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Lupus Nephritis Susceptibility Loci in Women with Systemic Lupus Erythematosus

†‡ | Sharon A. Chung,* Elizabeth E. Brown, Adrienne H. Williams,§ Paula S. Ramos, ††‡‡ Celine C. Berthier,¶ Tushar Bhangale,** Marta E. Alarcon-Riquelme, Timothy W. || Behrens,§§ Lindsey A. Criswell,* Deborah Cunninghame Graham, F. Yesim Demirci,¶¶ ‡ †† †† †††‡‡‡ Jeffrey C. Edberg, Patrick M. Gaffney, John B. Harley, *** Chaim O. Jacob,§§§ †† ||| †† M. Ilyas Kamboh,¶¶ Jennifer A. Kelly, Susan Manzi, ¶¶¶ Kathy L. Moser-Sivils, **** †††† ‡‡‡‡ || Laurie P. Russell,§ Michelle Petri, Betty P. Tsao, Tim J. Vyse, Raphael Zidovetzki,§§§§ ‡ |||| Matthias Kreztler,¶ Robert P. Kimberly, Barry I. Freedman, Robert R. Graham,§§ and Carl D. Langefeld§ for the and International Consortium for Systemic Lupus Erythematosus Genetics

Due to the number of contributing authors, the affiliations are listed at the end of this article.

ABSTRACT Lupus nephritis is a manifestation of SLE resulting from glomerular immune complex deposition and inflammation. Lupus nephritis demonstrates familial aggregation and accounts for significant morbidity and mortality. We completed a meta-analysis of three genome-wide association studies of SLE to identify lupus nephritis–predisposing loci. Through genotyping and imputation, .1.6 million markers were assessed in 2000 unrelated women of European descent with SLE (588 patients with lupus nephritis and 1412 patients with lupus without nephritis). Tests of association were computed using logistic regression adjusting for population substructure. The strongest evidence for association was observed outside the 2 MHC and included markers localized to 4q11-q13 (PDGFRA, GSX2; P54.5310 7), 16p12 (SLC5A11; 2 2 2 P55.1310 7), 6p22 (ID4; P57.4310 7), and 8q24.12 (HAS2, SNTB1; P51.1310 6). Both HLA-DR2 and HLA-DR3, two well established lupus susceptibility loci, showed evidence of association with lupus ne- 2 phritis (P=0.06 and P53.7310 5, respectively). Within the class I region, rs9263871 (C6orf15-HCG22)had the strongest evidence of association with lupus nephritis independent of HLA-DR2 and HLA-DR3 2 (P58.5310 6). Consistent with a functional role in lupus nephritis, intra-renal mRNA levels of PDGFRA and associated pathway members showed significant enrichment in patients with lupus nephritis (n=32) compared with controls (n=15). Results from this large-scale genome-wide investigation of lupus nephritis provide evidence of multiple biologically relevant lupus nephritis susceptibility loci.

J Am Soc Nephrol 25: ccc–ccc, 2014. doi: 10.1681/ASN.2013050446

SLE is a prototypic autoimmune disease that dispro- of women of European descent with SLE and ac- portionately affects women (ratio of female to male counting for significant morbidity and mortality.1 patients, 9:1). It is characterized by the development CKDs are heavily influenced by both genetic and ofautoantibodiesdirectedagainstnuclearandcellular environmental factors.2 A genetic component to LN components and the activation of inflammatory susceptibility is supported by an over-representation cascades, resulting in multisystem organ damage. of LN among children of parents with SLE, familial Lupusnephritis(LN)iscommon,affecting30%–40% aggregation of ESRD in African Americans with

Received May 2, 2013. Accepted March 14, 2014. Correspondence: Dr. Carl D. Langefeld, Division of Public Health Sciences, Department of Biostatistical Sciences, Wake S.A.C. and E.E.B. are co-first authors. Forest School of Medicine, Medical Center Boulevard, Winston- Salem, NC 27157. Email: [email protected] Published online ahead of print. Publication date available at www.jasn.org. Copyright © 2014 by the American Society of Nephrology

J Am Soc Nephrol 25: ccc–ccc, 2014 ISSN : 1046-6673/2511-ccc 1 BASIC RESEARCH www.jasn.org

LN,3 linkage studies and candidate gene studies.4–7 Genome- To test whether the MHC associations observed with LN wide association studies (GWAS) have been extremely successful were influenced by linkage disequilibrium with HLA-DR2 and in identifying susceptibility loci for many disease phenotypes, HLA-DR3, each SNP in the MHC region was tested for asso- including SLE8–15 and related endophenotypes.16,17 Herein, we ciation while including the HLA-DR2 and HLA-DR3 tagSNPs report the first large-scale GWAS to identify loci predisposing as covariates in the logistic regression model (Figure 2B, Sup- to LN among women with SLE. plemental Table 3). In these analyses, the previously most significantly associated MHC SNP, rs9267972, was weakly asso- ciated with LN (OR, 1.35; 95% CI, 1.00 to 1.84; Padjusted=0.06). RESULTS The most significantly associated MHC locus independent of HLA-DR2 and HLA-DR3 was rs9263871, located within 26 Table 1 summarizes the clinical characteristics of the 2000 un- HCG27 (OR, 1.7; 95% CI, 1.35 to 2.13; Padjusted=8.5310 ; related women of European ancestry who meet the American Figure 2B, Supplemental Table 3) in the MHC class I re- College of Rheumatology (ACR) classification criteria for SLE gion. No other MHC SNPs were associated with LN at 25 and are included in this study. Of the 2000 patients with SLE, Padjusted,1.0310 . 588 had LN defined by ACR criteria and 1412 had SLE with no evidence of LN. Sets I and II are the largest contributors to the LN Associations outside the MHC meta-analysis and had comparable proportions of patients with Five loci outside the MHC region showed comparable or LN. Interestingly, the smallest sample, set III, had nearly double stronger evidence of association than those within the MHC 2 the proportion of LN and a slightly earlier median age of SLE (approximate P=1.0310 6;Figure3,Table2).Thestron- onset. Set II had the highest proportion of patients with SLE from gest statistical evidence of association with LN was with 2 multiplex pedigrees (set I, 0.08; set II, 0.82; and set III, 0.43). rs1364989 (OR, 3.41; 95% CI, 2.10 to 5.54; P=4.5310 7) After applying quality control measures, 1,621,689 single on 4q11-q13. This association localized to an intergenic re- nucleotide polymorphisms (SNPs) with genotype or imputed gion 83.5 kb upstream of PDGF receptor-a (PDGFRA). The genotype data were available for these 2000 unrelated indi- next strongest statistical evidence of association with LN was viduals. After adjusting for potential population substructure with rs274068, located within an intronic region of sodium- in each set via principal components, the meta-analysis infla- dependent glucose cotransporter SCL5A11 at 16p12.1 (OR, 2 tion factor was 1.05; sets I–III had inflation factors of 1.16, 2.85; 95% CI, 1.93 to 4.22; P=5.1310 7; Table 2). A potentially 1.09, and 1.03, respectively. The inflation factor for the best intriguing region of association was within 8q24.12 2 P value (minimum of dominant, additive, and recessive) was (rs7834765; OR, 3.15; 95% CI, 1.97 to 5.03; P=1.1310 6). 1.70. Supplemental Figure 1 shows the corresponding probability- Although the associated SNPs in this region are intergenic probability plot. Given the exploratory nature of the study, we and are not in linkage disequilibrium with any specific gene, report the results considering all genetic models (Table 2) as the region contains a DNase I hypersensitivity cluster and well as only the additive model (Supplemental Table 1). P values HAS2 (see the Discussion). The remaining two regions with 2 were genomic control adjusted based on the best P value infla- an approximate P=1310 6 were in intergenic regions on 6p22 tion factor. Supplemental Figure 2 presents the power analysis near ID4 and 9p21 (Table 2). Supplemental Tables 1 and 4 for the 588 patients with LN versus 1412 patients with SLE with- provide the summary statistics for the top non-MHC associa- out nephritis. Figure 1 shows a Manhattan plot of the associa- tions for the additive and all genetic models, respectively. tions across the genome. SLE Susceptibility Loci LN Associations within the MHC Given the frequency of LN among patients with SLE and the The MHC (chromosome 6: 25–32 Mb) is the most important manner in which SLE loci have been discovered (i.e., SLE cases region for SLE susceptibility, but its role in LN susceptibility is versus unaffected controls), some previously discovered SLE not established. In this study, the SNP most strongly associated susceptibility loci may be LN loci. This hypothesis was tested with LN within the MHC was rs9267972 (odds ratio [OR], 1.85; by taking 31 previously identified SLE susceptibility loci and 2 95% confidence interval [95% CI], 1.46 to 2.33; P=1.5310 6; testing for association with LN under the above case-only de- Figure 2A, Supplemental Table 2), which is located between sign (i.e., patients with LN versus patients with SLE without NOTCH4 and C6orf10. nephritis; Table 3). Three loci met the Bonferroni corrected 2 Because HLA-DRB1*1501 (HLA-DR2)andHLA- significance level (a=0.05/31=1.61310 3). The most strongly DRB1*0301 (HLA-DR3) are well established SLE susceptibility associated SLE susceptibility locus was rs2187668 within the 2 loci, these two loci were examined using their tagSNPs HLA region (OR, 1.55; 95% CI, 1.25 to 1.92; P=3.67310 5). rs9271366 (HLA-DR2) and rs2187668 (HLA-DR3).18 As as- This SNP tags the well known HLA-DR3 lupus-risk haplotype.18 sessed by these proxies, both HLA-DR2 (OR, 1.37; 95% CI, However, the magnitude of the OR for LN was significantly 1.09 to 1.71; P=0.06) and HLA-DR3 (OR, 1.55; 95% CI, 1.25 to lower than for SLE. The second most strongly associated SNP 2 1.92; P=3.7310 5) showed evidence of association with LN. was rs2205960 within the 1q25.1 region near TNFSF4 (OR, 2 Supplemental Table 2 summarizes the MHC associations. 2.41; 95% CI, 1.59 to 3.64; P=7.82310 5). The other SNP

