, metacarpophalangeal joints, and knee joints were consistent with the clinical scoring data. Joint pathology, as assessed by inflammation,

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synovial hyperplasia, and bone/cartilage erosion, was reduced in DOCK2-/- mice relative to WT mice (Figures 2 and 3). The detection of histopathology features in the knees of WT and DOCK2 deficient mice was unexpected considering that the K/BxN serum-transfer arthritis model primarily effects the most distal joints (i.e. forepaws and hindpaws) [43, 44] and not the knees.

This parallels oligoarticular and poly RF- JIA to an extent, as oligoarticular JIA typically affects joints such as the knees and ankles that can extend to the smaller joints (i.e. digits) and wrists; similarly, poly RF- JIA tends to affect smaller joints, but disease can also be present in larger joints

(e.g. knees) as well [40].

The K/BxN serum-transfer arthritis model requires that neutrophils and macrophages are present to drive disease, since neutrophil and macrophage depleted mice are completely resistant to the development of arthritis [26, 27, 45]. Moreover, DOCK2 expression is required for neutrophil, but not monocyte, chemotaxis [20, 35]. Thus, one mechanism by which DOCK2 deficient mice modulate the progression of arthritis was hypothesized and subsequently consistent with a decreased neutrophil population in the joint (Figure 4). Overall, our results are indicative of a role for neutrophil-expressed DOCK2 during the course of arthritis and highlight the importance of the role of DOCK2 in cellular migration, particularly of neutrophils, to the joint.

Considering the established role of DOCK2 in immune cell migration and effector function [20,

34-39], as well as the characteristic cellular infiltrate into the joints of JIA patients (e.g. neutrophils, macrophages, T and B cells) [28, 40], the development of a DOCK2-RAC protein- protein inhibitor is desirable and could prove to be a beneficial therapeutic intervention for not only JIA, but other autoimmune diseases and inflammatory immune-related disorders as well.

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Indeed, a small molecule inhibitor, CPYPP, has been reported to suppress DOCK2-RAC protein- protein interactions, resulting in decreased cellular chemotaxis and T cell activation [46].

However, there is high sequence homology among the DOCK family of proteins, and broader effects of CPYPP were detected as it also inhibited DOCK1 and DOCK5 activity [46], which may not be desirable. Recently, a DOCK2-specific inhibitory peptide has been described that impedes migration in a human B cell line at nanomolar concentrations [47]. This peptide may be a candidate for treatment of arthritis or other inflammatory conditions based on our findings for DOCK2 in a mouse model of arthritis and requires further study.

The use of the K/BxN serum-transfer arthritis model is limited by the fact that it is driven by the transfer of autoantibodies to glucose-6-phosphate isomerase (G6PI) [43, 48], which is not a known autoantigen for JIA or the clinically similar, rheumatoid arthritis (RA). However, the K/BxN serum-transfer arthritis model does offer insight for autoantibody-driven progression of arthritis, but only mimics the effector phase of the disease process. Through bypassing the requirement for

T and B cells [49, 50], we are limited in understanding the full impact that DOCK2 has in the pathogenesis of arthritis. Therefore, there is a need for further studies in a model that involves T and B cell activation, such as the collagen-induced arthritis (CIA) model, given the roles of these cells in JIA pathogenesis and the role of DOCK2 in lymphocyte chemotaxis and T cell proliferation

[20, 36, 40]. While the use of the DOCK2-/- mouse in a murine model of inflammatory arthritis was the first step in understanding how rare variant detection can lead to gene and pathway discovery, further work to recreate the DOCK2 DNM in a mouse is necessary in order to study its relevance to a murine model of arthritis. Moreover, the same strategy can be employed for the

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other validated DNMs described in Table 1, with priority being given to those mutations predicted by SIFT and PolyPhen2 to be damaging.

In conclusion, the results of this study support a role for rare variants contributing to JIA pathogenesis and have demonstrated that DNM detection may lead to the discovery of new genes and pathways that further the understanding of the genetic architecture underlying oligoarticular and poly RF- JIA risk. The studies presented here suggest that intervening with DOCK2-ELMO1-

RAC complex activity could provide significant benefit to limit the progression of arthritis. Further work evaluating the consequences of inhibiting DOCK2 activation on not only arthritis, but also in other models of inflammation, is necessary to fully appreciate the contribution of DOCK2 to immune regulation and its potential as a therapeutic target in clinical care.

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Acknowledgements

The authors thank Matt Flick, Heather Bear, Mackenzie Gauck, Lorie Luyrink, Seth Reighard, and

Marc Sudman for reagents and technical assistance. The authors would also like to thank the

Exome Aggregation Consortium and the groups that provided exome variant data for comparison.

A full list of contributing groups can be found at http://exac.broadinstitute.org/about.

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22. Latham, K.A., et al., Ex vivo characterization of the autoimmune T cell response in the HLA- DR1 mouse model of collagen-induced arthritis reveals long-term activation of type II collagen- specific cells and their presence in arthritic joints. J Immunol, 2005. 174(7): p. 3978-85. 23. Hollenbach, J.A., et al., Juvenile idiopathic arthritis and HLA class I and class II interactions and age-at-onset effects. Arthritis Rheum, 2010. 62(6): p. 1781-91. 24. Lek, M., et al., Analysis of protein-coding genetic variation in 60,706 humans. Nature, 2016. 536(7616): p. 285-91. 25. Ji, H., et al., Genetic influences on the end-stage effector phase of arthritis. J Exp Med, 2001. 194(3): p. 321-30. 26. Monach, P.A., et al., Neutrophils in a mouse model of autoantibody-mediated arthritis: critical producers of Fc receptor gamma, the receptor for C5a, and lymphocyte function-associated antigen 1. Arthritis Rheum, 2010. 62(3): p. 753-64. 27. Wang, J.X., et al., Ly6G ligation blocks recruitment of neutrophils via a beta2-integrin- dependent mechanism. Blood, 2012. 120(7): p. 1489-98. 28. Petty, R. and J. Cassidy, Textbook of Pediatric Rheumatology, ed. J. Cassidy and R. Petty. 2001, Philadelphia: WB Saunders Co. 29. Nishikimi, A., et al., Immune regulatory functions of DOCK family proteins in health and disease. Exp Cell Res, 2013. 319(15): p. 2343-9. 30. Nishihara, H., et al., Non-adherent cell-specific expression of DOCK2, a member of the human CDM-family proteins. Biochim Biophys Acta, 1999. 1452(2): p. 179-87. 31. Sanui, T., et al., DOCK2 regulates Rac activation and cytoskeletal reorganization through interaction with ELMO1. Blood, 2003. 102(8): p. 2948-50. 32. Stevenson, C., et al., Essential role of Elmo1 in Dock2-dependent lymphocyte migration. J Immunol, 2014. 192(12): p. 6062-70. 33. Hanawa-Suetsugu, K., et al., Structural basis for mutual relief of the Rac guanine nucleotide exchange factor DOCK2 and its partner ELMO1 from their autoinhibited forms. Proc Natl Acad Sci U S A, 2012. 109(9): p. 3305-10. 34. Gotoh, K., et al., Differential requirement for DOCK2 in migration of plasmacytoid dendritic cells versus myeloid dendritic cells. Blood, 2008. 111(6): p. 2973-6. 35. Kunisaki, Y., et al., DOCK2 is a Rac activator that regulates motility and polarity during neutrophil chemotaxis. J Cell Biol, 2006. 174(5): p. 647-52. 36. Sanui, T., et al., DOCK2 is essential for antigen-induced translocation of TCR and lipid rafts, but not PKC-theta and LFA-1, in T cells. Immunity, 2003. 19(1): p. 119-29. 37. Tanaka, Y., et al., T helper type 2 differentiation and intracellular trafficking of the interleukin 4 receptor-alpha subunit controlled by the Rac activator Dock2. Nat Immunol, 2007. 8(10): p. 1067-75. 38. Watanabe, M., et al., DOCK2 and DOCK5 act additively in neutrophils to regulate chemotaxis, superoxide production, and extracellular trap formation. J Immunol, 2014. 193(11): p. 5660-7. 39. Sakai, Y., et al., The Rac activator DOCK2 regulates natural killer cell-mediated cytotoxicity in mice through the lytic synapse formation. Blood, 2013. 122(3): p. 386-93. 40. Macaubas, C., et al., Oligoarticular and polyarticular JIA: epidemiology and pathogenesis. Nat Rev Rheumatol, 2009. 5(11): p. 616-26. 41. Guo, X., et al., DOCK2 deficiency mitigates HFD-induced obesity by reducing adipose tissue inflammation and increasing energy expenditure. J Lipid Res, 2017. 58(9): p. 1777-1784. 42. Jiang, H., et al., Deletion of DOCK2, a regulator of the actin cytoskeleton in lymphocytes, suppresses cardiac allograft rejection. J Exp Med, 2005. 202(8): p. 1121-30.