2 Journal of the American Society of Nephrology J Am Soc Nephrol 25: ccc–ccc,2014 www.jasn.org BASIC RESEARCH

Table 1. Clinical characteristics of women with SLE included in the meta- random SNPs showed a significant lower analysis of LN genetic susceptibility markers percentage of significantly regulated tran- SLE Characteristic Set I (n=1162) Set II (n=690) Set III (n=148) scripts (Supplemental Tables 6 and 7). Age at SLE diagnosis (yr) 33 (25–43) 33 (3–72) 25 (8–62) Because LN is primarily characterized by Mean ACR criteria (n)a 5(4–6) 6 (5–7) 6 (5–7) intraglomerular histopathology, we focused ACR criteria for SLE our analysis on the entire glomerular tran- LN (proteinuria or cellular casts) 310 (27) 198 (29) 80 (54) scriptdataset(961genesregulatedinpatients Malar rash 562 (48) 419 (61) 89 (60) with LN versus living donors with a q value Discoid rash 106 (9) 82 (12) 9 (6) ,0.05, and a fold change $1.5 and #0.7 for Photosensitivity 832 (72) 455 (66) 73 (49) the upregulated and downregulated genes, Oral ulcers 510 (44) 293 (43) 59 (40) respectively). Using Ingenuity Pathway Anal- Arthritis 918 (79) 587 (85) 117 (79) ysis, the PDGF signaling pathway containing Serositis (pericarditis or pleuritis) 432 (37) 325 (47) 73 (49) PDGFRA showed a significant enrichment Neurologic (seizure or psychosis) 106 (9) 112 (16) 27 (18) Hematologic (leukopenia, lymphopenia, 706 (61) 403 (59) 91 (61) of LN regulated transcripts with 12 of 79 hemolytic anemia, or molecules being differentially expressed thrombocytopenia) (P=0.01 compared with a random gene Immunologic (anti-double-stranded 772 (66) 480 (70) 115 (78) set), corroborating the role of PDGFRA in DNA, anti-Smith, or antiphospholipid LN. Independent of predefined canonical antibodies) pathways, a co-citation literature-based Anti-nuclear antibody 1102 (95) 660 (96) 144 (97) transcriptional network built from the 961 Data are presented as the median (interquartile range) or n (%). LN genes using GePS software identified a 23,24 Eligible patients had a minimum of 4 of 11 ACR criteria for SLE. PDGFRA as one of the main nodes. that showed association was rs9888739 within ITGAM, located DISCUSSION on chromosome 16p11.2 (OR, 1.42; 95% CI, 1.17 to 1.72; 2 P=1.34310 3), which had an OR for LN that was comparable This study presents the first GWAS of LN among individuals with SLE.10,19 with SLE. This study is particularly notable because it The number of SLE risk polymorphisms that an individual incorporates genetic data across the three largest GWAS of carries (i.e., genetic load) may influence risk and may be a SLE in individuals of European descent, focuses on unrelated strong predictor of LN. However, after adjusting for the above women, and assesses the biologic relevance of genes in three SLE loci, the risk of LN as a function of the sum of the proximity of the genetic associations. Given that the frequency number of risk alleles across the remaining 28 loci was not of LN among individuals diagnosed with SLE is high, a GWAS statistically significant. of patients with LN versus healthy controls will detect SLE- predisposing loci that do not influence the risk of nephritis. Gene Expression in Renal Biopsies Thus, the study design reported contrasts LN patients with Renal LN gene expression profiles were examined for the lupus patients without nephritis. associated regions identified in the LN GWAS meta-analysis The most significant evidence of an association with LN was (Tables 2 and 3); clinical characteristics of the samples are de- observed with rs1364989, located 83 kb from PDGFRA,agene scribed in Supplemental Table 5. Thirteen transcripts (Table 4) that encodes the a polypeptide of the PDGF receptor. PDGF were detectable in the LN susceptibility regions displaying the and its associated pathways act to promote local cell prolifer- strongest GWAS association (Table 2). Most of these 13 tran- ation, synthesis of extracellular matrix, chemotaxis, and cyto- scripts were regulated in the glomerular and tubulointerstitial kine production, and play a regulatory role in inflammation.20 compartments of patients with LN compared with living donor Both PDGFRA and PDGFRB are expressed in renal glomeruli controls (Table 4). In both compartments, PDGFRA and and in the interstitium. Signaling through the PDGFRA path- COL4A1 had the greatest mRNA expression increase, whereas way can activate interstitial and mesangial cells, which can lead ID4 was underexpressed (Table 4). Similarly, several transcripts to renal fibrosis and tubulointerstitial scarring.20 Overproduc- from other previously reported SLE GWAS were also regulated tion of PDGF, the ligand for PDGFRA and PDGFRB,hasbeen in both renal compartments of patients with LN versus living implicated in the cellular proliferation and extracellular ma- donors (Table 4). Among the established and confirmed SLE trix production that accompanies experimental GN in animal susceptibility genes, ITGAM exhibited the highest and most models of SLE (NZB/W and MRL-lpr mice) and spontaneous significant change within the glomerular compartment (Table 4). LN in humans PDGF and PDGFR gene expression is known to To verify the relevance of those genes in LN disease, an equiv- be increased in kidney tissue from patients with proliferative alent number of unassociated loci were randomly chosen. The forms of GN, including LN, IgA nephropathy, and Henoch– mRNA level of each transcript located around each of the Schönlein purpura.21,22 Administration of the tyrosine kinase

J Am Soc Nephrol 25: ccc–ccc, 2014 GWAS of Lupus Nephritis in SLE 3 4

Table 2. Summary of LN susceptibility markers with the strongest and most consistent evidence for association RESEARCH BASIC Meta-Analysisa Set I Set II Set III Genetic Genes within ora fteAeia oit fNephrology of Society American the of Journal dbSNP Model of Location Interval RA Genomic Genomic Genomic Genomic Identifier Inheritance (r2>0.20) OR (95% CI) Control OR (95% CI) Control OR (95% CI) Control OR (95% CI) Control P Valueb P Value P Value P Value rs1364989 R 4q12 PDGFRA, GSX2 T 3.41 (2.10 to 5.54) 4.52E-07 4.57 (2.48 to 8.42) 1.30E-06 2.32 (1.06 to 5.08) 3.91E-02 rs274068 R 16p12.1 SLC5A11 C 2.85 (1.93 to 4.22) 5.08E-07 2.26 (1.38 to 3.70) 1.40E-03 3.87 (2.06 to 7.29) 2.91E-05 www.jasn.org rs8012283 A 14q22.1 NIN, SAV1, SPG3A, G 1.64 (1.35 to 1.98) 5.26E-07 1.68 (1.31 to 2.14) 3.84E-05 1.59 (1.17 to 2.14) 2.94E-03 MAP4K5 rs7773456 D 6p22.3 None G 0.57 (0.46 to 0.70) 7.36E-07 0.63 (0.48 to 0.83) 1.02E-03 0.49 (0.35 to 0.7) 7.97E-05 rs7834765 R 8q24.12 None T 3.15 (1.97 to 5.03) 1.06E-06 3.79 (2.13 to 6.76) 7.39E-06 2.48 (1.15 to 5.35) 2.29E-02 rs601162 R 9p21.1 None A 3.11 (1.99 to 4.88) 1.42E-06 2.85 (1.58 to 5.16) 5.93E-04 3.49 (1.75 to 6.94) 4.02E-04 rs9267972 D 6p21.32 C6orf10, NOTCh4 A 1.85 (1.46 to 2.33) 1.49E-06 1.52 (1.15 to 2.02) 4.25E-03 1.96 (1.33 to 2.89) 7.32E-04 2.78 (1.28 to 6.04) 1.03E-02 rs4901847 A 14q23.1 C14orf37 T 1.48 (1.28 to 1.71) 1.71E-06 1.23 (1.02 to 1.48) 3.92E-02 1.66 (1.32 to 2.10) 2.23E-05 1.91 (1.22 to 3.00) 5.16E-03 rs752010 D 1p34.2 HIVEP3 C 0.57 (0.45 to 0.71) 2.31E-06 0.59 (0.44 to 0.79) 4.15E-04 0.61 (0.42 to 0.89) 1.02E-02 0.43 (0.2 to 0.93) 3.31E-02 rs6538678 A 12q23.1 FLJ40089 A 1.57 (1.30 to 1.88) 3.33E-06 1.52 (1.21 to 1.91) 3.54E-04 1.63 (1.20 to 2.21) 2.04E-03 rs10041935 R 5q11.2 None C 2.50 (1.71 to 3.66) 3.46E-06 2.40 (1.49 to 3.88) 3.86E-04 2.64 (1.44 to 4.85) 1.94E-03 rs2236178 A 20p11.23 C20orf19, XRN2, T 0.68 (0.58 to 0.79) 4.70E-06 0.70 (0.58 to 0.85) 4.87E-04 0.78 (0.61 to 1.00) 5.63E-02 0.45 (0.28 to 0.74) 1.66E-03 NKX2-4, NKX2-2 rs2786111 R 1q31.3 CRB1, ZBTB41, C 2.26 (1.6 to 3.19) 5.31E-06 2.44 (1.56 to 3.82) 1.10E-04 2.04 (1.19 to 3.52) 1.10E-02 ASPM, F13B, CFHR5 rs648705 R 13q34 COL4A1 A 0.48 (0.34 to 0.66) 1.09E-05 0.42 (0.28 to 0.64) 5.86E-05 0.57 (0.34 to 0.95) 3.49E-02 rs2399985 D 10p13 PRPF18, FRMD4A T 1.65 (1.33 to 2.06) 1.16E-05 1.58 (1.19 to 2.08) 1.64E-03 1.76 (1.25 to 2.48) 1.42E-03 The mode of inheritance is identical for each of the discovery, replication, and combined populations. Common variants listed in this table include only those with a level of statistical significance P#0.05 across all three populations, a level of statistical significance P#1026 in the meta-analysis, and consistent effects across all populations (i.e., protective or at-risk effects). For multiple common variants in a single gene or gene region meeting these criteria, we list the single common variant with the lowest P value. Chromosome positions are based on build 36.1. dbSNP, Single Nucleotide Polymorphism Database; RA, reference allele; R, recessive; A, additive; D, dominant. aThe numbers of participants were as follows: meta-analysis, 588 patients with LN versus 1412 patients without LN; set I, 310 patients with LN versus 852 patients without LN; set II, 198 patients with LN versus 492 patients without LN; and set III, 80 patients with LN versus 68 patients without LN. bGenomic control adjustment to the P value for the minimum of the dominant, additive, and recessive genetic models. mScNephrol Soc Am J 25: ccc – ccc ,2014 www.jasn.org BASIC RESEARCH

Figure 1. Manhattan plot showing patients with LN in contrast with patients with lupus without LN.