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43. Matsumoto, I., et al., How antibodies to a ubiquitous cytoplasmic enzyme may provoke joint- specific autoimmune disease. Nat Immunol, 2002. 3(4): p. 360-5. 44. Wipke, B.T., et al., Dynamic visualization of a joint-specific autoimmune response through positron emission tomography. Nat Immunol, 2002. 3(4): p. 366-72. 45. Solomon, S., et al., A crucial role for macrophages in the pathology of K/B x N serum-induced arthritis. Eur J Immunol, 2005. 35(10): p. 3064-73. 46. Nishikimi, A., et al., Blockade of inflammatory responses by a small-molecule inhibitor of the Rac activator DOCK2. Chem Biol, 2012. 19(4): p. 488-97. 47. Sakamoto, K., et al., Novel DOCK2-selective inhibitory peptide that suppresses B-cell line migration. Biochem Biophys Res Commun, 2017. 483(1): p. 183-190. 48. Matsumoto, I., et al., Arthritis provoked by linked T and B cell recognition of a glycolytic enzyme. Science, 1999. 286(5445): p. 1732-5. 49. Korganow, A.S., et al., From systemic T cell self-reactivity to organ-specific autoimmune disease via immunoglobulins. Immunity, 1999. 10(4): p. 451-61. 50. Maccioni, M., et al., Arthritogenic monoclonal antibodies from K/BxN mice. J Exp Med, 2002. 195(8): p. 1071-7.

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Figures

Figure 1. DOCK2 deficiency decreases measures of joint inflammation in the K/BxN serum- transfer model of arthritis. A-C, Time-course evaluations of arthritis (days 0-9, n = 16; days 9-14, n = 12) Data are median (A) or means ± SEM (B, C). Mann-Whitney U test. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. D, Photographs of representative WT and DOCK2-/- hindpaws taken at day 14 of experiment. Data are representative of two independent experiments.

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Figure 2. DOCK2 deficiency diminishes K/BxN serum-transfer arthritis in the forepaws of C57/BL6 mice. A, Representative hematoxylin and eosin (H&E)-stained forepaw sections of unchallenged and arthritic (day 14) mice with and without DOCK2. Following induction of arthritis, WT mice display significant inflammation in their forepaw. Conversely, DOCK2-/- mice show markedly attenuated cellular infiltration. B, Quantitative microscopic inflammatory analysis of individual H&E-stained forepaw sections from WT and DOCK2-/- arthritic mice (day 14). Bars show mean + SEM (n = 16/group). C, Representative hematoxylin and eosin-stained metacarpophalangeal joint sections of unchallenged and arthritic (day 14) mice with and without DOCK2. Note that arthritic, WT mice exhibit synovial hyperplasia (asterisk) and pannus formation (arrow) compared to DOCK2-/- mice. D, Quantitative microscopic analysis of individual histopathology features from H&E-stained metacarpophalangeal joint sections of WT and DOCK2-/- mice. Bars show mean + SEM (n = 16/group). E, Scatterplot of composite histopathology index analysis of H&E-stained metacarpophalangeal joint sections. Symbols represent the cumulative histopathology score given to one metacarpophalangeal joint from each forepaw (n = 16/group). Horizontal bar defines the median. P values determined by Mann-Whitney U tests in B, D, and E. *P < 0.05; **P < 0.01. Scale bars represent 500μm in A and 100μm in C.

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Figure 3. DOCK2 deficiency ameliorates K/BxN serum-transfer arthritis in the knees of C57/BL6 mice. A, Representative hematoxylin and eosin-stained knee joint sections of unchallenged and arthritic (day 14) mice with and without DOCK2. Upon arthritis induction, WT mice show visible evidence of joint pathology, including inflammation, synovial hyperplasia (asterisk), and erosive pannus (arrow), whereas the knees of DOCK2-/- mice exhibit diminished pathological characteristics. Bars represent 300μm. B, Quantitative microscopic analysis of knee joint pathology from WT and DOCK2-/- mice (n = 32/group; data combined from two independent experiments). Bars show mean + SEM. Mann-Whitney U test. *P < 0.05.

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Figure 4. DOCK2 deficiency decreases hindpaw neutrophil infiltration in K/BxN serum-transfer arthritis. Joint cells from hindpaws were harvested at day 9 and stained for neutrophil markers, CD11b and Ly6G. A, Representative contour plots indicate neutrophil populations in the hindpaws of arthritic WT and DOCK2-/- mice. B, Scatterplots of the percentage and total number of neutrophils in the hindpaws of arthritic WT (n = 8) and DOCK2-/- (n = 7) mice. Bars indicate mean ± SEM. Mann-Whitney U test. **P < 0.01. Independent experiment for replication, P = 0.06.