Figure 2. HLA region associations with patients with LN in contrast with patients with SLE without LN. (A) Associations adjusting for principal components. (B) Associations adjusting for principal components and HLA SLE risk tagging SNPs rs9271366 (HLA-DR2) and rs2187668 (HLA-DR3). inhibitor imatinib to NZB/W mice with established lupus im- influence the development of LN in humans. Further analyses mune complex mediated GN improved survival and reduced are needed to define the causal variation and specificmecha- proteinuria, tubulointerstitial fibrosis, and renal invasion of nisms impacting the PDGFRA function in LN. macrophages and monocytes.23,24 Similar effects were ob- The second strongest signal of association was observed served in MRL-lpr mice.25 Mesangial cell proliferation is ef- with rs274068, an intronic SNP located within SLC5A11 on fectively inhibited by anti-PDGF antibodies in animal models chromosome 16p12.1. This sodium-dependent glucose co- of GN with resultant reductions in mesangial matrix deposi- transporter is responsible for active cellular uptake of glucose tion and glomerulosclerosis.26,27 The expression data presen- and other nutrients. SLC5A11 was initially proposed as a can- ted in this report provide evidence that increased PDGFRA didate gene for SLE because of evidence of linkage and inter- mRNA is found in both the renal glomeruli and the tubuloin- action between the pericentromeric region of chromosome 16 terstitium of patients with LN, suggesting that this gene may and chromosome 1q23.28 A candidate gene association anal- mediate the pathogenesis of LN. Integrative analysis of gene ysis performed in 95 Korean patients with SLE implicated expression data, pathway mapping, and coregulation tran- SLC5A11 polymorphisms in susceptibility to SLE and select scriptional networks provided multiple lines of evidence disease manifestations.29 These authors identified gene–gene for a key role of PDGFRA in LN. Together, these data suggest interactions between SLC5A11 and immune-function genes that common variation associated with PDGFRA may (TNF, LTA,andC4) and the T and B cell costimulatory

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Figure 3. Regional plots of LN loci. Genotyped and imputed SNPs are plotted with their meta-analysis P values (as -log10 values) as a function of genomic position (Human Genome Build 18) within a 500-kb region surrounding the most significant SNP. Recombination rates from the HapMap phase II CEU (Utah residents with ancestry from northern and western Europe) are plotted in blue to reflect the regional LD structure. In each region, the index SNP is represented by a purple diamond, and the color of all other SNPs (circles) indicates LD with the index SNP based on pairwise r2 values from HapMap CEU (red, r2.0.80; orange, r2=0.60–0.80; green, r2=0.40– 0.60; light blue, r2=0.20–0.40; dark blue, r2,0.20). Known human genes in the UCSC Genome Browser (University of California, Santa Cruz, CA) are below each plot.

6 Journal of the American Society of Nephrology J Am Soc Nephrol 25: ccc–ccc,2014 mScNephrol Soc Am J Table 3. Reported SLE susceptibility loci and risk of LN among loci included in the LN meta-analysis a dbSNP Genetic Model Genomic Control Direction Gene Location Samples (n) RA OR (95% CI) References Identifier of Inheritance P Value Set I Set II Set III IL12RB2 rs1874791 D 1p31.2 1987 A 0.85 (0.68 to 1.06) 5.88E-01 2 + 2 41

25: PTPN22 rs2476601 A 1p13.2 690 A 0.83 (0.22 to 3.1) 9.84E-01 ? + ? 10, 41–43

ccc FCGR2A rs1801274 D 1q23.3 1786 A 1.12 (0.89 to 1.41) 5.42E-01 + + ? 10, 43, 44

– TNFSF4 rs2205960 R 1q25.1 1770 T 2.41 (1.59 to 3.64) 7.82E-05 + + ? 9, 41 ccc NMNAT2 rs2022013 D 1q25.3 1969 C 1.07 (0.86 to 1.32) 8.23E-01 22 29, 10, 41 2014 , IL10 rs3024505 A 1q32.1 690 A 0.89 (0.66 to 1.21) 7.67E-01 ? 2 ?9,41 LYST rs9782955 D 1q42.3 832 T 0.86 (0.63 to 1.18) 6.05E-01 ? 2241 IFIH1 rs1990760 R 2q24.2 1779 C 0.80 (0.57 to 1.08) 2.96E-01 + + ? 41 STAT4 rs7574865 D 2q32.2 1137 T 1.38 (1.06 to 1.81) 2.84E-02 2 ? ? 9, 10, 41, 43, 45 PXK rs6445975 D 3q14.3 1988 G 0.98 (0.8 to 1.21) 1.00E+00 + + 2 10, 43 BANK1 rs10516487 A 4q24 1834 A 0.84 (0.72 to 0.99) 4.10E-02 22 ?9–12, 41, 43 PTTG1 rs2431697 D 5q33.3 1781 C 0.86 (0.69 to 1.07) 2.60E-01 + + ? 10, 41, 43 HLA-DR2 rs9271366 D 6p21.32 1798 G 1.37 (1.09 to 1.71) 5.73E-02 + + + HLA-DR3 rs2187668 D 6p21.32 1955 T 1.55 (1.25 to 1.92) 3.67E-05 + + + 11, 41, 43 UHRF1BP1 rs11755393 D 6p21.31 1844 G 1.08 (0.87 to 1.34) 8.04E-01 22 ?41 ATG5 rs6568431 A 6q21 1931 A 1.11 (0.96 to 1.29) 1.68E-01 + + 2 10, 41, 43 TNFAIP3 rs6920220 D 6q23.3 1965 A 0.92 (0.75 to 1.14) 5.51E-01 22 +41 ICA1 rs10156091 A 7p21.3 689 T 0.93 (0.66 to 1.32) 1.00E+00 ? 2 ? 10, 41, 43 JAZF1 rs849142 R 7p15.1 1993 C 1.05 (0.83 to 1.35) 1.00E+00 22 +41 IRF5 rs12537284 A 7q32.1 1800 A 1.02 (0.84 to 1.23) 1.00E+00 2 + ? 10, 41 BLK rs2248932 R 8p23.1 1836 A 1.32 (0.97 to 1.78) 9.30E-02 + + ? 9, 10 LYN rs7829816 R 8q12.1 1119 G 1.30 (0.72 to 2.36) 6.65E-01 2 ??10 PHRF1-IRF7 rs4963128 R 11p15.5 680 T 0.62 (0.34 to 1.13) 2.02E-01 ? 2 ? 10, 41, 43 PDHX-CD44 rs2732552 A 11p13 1966 T 0.82 (0.7 to 0.94) 1.15E-02 22 246 DDX6 rs503425 R 11q23.3 1130 C 2.02 (1.15 to 3.53) 2.30E-02 2 ? ? 9, 41 SLC15A4 rs6486730 R 12q24.32 1073 G 1.11 (0.79 to 1.56) 9.11E-01 2 ??41 ITGAM rs9888739 A 16p11.2 1841 T 1.42 (1.17 to 1.72) 1.34E-03 + + ? 10, 41, 43 IRF8 rs12444486 R 16q24.1 1148 T 0.96 (0.72 to 1.29) 1.00E+00 2 ??41 CD226 rs727088 D 18q22.2 1842 A 1.13 (0.88 to 1.44) 5.95E-01 + + ? 47 UBE2L3 rs5754217 D 22q11.21 1974 T 0.98 (0.79 to 1.21) 1.00E+00 2 + + 10, 41, 43 WSo uu ehii nSLE in Nephritis Lupus of GWAS SCUBE1 rs2071725 D 22q13.2 1794 A 0.89 (0.69 to 1.14) 6.68E-01 22 ?10 www.jasn.org dbSNP, Single Nucleotide Polymorphism Database; RA, reference allele; D, dominant; A, additive; R, recessive. aSymbols represent the direction of the risk effect in sets I, II, and III, respectively: ?, not in meta-analysis; 2,OR,1; +, OR .1. AI RESEARCH BASIC 7 BASIC RESEARCH www.jasn.org

Table 4. Renal expression of the genes having a SNP closely localized as assessed by HGU133A arrays from European Renal cDNA Bank Consortium patients with LN compared with controls Genes in the SNP Region Glomerular Compartment Tubulointerstitial Compartment SNP Gene ID Gene Symbol Fold Change qPValue Fold Change qPValue SNPs from Table 2 rs1364989 5156 PDGFRAa 2.57 ,1.1E-04 2.86E-05 2.40 ,1.3E-04 6.03E-06 rs7773456 3400 ID4a 0.76 6.1E-04 6.20E-03 1.04 1.8E-01 5.98E-01 rs7834765 3037 HAS2a 0.95 4.3E-02 6.22E-02 0.92 4.2E-03 2.53E-02 6641 SNTB1a 1.16 2.2E-03 2.94E-04 1.02 2.0E-01 5.97E-01 rs8015968 60485 SAV1a 1.06 2.4E-01 6.52E-01 1.27 ,1.3E-04 1.71E-03 11183 MAP4K5a 1.24 2.2E-03 5.64E-04 1.08 7.0E-03 5.14E-04 rs752010 59269 HIVEP3a 0.99 1.0E+00 7.05E-01 0.93 1.1E-02 2.82E-02 rs2236178 55857 C20orf19a 0.95 1.3E-01 4.15E-01 1.20 1.5E-03 7.83E-03 rs2786111 23418 CRB1a 0.98 1.4E-01 2.91E-01 0.93 1.9E-02 6.15E-02 259266 ASPM 1.11 1.6E-01 1.44E-01 1.01 2.0E-01 5.16E-01 rs648705 1282 COL4A1a 2.61 ,1.1E-04 7.77E-10 1.89 ,1.3E-04 7.72E-06 rs2399985 8559 PRPF18a 1.58 ,1.1E-04 3.57E-08 1.19 1.7E-02 5.11E-02 55691 FRMD4Aa 1.12 7.3E-02 4.04E-02 0.99 1.0E+00 6.84E-01 SNPs from Table 3 rs2205960 7292 TNFSF4a 0.91 2.0E-02 2.65E-02 0.95 2.5E-02 7.33E-02 rs2022013 23057 NMNAT2a 0.96 1.2E-01 3.69E-01 0.94 2.1E-02 3.21E-02 rs7601754 6775 STAT4a 1.68 1.0E-03 3.13E-04 0.95 8.0E-02 3.27E-01 rs10516487 55024 BANK1a 1.06 1.4E-01 4.03E-01 1.11 2.3E-02 9.82E-03 rs2431697 9232 PTTG1a 1.58 ,1.1E-04 1.10E-05 1.20 8.4E-03 4.07E-03 rs2187668 3123 HLA-DR3 (HLA-DRB1, 1.88 ,1.1E-04 1.24E-06 2.22 ,1.3E-04 6.96E-07 allele 0301)a rs6568431 9474 ATG5a 1.11 4.3E-02 1.71E-02 1.22 ,1.3E-04 8.58E-05 rs6920220 7128 TNFAIP3a 1.19 4.7E-02 1.00E-01 0.85 8.4E-03 7.14E-02 rs4917014 10320 IKZF1a 1.01 1.0E+00 7.93E-01 0.93 4.3E-03 1.44E-02 rs10239340 3663 IRF5a 1.01 1.0E+00 8.67E-01 0.92 1.2E-02 3.98E-02 rs2248932 640 BLKa 1.12 1.7E-01 1.67E-01 0.95 3.5E-02 1.06E-01 rs9937837 3684 ITGAMa 3.21 ,1.1E-04 9.83E-08 1.08 7.6E-02 1.29E-01 rs5754217 7332 UBEL2L3a 0.96 1.1E-01 2.87E-01 1.12 6.6E-03 1.31E-02 dbSNP, Single Nucleotide Polymorphism Database. aGenes significantly regulated in patients with LN compared with controls (q,0.05). receptor gene (PDCD1), a confirmed LN susceptibility locus In contrast with the GWAS of SLE and other autoimmune among European descendants.30 diseases in individuals of European ancestry, the MHC does not Hyaluronan synthase 2 (HAS2) located on 8q24 leads to the dominate the list of most strongly LN-associated regions. In production of the extracellular matrix component hyaluronan. fact, the LN ORs for MHC loci were comparable with that of Hyaluronan accumulates in the renal cortex in the scarring non-MHC loci in women of European descent. Although some phase of immune-mediated kidney disease, producing patho- studies suggested an association with HLA-DR2 and HLA- logic renal fibrosis. For example, hyaluronan deposition ap- DR3, the two best established MHC susceptibility loci for pears to be prominent in MRL-Fas(lpr) mice with renal disease, SLE, not all studies are in agreement regarding the role of an effect mediated in part by the local synthesis of HAS2. In a the MHC in LN.32,33 In our study that contrasts patients previous study, large amounts of hyaluronan were deposited in with LN with patients with lupus without nephritis, modest the cortical interstitium of MRL-Fas(lpr) mice with autoim- associations were observed with both of these MHC class II mune renal injury, but not in congenic MRL-++ mice.31 Steady alleles (as assessed by proxies). Analyses conditioned on state mRNA levels of HAS2 correlated with the activity of kid- rs9271366 and rs2187668 indicate that loci outside of MHC ney disease. Enhanced synthesis of hyaluronan may be medi- class II genes may also contribute to LN risk, as seen in other ated by the effects of proinflammatory cytokines because TNF-a, studies of SLE.34 We posit that genetic variation in the MHC IFN-g, and their combination markedly enhanced hyaluronan may strongly predispose individuals to develop SLE, but non- synthesis and HAS2 gene expression in kidney tubule cell lines MHC factors may play a greater role in promoting the devel- in this study. Our findings support a role for HAS2 in LN opment of LN. pathogenesis via the inflammatory activation, which is ob- Evaluation of the association between other previously served in LN in humans. identified SLE susceptibility loci and LN indicates that only a