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Tables

Table 1. Validated DNMs among 10 trio probands with oligoarticular or RF-negative polyarticular JIA

SIFT PolyPhen2 Trio Gene Chr:Position* Classification DNA Coding Protein Identifier† Prediction Prediction

Possibly MAP1B 5:71493071 Nonsyn c.3889G>T p.Val129Met Damaging Damaging

Possibly 1 TNFAIP8 5:118728994 Nonsyn c.485A>G p.Tyr162Cys Damaging Damaging

DOCK2 5:169098158 Nonsyn c.301A>G p.Ile101Val Tolerated Benign

ZNF485‡ 10:44104793 Nonsyn c.242A>G p.His81Arg Tolerated Benign

SYCP2L 6:10935372 Nonsyn c.1765C>G p.Gln589Glu Tolerated Benign 2 ARFGEF1‡ 8:68115462 Nonsyn c.4984C>T p.Arg1662Cys rs146795624 Damaging Benign

Possibly 3 MLL2 12:49443503 Nonsyn c.3868C>T p.Arg1290Trp Damaging Damaging

c.2835-2837 p.945-946 4 PRR12 19:50100427 Deletion CTT>DelCTT delinsSer

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5 GCC2 2:109102107 Nonsyn c.3629C>T p.Ser1210Leu Tolerated Benign

6 No DNMs

7 No DNMs

Possibly 8 CELSR3‡ 3:48682525 Nonsyn c.7915C>T p.Arg2639Cys rs145413655 Tolerated Damaging

APOD 3:195300829 Stop Gain c.137G>A p.Trp46*

C10orf12‡ 10:98742112 Nonsyn c.965G>A p.Gly322Asp Tolerated Benign

Probably 9 LONP1 19:5707145 Nonsyn c.1072C>T p.Arg358Trp Damaging Damaging

Probably DOCK11 X:117714115 Nonsyn c.1568A>G p.Tyr523Cys Damaging Damaging

Probably 10 CHD2 15:93489342 Nonsyn c.1273T>C p.Cys425Arg Damaging Damaging

DNMs = de novo mutations; JIA = juvenile idiopathic arthritis; Chr = chromosome; Nonsyn = Nonsynonymous mutation

* Coordinates are based on the GRCh37 assembly.

† Identifiers come from dbSNP.

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‡ Identical mutations have been reported in the ExAC database [24]; allele frequencies for the indicated mutation are as follows:

ZNF485 = 1.673x10-5, ARFGEF1 = 1.585x10-3, CELSR3 = 3.044x10-4, and C10orf12 = 1.648x10-5.

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Figure S1. Depiction of hindpaw and ankle thickness measurements. Red lines indicate locations where measurements are made for hindpaw thickness (A) and ankle circumference (B). The two measurements in B are used to calculate the elliptical area for the measure of ankle thickness.

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Figure S2. Cellular homing of T and B cells to the spleen is impaired with genetic loss of DOCK2 in K/BxN serum-transfer arthritis. Splenocytes were harvested at day 14 and stained for CD3, CD4, CD8, CD19, CD11b, and Ly6G. A, Representative contour plots of CD4+ T cell, CD8+ T cell, B cell, and neutrophil populations in the spleen of arthritic WT and DOCK2-/- mice. B, Scatterplots of the percentage and total number of the aforementioned cell populations in the spleen of arthritic WT and DOCK2-/- mice (n = 8/group). Bars indicate mean ± SEM. Mann-Whitney U test. *P < 0.05; ***P < 0.001.

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Table S1. Demographic and allele-specific genotypes of trio probands PTPN2 PTPN22 STAT4 IL-2/IL-21 Total

AaO HLA-DRB1 rs34846641 rs6679677 rs10174238 rs78863329 Number Trio Disease Subtype Gender (Years) Alleles Genotype Genotype Genotype Genotype of Risk

(Risk = G) (Risk = A) (Risk = G) (Risk = T) Alleles

*0101, 1 Oligoarthritis Female 1.0 AG CC AA CT 2 *1101

*1401, 2 RF- Polyarthritis Female 1.8 AG CC AA CT 2 *1501

*0301, 3 RF- Polyarthritis Female 2.0 AA CC AG CT 2 *0901

*0803, 4 Oligoarthritis Female 1.6 AA CC AA CC 0 *0901

*1101, 5 Oligoarthritis Female 0.2 AA CC AA CC 0 *1501

*0101, 6 Oligoarthritis Female 1.0 AA CC AG CT 2 *1402

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*0301, 7 RF- Polyarthritis Female 1.6 AA CC AA CC 0 *0904

*0301, 8 RF- Polyarthritis Female 1.5 AG AC AA CC 2 *0301

*0101, 9 Oligoarthritis Female 1.6 AA CC AG CC 1 *1201

*0101, 10 Oligoarthritis Male 1.5 AG CC AG CC 2 *1101

AaO = age at onset; RF = rheumatoid factor

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Chapter 4: Summary, discussion, and future directions

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Overall Summary

The pathogenesis of JIA is due to, in part, multiple genetic factors that predispose individuals to disease. The number of JIA genetic association studies has been somewhat limited compared to other autoimmune diseases. This is most likely attributable to the following factors. JIA is a relatively rare and heterogeneous disease that occurs in a pediatric population, which limits the number of patients with clinically similar phenotypes to study and the availability of samples designated for research purposes. Indeed, the JIA GWAS published to date that identify common

SNPs associated with disease have been limited to small sample sizes or included heterogeneous populations of JIA patients [1-4]. However, these studies have provided evidence for a number of loci associated with JIA risk. Alternatively, studies investigating the role of rare variants, such as

DNMs, to JIA pathogenesis have not been performed in the two most common JIA subtypes, oligoarticular and poly RF-. Such an approach has proven valuable in other polygenic disorders and diseases, such as ID, ASDs, SLE, and CeD [5-10], and have led to the identification of new genes and signaling pathways contributing to risk.