8 Journal of the American Society of Nephrology J Am Soc Nephrol 25: ccc–ccc,2014 www.jasn.org BASIC RESEARCH small number of these loci seem to significantly influence the the potential influence of SLE susceptibility variants in our tests of development of LN. In this analysis, SNPs in or near TNFSF4 association with LN. To account for potential population substruc- and ITGAM were associated with LN, albeit not as strongly as ture, principal component analyses were computed using SNPs that the LN susceptibility loci listed in Table 2. We hypothesize that passed quality control.35 All tests of association were computed and LN loci do not necessarily predispose to SLE but rather in- adjusted for five principal components in the set I samples and four fluence the response of the kidney to the immunologic chal- principal components in the set II and set III samples. Within each lenges posed by SLE, as exemplified in the case of PDGFRA. GWAS set, autosomal SNPs that passed quality control filters and Although this is the first GWAS of LN among individuals exhibited a minor allele frequency .0.01 were used to impute the with SLE, the meta-analysis has limitations. First, some SLE approximately 2.5 million SNPs in HapMap2 (Build 35) using IM- cases with no evidence of LN may develop LN in the future. PUTE.36 The reference set for imputation was the Utah residents with Common to case-control studies, future conversion or mis- ancestry from northern and western Europe available via the HapMap. classification reduces statistical power and results in conser- Within each GWAS set, logistic regression models included the above- vative estimates of effect size. Second, the overall presence of stated principal components and accounted for the imputation un- LN was chosen as the case phenotype because more than one certainty via the posterior genotype probabilities.36 Dominant, additive, subclass of LN can be present at the same time (e.g., prolifer- and recessive genetic models were computed assuming at least 10 and ative occurring with membranous lesions), and the type of 20 individuals homozygous for the minor allele were observed. Be- subclass a patient has can change over the course of disease. cause of the modest sample size, this requirement caused many SNPs Other indicators of renal disease (e.g., albuminuria or GFR) to not have a test computed in set III. The evidence of association from were not selected as the renal phenotype because they are each of the three GWAS sets was weighted by sample size and com- influenced by prior and current medication use (e.g., immu- bined using the weighted inverse normal method as implemented in nosuppressants). Although using LN allowed us to identify METAL.37 To account for any inflation, the genomic control-adjusted genetic susceptibility toward renal involvement in SLE, more P value was reported. homogeneous phenotypes might increase power for specific Renal biopsies from 15 healthy pretransplant living donor controls risk loci. Third, although this study examined patients with and32patientswithLNwerecollectedfromaninternationalmulticenter SLE who were of European descent, LN is more prevalent and repository (European Renal cDNA Bank).38 Healthy controls had nor- severe among patients with SLE who have other ethnic back- mal kidney function (i.e., GFR between 80 and 120 ml/min per 1.73 m2 grounds. Finally, this study incorporates data from three large- estimated using the Modification of Diet in Renal Disease equation). scale GWAS of SLE in women of European descent and is well Glomerular and tubulointerstitial compartments of kidney biopsies powered for intermediate effect sizes. Although it is the largest were microdissected.38–40 The mRNA extracted from each renal com- study to date, additional well powered studies are needed that partment was analyzed using Affymetrix Human Genome U133A include both male and female participants and other ethnici- Genechips (Affymetrix, Santa Clara, CA).40 mRNA expression levels ties and that attempt to replicate the findings in this study. generated from the biopsies of patients with LN and from healthy In summary, we report novel LN susceptibility loci, in- controls (no lupus, no nephritis) were compared using unpaired cluding loci near PDGRFA, HAS2,andSLC5A11,among t tests. A q value(falsediscoveryrate),0.05 was considered significant. women with SLE of European descent. Although an overlap between previously identified SLE and LN susceptibility loci (i.e., TNFSF4, ITGAM) exists, it is not strong and underscores the need to search for LN susceptibility loci independent of ACKNOWLEDGMENTS SLE loci. Delineating the genetic factors that lead to LN among patients with SLE may facilitate our understanding of the eti- Out-of-study controls for the set I and set II GWAS were provided by ology of LN, provide improved SLE complication risk predic- Peter K. Gregersen at the Robert S. Boas Center for Genomics and tion, and ultimately motivate novel therapeutic targets. Human Genetics, Feinstein Institute for Medical Research (Manhasset, NY). The authors also acknowledge computing support from the Wake Forest School of Medicine Center of Public Health Genomics. CONCISE METHODS Theauthors gratefully acknowledge the followingfundingsourcesfor this research. Genotyping funds for set I were provided by Genentech. This study reports the results of a meta-analysis for LN based on three The Alliance for Lupus Research funded the International Consortium GWAS of unrelated women of European descent with SLE. The three forSystemicLupusErythematosusGeneticsandthegenotypingforsetII. GWAS used include the following: set I, samples genotyped using Set III was funded by grants from the National Institutes of Health Illumina HumanHap550v1 as described by Hom et al.11;setII,sam- (AI063274 and AR052125 to P.M.G. and AR043247 to K.L.M.; National ples genotyped using Illumina HumanHap300 as described by Harley Research Service Award 5F32-AR50927 to R.R.G.), the Lupus Foun- et al.10; and set III, samples genotyped using Affymetrix 5.0 as de- dation of Minnesota (to P.M.G. and K.L.M.-S.), and the Arthritis scribed by Graham et al.8 The primary inference of this study is based Foundation(toK.L.M.-S.). This studywasalsosupportedby grantsfrom on a female-only case–case (i.e., patients with SLE with nephritis the National Institute of Diabetes and Digestive and Kidney Diseases versus patients with SLE without nephritis) analysis to minimize (R01-DK079912 and P30-DK081943 to M.K.), the Alliance for Lupus

J Am Soc Nephrol 25: ccc–ccc, 2014 GWAS of Lupus Nephritis in SLE 9 BASIC RESEARCH www.jasn.org