The work reported in this dissertation includes a new GWAS that utilizes a large cohort of oligoarticular and poly RF- JIA patients to identify novel susceptibility loci and WES to explore the presence of DNMs among early-onset JIA patients of the same subtypes that lacked genotypes of strongly associated risk loci. Furthermore, DOCK2, a gene in which a DNM was identified, was investigated for its role in a murine model of autoantibody-induced inflammatory arthritis. The main findings are outlined below:

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Chapter 2: Genome-wide association meta-analysis reveals novel juvenile idiopathic arthritis susceptibility loci

1. A meta-analysis discovers nine, novel oligoarticular and poly RF- JIA loci (P < 1x10-6), which includes: JAK1, PRR9_LOR, PTH1R, ILDR1_CD86, LINC00951 (FLJ41649),

AHI1_LINC00271, HBP1, WDFY4, and RNF215 (Figure 1 and Table 1).

2. Nine previously reported JIA-associated loci at genome-wide levels of significance [11] reach similar P values in the current study (Figure 1).

3. Four of the newly identified JIA susceptibility loci, JAK1, PTH1R, AHI1_LINC00271, and

WDFY4, have previously been reported for association with other autoimmune diseases (Table 2); thus, five loci are novel to both JIA and autoimmune diseases.

4. Associated SNPs are strong cis eQTLs that affect transcription for self or nearby genes, including WDFY4, CCDC12, MTP18, SF3A1, AHI1, COG5, HBP1, and GPR22 (Table 3).

5. Ingenuity Pathway Analysis using associated loci from the current study and previous

Immunochip studies [11, 12] reveals that the novel JIA loci, CD86 and JAK1, are seemingly central molecules in key signaling pathways that involve T cell differentiation and proliferation (Figure

2).

Chapter 3: Whole exome trio sequencing implicates DOCK2 in juvenile idiopathic arthritis

1. Whole exome sequencing of oligoarticular and poly RF- JIA patient-parent trios identifies

15 confirmed DNMs among 8 probands (Table 1).

2. A confirmed DNM in DOCK2 reveals that the DOCK2 complex may be important to the pathogenesis of JIA, as the gene products of two JIA-associated loci, ELMO1 [13] and RAC2

(JACI, data not published), form a ternary complex with the gene product of DOCK2.

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3. DOCK2 is a molecular determinant of autoantibody-induced arthritis and a novel driver of joint tissue pathology (Figures 1-3).

4. The potential mechanism by which DOCK2 deficiency attenuates the severity and pathology of arthritis is by decreasing neutrophil infiltration into the hindpaws where disease is actively occurring (Figure 4).

Together, these findings highlight the importance of understanding the genetic architecture underlying oligoarticular and poly RF- JIA in the form of both common and rare variants. These studies have identified biological pathways of significance to JIA pathogenesis for which therapeutic targets may be developed in order to benefit clinical care.

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Discussion and Future Work

The influence of genetics to the predisposition of autoimmune diseases, like JIA, has been appreciated for some time. The support for a genetic influence in disease susceptibility is evidenced by the establishment of numerous susceptibility loci using association studies [1-4, 11], a sibling recurrence risk ratio of 11.6 [14], and a 25-40% monozygotic twin concordance rate [15].

Limitations of these association studies include relatively small sample sizes, the use of heterogeneous patient populations, or inclusion of only candidate regions. Furthermore, it is estimated that the fraction of JIA risk attributable to the common SNP variation elucidated by the aforementioned association studies accounts for only about one-third of the predicted JIA heritability [3, 11]. Therefore, there is much more to learn in regard to the genetic architecture influencing JIA risk; the need to investigate and identify new associated loci among a well- powered, homogeneous patient cohort at the genome-wide level in order to further elucidate JIA genetic architecture still remained.

In Chapter 2, we addressed this need and identified new JIA associations in the largest cohort of oligoarticular and poly RF- patients of European ancestry studied to date using genome-wide platforms. Despite our efforts to maximize cohort size of a homogeneous group of JIA patients, the association findings did not meet the accepted P value for genome-wide significance used in this field, P < 5x10-8 (value calculated based on a genome-wide type I error rate of 0.05, which is then divided by the assumption that there are one million independent loci tested in a GWAS).

However, this threshold is somewhat arbitrary and may not accurately reflect the number of independent tests of association in our cohort of European ancestry. Nevertheless, there remains a need to validate our findings in an independent cohort, which may prove challenging given that

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JIA is a rare disease that affects young children.

When compared to the GWAS reported in this dissertation, the JIA Immunochip study had a slightly larger cohort of oligoarticular and poly RF- patients and used an array that densely covered 187 regions [11]. Of the 28 loci reported in the Immunochip studies [11, 12], nine remained significant at P < 5x10-8; two more regions achieved suggestive levels of significance at P < 1x10-6. The association statistics in the GWAS for the lead SNP of each of these 11 identified Immunochip regions, excluding HLA, are listed in Table 1.

Table 1. Top statistical associations from genome-wide meta-analysis for oligoarticular and poly RF- juvenile idiopathic arthritis (JIA) with P < 1.0x10-6 for loci originally reported in the Immunochip study [11] Minor MAF MAF SNP Lead SNP Gene Region Chr:Positiona P-value Model OR (95% CI) Allele Casesb Controlsb Position rs2476601 PTPN22 1:114377568 A 0.14 0.10 3.11x10-17 Add 1.58 (1.43-1.75) Intergenic rs111908494 ATP8B2_IL6R 1:154368095 G 0.12 0.10 2.20x10-10 Dom 1.44 (1.29-1.62) Intergenic rs11889341 STAT4 2:191943742 T 0.26 0.22 1.26x10-10 Add 1.28 (1.19-1.38) Intronic rs62322747 IL-2_IL-21 4:123456457 G 0.38 0.34 2.21x10-10 Add 1.24 (1.16-1.32) Intergenic rs38044 ERAP2_LNPEP 5:96337790 T 0.47 0.43 3.33x10-8 Dom 1.31 (1.19-1.44) Intronic rs3792894 C5orf56_IRF1 5:131547271 T 0.48 0.45 9.60x10-7 Add 1.16 (1.09-1.24) Intronic rs3118471 IL2RA 10:6102757 G 0.33 0.30 8.89x10-9 Add 1.22 (1.14-1.30) Intronic rs7114403 PRR5L 11:36361607 T 0.46 0.50 2.81x10-7 Dom 0.74 (0.66-0.83) Intronic rs7986796 COG6 13:40351064 G 0.33 0.37 3.81x10-8 Dom 0.78 (0.71-0.85) Intronic rs45450798 PTPN2 18:12792940 C 0.18 0.15 1.95x10-11 Add 1.32 (1.21-1.44) Intronic aCoordinates are based on the GRCh37 assembly bCase n=2,751, Control n=15,886 Add=Additive, Rec=Recessive, D=Dominant, MAF=Minor Allele Frequency, OR=Odds Ratio, CI=Confidence Interval

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A notable proportion, approximately 65%, of the JIA patients included in the Immunochip studies

[11, 12] were also utilized in our GWAS study. The higher density SNP coverage that the

Immunochip array provides (relative to genome-wide arrays) and the use of the Exome Array to genotype a subset of our cohort may account for the differences in the results. However, we did find comparable magnitudes of effect (Spearman’s correlation coefficient = 0.89) between the odds ratios reported for the most statistically significant SNPs from the Immunochip study [11] and the

GWAS study reported here. Moreover, we directly genotyped a subset of our imputed findings, of which > 98% concordance was achieved between imputed and genotyped SNPs. When the gene products identified in the GWAS described in this dissertation and those described in previous

Immunochip studies [11, 12] are considered together, we find they represent signaling pathways relating to T cell differentiation and proliferation that are consistent with known JIA pathophysiology. For example, increased populations of CD4+ T cells with a proliferating, activated memory phenotype have been reported to be present in the peripheral blood and synovium of JIA patients [16-19].

Having identified novel JIA risk loci, we sought to find support for these regions among other

AIDs. Immunobase (https://www.immunobase.org) and the National Human Genome Research

Institute (NHGRI)-European Bioinformatics Institute (EBI) GWAS Catalog [20] were utilized to evaluate support. Despite the fact that these databases are incomplete, they provide a context for our results. Four of the oligoarticular and poly RF- JIA loci identified in our GWAS have been reported in other AIDs: JAK1, PTH1R, AHI1_LINC00271, and WDFY4 [8, 21-24]. These overlapping findings suggest that there are common pathophysiological mechanisms underlying

AIDs.