Research (M.K., B.P.T., L.A.C., and M.K.), and the Swedish Research in systemic lupus erythematosus stratified by nephritis. Am J Hum Council ofMedicine (to M.E.A.-R.), as well as a research fellowship from Genet 75: 346–348, 2004 the National Kidney Foundation (FLB1245 to C.C.B.), an Arthritis 6. Karassa FB, Trikalinos TA, Ioannidis JP; Fc gamma RIIIA-SLE meta- analysis investigators: The Fc gamma RIIIA-F158 allele is a risk factor for Research UK Special Strategic Award (19289 to T.J.V.), and a Kirkland the development of lupus nephritis: a meta-analysis. Kidney Int 63: fi Scholar Award (to L.A.C). Sample collections and additional nancial 1475–1482, 2003 support were also obtained from grants from the National Institutes of 7. Lee YH, Woo JH, Choi SJ, Ji JD, Song GG: Association of programmed Health (KL2-TR000143 to S.A.C.; R01-AR033062, N01-AR062277, cell death 1 polymorphisms and systemic lupus erythematosus: A meta- – RC2-AR058951, and UL1-TR000165 to E.E.B. and R.P.K.; P60- analysis. Lupus 18: 9 15, 2009 8. Graham RR, Cotsapas C, Davies L, Hackett R, Lessard CJ, Leon JM, Burtt AR053308, K24-AR02175, R01-AR052300, and UL1-TR000004 to NP, Guiducci C, Parkin M, Gates C, Plenge RM, Behrens TW, Wither JE, L.A.C.;AR057028toF.Y.D.;IMMA9,5R37AI024717-25,5P01AI083194, Rioux JD, Fortin PR, Graham DC, Wong AK, Vyse TJ, Daly MJ, Altshuler 5P01AR049084, PR094002, and 3R37AI024717-23S1 to J.B.H.; R01- D, Moser KL, Gaffney PM: Genetic variants near TNFAIP3 on 6q23 are AR057172 to C.O.J.; HL092397 to M.I.K.; R01-AR046588, National associated with systemic lupus erythematosus. Nat Genet 40: 1059– Institute of Arthritis and Musculoskeletal and Skin Diseases [NIAMS] 1061, 2008 Progression of Cardiovascular Disease in Lupus K24-AR002213 to S.M.; 9. Han JW, Zheng HF, Cui Y, Sun LD, Ye DQ, Hu Z, Xu JH, Cai ZM, Huang W, Zhao GP, Xie HF, Fang H, Lu QJ, Xu JH, Li XP, Pan YF, Deng DQ, AR43727 and UL1-RR025005 to M.P.; R01-AR043814 to B.P.T.; R01- Zeng FQ, Ye ZZ, Zhang XY, Wang QW, Hao F, Ma L, Zuo XB, Zhou FS, AR057172 to C.O.J.; and R01-HL56266 and R01-DK070941 to B.I.F.). Du WH, Cheng YL, Yang JQ, Shen SK, Li J, Sheng YJ, Zuo XX, Zhu WF, The following individuals were members of the European Renal Gao F, Zhang PL, Guo Q, Li B, Gao M, Xiao FL, Quan C, Zhang C, Zhang cDNA Bank–Kroener-Fresenius Biopsy Bank at the time of this study: Z, Zhu KJ, Li Y, Hu DY, Lu WS, Huang JL, Liu SX, Li H, Ren YQ, Wang ZX, C.D. Cohen, M. Fischereder, H. Schmid, P.J. Nelson, M. Kretzler, Yang CJ, Wang PG, Zhou WM, Lv YM, Zhang AP, Zhang SQ, Lin D, Li Y, Low HQ, Shen M, Zhai ZF, Wang Y, Zhang FY, Yang S, Liu JJ, Zhang XJ: D. Schloendorff, and W. Samtleben (Munich, Germany); J.D. Sraer Genome-wide association study in a Chinese Han population identifies ’ and P. Ronco (Paris, France); M.P. Rastaldi and G. D Amico (Milan, nine new susceptibility loci for systemic lupus erythematosus. Nat Italy); F. Mampaso (Madrid, Spain); P.Doran and H.R. Brady (Dublin, Genet 41: 1234–1237, 2009 Ireland); D. Moenks (Gottingen, Germany); P. Mertens and J. Floege 10. Harley JB, Alarcón-Riquelme ME, Criswell LA, Jacob CO, Kimberly (Aachen, Germany); N. Braun and T. Risler (Tübingen, Germany), RP, Moser KL, Tsao BP, Vyse TJ, Langefeld CD, Nath SK, Guthridge L. Gesualdo and F.P. Schena (Bari, Italy); J. Gerth and G. Wolf (Jena, JM, Cobb BL, Mirel DB, Marion MC, Williams AH, Divers J, Wang W, Frank SG, Namjou B, Gabriel SB, Lee AT, Gregersen PK, Behrens TW, Germany); R. Oberbauer and D. Kerjaschki (Vienna, Ausria); Taylor KE, Fernando M, Zidovetzki R, Gaffney PM, Edberg JC, Rioux B. Banas and B.K. Kraemer (Regensburg, Germany); H. Peters and JD, Ojwang JO, James JA, Merrill JT, Gilkeson GS, Seldin MF, Yin H, H.H. Neumayer (Berlin, Germany); K. Ivens and B. Grabensee Baechler EC, Li QZ, Wakeland EK, Bruner GR, Kaufman KM, Kelly JA; (Dusseldorf, Germany); R.P.Wuethrich (Zurich, Switzerland); and International Consortium for Systemic Lupus Erythematosus Ge- V. Tesar (Prague, Czech Republic). netics (SLEGEN): Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet 40: 204–210, 2008 DISCLOSURES 11. Hom G, Graham RR, Modrek B, Taylor KE, Ortmann W, Garnier S, Lee T.W.B. and R.R.G. are full-time employees of Genentech, Inc. 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J Am Soc Nephrol 25: ccc–ccc, 2014 GWAS of Lupus Nephritis in SLE 11 BASIC RESEARCH www.jasn.org

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AFFLIATIONS *Division of Rheumatology, Rosalind Russell-Ephraim P. Engleman Medical Research Center for Arthritis, University of California, San Francisco, California; †Department of Epidemiology, University of Alabama, Birmingham, Alabama; ‡Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama, Birmingham, Alabama; §Department of Biostatistical Sciences, Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina; |Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina; ¶Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; ††Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma; ‡‡Human DNA Variability Area, Pfizer–University of Granada–Andalusian Government Centre for Genomics and Oncological Research, Granada, Spain; **Department of Bioinformatics and Computational Biology, and §§Immunology Tissue Growth and Repair Human Genetics Group, Genentech Inc., South San Francisco, California; ||Divisions of Genetics and Molecular Medicine and Immunology, Infection, and Inflammatory Disease, Kings College, London, United Kingdom; ¶¶Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania; ***Division of Rheumatology, Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; †††University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; ‡‡‡US Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma; §§§Department of Medicine, University of Southern California, Los Angeles, California; |||Department of Medicine, West Penn Allegheny Health System, University of Pittsburgh, Pittsburgh, Pennsylvania; ¶¶¶Temple University School of Medicine, Philadelphia, Pennsylvania; ****College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; ††††Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; ‡‡‡‡Division of Rheumatology, Department of Medicine, University of California, Los Angeles, California; §§§§Department of Cell Biology and Neuroscience, University of California, Riverside, California; and ||||Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina

12 Journal of the American Society of Nephrology J Am Soc Nephrol 25: ccc–ccc,2014 Lupus Nephritis Susceptibility Loci in Women with Systemic Lupus Erythematosus

*Sharon A. Chung,1 *Elizabeth E. Brown,2,3 Adrienne H. Williams,4 Paula S. Ramos,5 Celine C. Berthier,6 Tushar Bhangale,7 Marta E. Alarcon-Riquelme,8,9 Timothy W. Behrens,10 Lindsey A. Criswell,1 Deborah Cunninghame Graham,11 F. Yesim Demirci,12 Jeffrey C. Edberg,3 Patrick M. Gaffney,8 John B. Harley,8,13,14,15 Chaim O. Jacob,16 M. Ilyas Kamboh,12 Jennifer A. Kelly,8 Susan Manzi,17,18 Kathy L. Moser-Sivils,8,19 Laurie P. Russell,4 Michelle Petri,20 Betty P. Tsao,21 Tim J. Vyse,11 Raphael Zidovetzki,22 Matthias Kreztler,6 Robert P. Kimberly,3 Barry I. Freedman,23 Robert R. Graham,10 Carl D. Langefeld,4 for the International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN)

* Co-First Authors

Corresponding author Carl D. Langefeld, Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, E-mail: [email protected] Phone: 336.713.0013

Running title: GWAS of Lupus Nephritis in SLE

Key words: lupus nephritis, systemic lupus erythematosus, glomerulonephritis, renal, genetics, GWAS Supplemental Figure 1: PP-plot for the lupus nephritis genome-wide association study (best p-value before genomic control adjustment)

Supplemental Figure S2: Power analysis for the 588 LN cases versus 1,412 SLE cases without nephritis over a range of allele frequencies, additive model and at type 1 error rates of a) α=5x10-8 and b) 5x10-8

Supplemental Table S1. Top additive genetic model associations (P<10-5) for lupus nephritis (LN) contrasting LN cases with lupus cases without nephritis.