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All but one of the newly identified JIA-associated SNPs are located in regulatory regions, which is consistent with the thought that JIA is a disease of disordered gene regulation. This parallels findings in other GWAS, including AID studies, as only a limited number of variants are located in protein-coding regions [25, 26]. Thus, determining the functional implications that these associated SNPs have on gene transcription was critical. The importance of gene expression

(eQTL) studies has been highlighted recently by investigating the association of UBE2L3 with

SLE [27, 28], where the risk haplotype of this locus results in increased UBE2L3 expression in B cells and monocytes [29]. Furthermore, this risk allele in SLE patients is associated with increased plasmablast proliferation [29], which may contribute to disease pathogenesis. Alternatively, identifying histone marks and regions with open chromatin among susceptibility loci is another useful approach for defining cell types that are relevant to disease. For example, enhancer profiles demonstrate that Th17 cells are the most enriched cell type for H3K4me1 marks among RA,

Crohn’s disease, and ulcerative colitis patients [30]. eQTL studies and histone mark analyses help to define variants that alter gene regulation among particular cell types and cell states. Thus, our findings suggesting that the newly identified JIA-associated SNPs appear to functionally relevant, as determined by eQTL studies and histone modification profiles, is noteworthy and allows future functional studies to be prioritized.

With the identification of additional JIA-associated SNPs, further work defining the functional consequences of each region and the relationship to disease pathogenesis is necessary. Generally speaking, this can be achieved by performing additional genetic studies and subsequent Bayesian analysis to identify the causal variant(s) in the region, bioinformatic analyses, computational

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approaches, and in vitro/in vivo screens [25]. Such strategies have been employed by a number of studies in order to define functional genetic variants identified at GWAS loci [31-36]. For example, fine mapping of the ETS1 locus among Asian and Asian American SLE patients revealed candidate causal variants that were evaluated for differential transcription factor binding, which was observed for only one SNP; subsequent studies determined that this variant, which is associated with decreased ETS1 expression in eQTL studies, increased phosphorylated-STAT1 binding at a nearby site that may directly repress ETS1 transcription [35]. A similar pipeline can be employed for the newly identified JIA susceptibility loci described in Chapter 2 to understand the contributions of associated SNPs to disease risk and the genomic basis influencing oligoarticular and poly RF- JIA. In fact, we are currently using a strategy complementary to the one described in the ETS1 SLE paper [35] to determine the functional impact of a SNP near the FASLG locus that reaches genome-wide significance (P < 5x10-8) and explains the majority of the association signal in the region (JACI, data not published).

In Chapter 3, we used an alternative approach to elucidate the genetic architecture underlying JIA pathogenesis by investigating the role of DNMs among oligoarticular and poly RF- patient-parent trios by WES. This approach was novel to these two most common JIA subtypes, as it has been reported in systemic JIA previously [37]. However, DNMs have been shown to contribute to the risk of ASDs, SLE, and early-onset sarcoidosis [6, 38, 39]. We reasoned that WES of early-onset

JIA patients that lacked highly associated risk alleles (HLA-DRB1, PTPN2, PTPN22, STAT4, and

IL-2/IL-21) would enrich for probands whose common variants were not likely to explain disease, and thus, the potential for discovering unknown genetic architecture. In turn, the identification of

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DNMs within genes could provide further insight into biological pathways of importance to JIA pathogenesis.

In total, we validated 15 nonsynonymous, DNMs among 8 JIA probands by Sanger sequencing.

These DNMs were unique to each individual patient and did not overlap with established JIA risk loci. Interestingly, confirmed DNMs were discovered in two DOCK family proteins, DOCK2 and

DOCK11, in this study of 10 JIA trios, perhaps suggesting a role for this family of proteins in JIA pathogenesis. The role of DOCK2 in disease became increasingly appealing when considered in the context of known JIA-associated loci. DOCK2 is a GEF expressed in hematopoietic cells that specifically activates RAC molecules necessary for actin polymerization and cytoskeletal rearrangement in processes such as cellular migration [40, 41]. Once activated, DOCK2 forms a molecular complex with ELMO1 and RAC molecules [42, 43]. We described ELMO1 as a susceptibility locus in Chapter 2 (P = 5.87x10-6) [13] and have new findings of association for

RAC2 that reach genome-wide levels of significance (P = 4.35x10-8). Furthermore, the identified

Ile101Val DOCK2 DNM is linearly adjacent to a mutation known to affect ELMO1 binding [44].

While isoleucine and valine are both hydrophobic amino acid residues, there is precedent for significant consequences of such conservative substitutions. For example, isoleucine to valine substitutions alter c-erbB and RhoB function and are associated with Creutzfeldt-Jakob and

Alzheimer diseases [45-47]. Moreover, valine to isoleucine mutations are the most common cause of transthyretin cardiac amyloidosis and have also been shown to cause Creutzfeldt-Jakob disease

[48, 49]. Both DOCK2 and ELMO1 are self-inhibited in unstimulated conditions, and in silico analysis predicts that the Ile101Val DOCK2 mutation may disrupt DOCK2 autoinhibition or

ELMO1 binding to DOCK2 (analysis performed by Dr. Jarek Meller); both predictions would

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result in aberrations to RAC activation. Collectively, these data suggest a role for the DOCK2-

ELMO1-RAC complex in inflammatory arthritis. This dissertation does not specifically address the role of the Ile101Val DOCK2 mutation in arthritis; rather, we began our studies by broadly addressing the role of DOCK2 on arthritis development and progression.

Given the independent lines of genetic evidence for the DOCK2 complex, we used DOCK2 deficient mice to determine the role of DOCK2 in the pathogenesis of autoantibody-induced arthritis for the first time using the K/BxN serum-transfer model. The progression of both macroscopic and microscopic arthritis was significantly impeded in DOCK2-/- mice compared to

WT mice in terms of disease severity and joint pathology. Having demonstrated that DOCK2 is a molecular determinant of arthritis pathogenesis, we sought to identify the mechanism by which this occurs. Analyzing the cellular infiltrate into the hindpaws revealed a decreased neutrophil population in DOCK2 deficient mice relative to WT mice. This was determined to be related to the inflammatory process rather than a global defect in neutrophil numbers. Our findings are consistent with studies documenting defects in neutrophil migration with loss of DOCK2 expression [50]. Thus, DOCK2 potentially regulates arthritis severity and pathology by driving neutrophil infiltration.

These findings are important when considered in the context of the pathophysiology of JIA. JIA is characterized by an infiltration of proliferating, activated immune cells, predominantly neutrophils, into the synovium [51]. Thus, limiting cellular influx into the joint could potentially reduce disease severity and joint pathology in JIA patients. Two DOCK2 protein-protein interaction inhibitors have been reported that prevent DOCK2-RAC interaction, resulting in a

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reduced capacity for cellular migration [52, 53]. One of these inhibitors, CPYPP, had broader effects and also inhibited DOCK1 and DOCK5 activity, molecules with high sequence homology to DOCK2 [52]. Conversely, the peptide inhibitor, R4-DCpep-2(V2W/K4R/ox)-NH2 (Ac-

RRRRCWARYHGYPWCRRRR-NH2), was specific for DOCK2 and effective at nanomolar concentrations [53]. Intervening in the migratory process could benefit individuals with inflammatory diseases, such as JIA. To date, therapeutic strategies disrupting cell migration have targeted selectins and integrins that mediate cellular rolling and adhesion for extravasation into the tissues, chemokines and their receptors, or molecules downstream of adhesion and chemokine receptors [54]. Several of these migratory therapeutic strategies targeting chemokines and their receptors, such as C5a receptor, CCR1, and LTB4 receptor, have been clinically tested in RA patients, but have failed at various stages of the clinical trial process [55-57]. Thus, the development of new therapeutic strategies is needed.

One important question still remaining is whether DOCK2 expression by neutrophils is a specific driver of K/BxN serum-transfer arthritis. This can be answered by neutrophil-specific deletion of

DOCK2 using the Cre/loxP system. Furthermore, there is a need to specifically identify the cell types and mediators regulating joint pathology in the arthritis model. DOCK2 deficiency not only causes migratory defects, but also impacts the effector function of immune cells. For example, loss of DOCK2 impairs the proliferation of CD4+ T cells [58] and skews differentiation toward a Th2 phenotype [59]. Moreover, DOCK2 deficient neutrophils have inhibited superoxide production and extracellular trap formation [60], natural killer cells have reduced cytotoxicity [61], and plasmacytoid DCs have impaired IFN-α production [62]. Thus, cellular presence may not be the only discrepancy in disease severity, but also defects in the production of inflammatory mediators

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may account for the observed differences. Determining if therapeutic intervention with DOCK2- mediated RAC activation influences the severity and disease-associated pathology is critical. The development of such a therapeutic could improve outcomes in all JIA patients and would not be limited to just an individual possessing DOCK2 mutations. Furthermore, such a therapy could also be extended to other inflammatory conditions, such as AIDs and inflammatory immune-related disorders. It is important to consider that ideally, a DOCK2-specific inhibitor must appropriately target the inflammatory process without interfering in the defense to pathogens. Lastly, there is a need to investigate the role of DOCK2 deficiency on arthritis progression using additional mouse models. While the K/BxN serum-transfer arthritis model recapitulates several aspects of human disease, it only mimics the effector phase of the disease process [63]. In bypassing the requirement for T and B cells [64, 65], we are limited in understanding the full impact that DOCK2 has in the pathogenesis of arthritis. Given the roles of these cells in the pathogenesis of JIA and the role of

DOCK2 in lymphocyte chemotaxis and T cell proliferation [40, 58], there is a need for further studies in a mouse model that involves T and B cell activation, such as the collagen-induced arthritis model.

In conclusion, the work presented in this dissertation demonstrates that the identification of both common and rare variation among oligoarticular and poly RF- JIA patients is necessary in understanding the genetic architecture underlying disease risk and determining genes and biological pathways of importance to disease pathogenesis.

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