Meta Add Meta OR Set I Set I OR Set II Set II OR Set III Set III OR MARKER CHR POSITION GENE RA N P-value (95% CI) P-value (95% CI) P-value (95% CI) P-value (95% CI)

rs8012283 14 50303910 NIN G 1807 3.10E-07 1.64 (1.35,1.98) 3.31E-05 1.68 (1.31,2.14) 2.70E-03 1.59 (1.17,2.14)

rs8015968 14 50308509 NIN A 1799 1.11E-06 1.72 (1.38,2.15) 2.56E-05 1.85 (1.39,2.46) 1.18E-02 1.57 (1.11,2.23) rs9275596 6 32789609 C 1911 1.18E-06 1.48 (1.28,1.72) 2.37E-03 1.35 (1.11,1.64) 2.80E-03 1.45 (1.14,1.85) 3.55E -03 2.02 (1.26,3.25) rs6910773 6 19928637 C 1826 1.59E-06 0.66 (0.56,0.78) 2.23E-03 0.72 (0.58,0.89) 9.82E-05 0.59 (0.46,0.77) rs967616 4 172262952 G 1920 1.68E-06 0.69 (0.59,0.81) 4.60E-05 0.66 (0.55,0.81) 2.97E-02 0.74 (0.57,0.97) 1.25E -01 0.67 (0.4,1.12) rs6936204 6 32325070 T 1950 1.72E-06 1.46 (1.26,1.69) 1.68E-03 1.36 (1.12,1.65) 6.93E-03 1.38 (1.09,1.75) 3.46E-03 1.99 (1.26,3.16)

rs6538678 12 94764036 CCDC38 A 1832 1.96E-06 1.57 (1.3,1.88) 3.06E-04 1.52 (1.21,1.91) 1.87E-03 1.63 (1.2,2.21) rs9267972 6 32325210 A 1911 2.08E-06 1.46 (1.26,1.69) 2.09E-03 1.35 (1.12,1.64) 4.99E-03 1.41 (1.11,1.78) 5.67E -03 1.95 (1.22,3.14)

rs752010 1 41865602 HIVEP3 C 1932 2.62E-06 0.71 (0.61,0.82) 1.51E-04 0.7 (0.58,0.84) 2.79E-02 0.76 (0.6,0.97) 5.56E-02 0.61 (0.37,1.01)

rs6664724 1 41762914 HIVEP3 G 1892 2.74E-06 0.71 (0.61,0.82) 1.58E-04 0.7 (0.58,0.84) 2.77E-02 0.76 (0.6,0.97) 5.59E-02 0.61 (0.37,1.01)

rs2077172 1 41865927 HIVEP3 A 1932 3.01E-06 0.71 (0.61,0.82) 1.76E-04 0.7 (0.58,0.84) 2.79E-02 0.76 (0.6,0.97) 5.58E-02 0.61 (0.37,1.01) rs7773456 6 19931217 G 1743 3.22E-06 0.68 (0.57,0.8) 1.06E-03 0.7 (0.57,0.87) 7.20E-04 0.64 (0.5,0.83) rs12206194 6 19927887 C 1845 3.80E-06 0.65 (0.54,0.78) 8.08E-04 0.67 (0.52,0.84) 1.26E-03 0.63 (0.48,0.83)

rs2038978 1 41867306 HIVEP3 A 1950 3.80E-06 0.71 (0.61,0.82) 2.35E-04 0.71 (0.59,0.85) 2.72E-02 0.76 (0.6,0.97) 5.60E -02 0.61 (0.37,1.01) rs9368127 6 19919970 A 1821 4.11E-06 0.65 (0.54,0.78) 7.85E-04 0.67 (0.53,0.84) 1.41E-03 0.63 (0.48,0.84) rs9350190 6 19919639 G 1820 4.17E-06 0.65 (0.54,0.78) 7.94E-04 0.67 (0.53,0.84) 1.42E-03 0.63 (0.48,0.84) rs13139444 4 172127251 A 1964 4.64E-06 0.7 (0.6,0.82) 1.29E-04 0.68 (0.56,0.83) 3.71E-02 0.75 (0.58,0.98) 1.07E -01 0.65 (0.39,1.1) rs2567952 4 172129725 C 1964 4.74E-06 0.7 (0.6,0.82) 1.32E-04 0.68 (0.56,0.83) 3.71E-02 0.75 (0.58,0.98) 1.07E-01 0.65 (0.39,1.1) rs2661917 4 172129968 C 1964 4.74E-06 0.7 (0.6,0.82) 1.32E-04 0.68 (0.56,0.83) 3.71E-02 0.75 (0.58,0.98) 1.07E-01 0.65 (0.39,1.1) rs2661923 4 172127242 C 1981 4.78E-06 0.7 (0.6,0.82) 1.46E-04 0.68 (0.56,0.83) 2.91E-02 0.74 (0.57,0.97) 1.46E-01 0.68 (0.4,1.14) rs2567956 4 172126317 C 1993 4.79E-06 0.7 (0.6,0.83) 1.33E-04 0.68 (0.56,0.83) 2.87E-02 0.74 (0.57,0.97) 1.68E-01 0.69 (0.41,1.17) rs1236448 4 172118655 C 1993 4.79E-06 0.7 (0.6,0.83) 1.33E-04 0.68 (0.56,0.83) 2.87E-02 0.74 (0.57,0.97) 1.68E-01 0.69 (0.41,1.17) rs17245674 4 172259440 A 1993 4.79E-06 0.7 (0.6,0.83) 1.33E-04 0.68 (0.56,0.83) 2.87E-02 0.74 (0.57,0.97) 1.68E-01 0.69 (0.41,1.17) rs2567960 4 172122108 T 1992 4.80E-06 0.7 (0.6,0.83) 1.33E-04 0.68 (0.56,0.83) 2.87E-02 0.74 (0.57,0.97) 1.68E-01 0.69 (0.41,1.17) rs17186543 4 172126746 T 1993 4.80E-06 0.7 (0.6,0.83) 1.33E-04 0.68 (0.56,0.83) 2.88E-02 0.74 (0.57,0.97) 1.68E-01 0.69 (0.41,1.17) rs9469220 6 32766288 A 1935 4.87E-06 0.7 (0.6,0.81) 4.30E-03 0.76 (0.62,0.92) 1.18E-03 0.66 (0.51,0.85) 6.71E-02 0.63 (0.39,1.03) rs12331863 4 172133772 G 1981 4.90E-06 0.7 (0.6,0.82) 1.51E-04 0.68 (0.56,0.83) 2.91E-02 0.74 (0.57,0.97) 1.45E-01 0.68 (0.4,1.14)

rs13041255 20 21078707 PLK1S1 T 1999 4.95E-06 0.69 (0.59,0.8) 8.75E-04 0.72 (0.59,0.87) 4.68E-02 0.78 (0.61,1) 1.53E-03 0.45 (0.28,0.74)

rs4813414 20 21081212 PLK1S1 A 1999 4.95E-06 0.69 (0.59,0.8) 8.75E-04 0.72 (0.59,0.87) 4.68E-02 0.78 (0.61,1) 1.53E-03 0.45 (0.28,0.74)

rs4815022 20 21072872 PLK1S1 T 1999 4.95E-06 0.68 (0.59,0.8) 8.76E-04 0.72 (0.59,0.87) 4.68E-02 0.78 (0.61,1) 1.53E-03 0.45 (0.28,0.74)

rs6047274 20 21083126 PLK1S1 T 1998 4.96E-06 0.69 (0.59,0.8) 8.77E-04 0.72 (0.59,0.87) 4.68E-02 0.78 (0.61,1) 1.53E-03 0.45 (0.28,0.74)

rs1884763 20 21076127 PLK1S1 A 1999 4.96E-06 0.69 (0.59,0.8) 8.78E-04 0.72 (0.59,0.87) 4.68E-02 0.78 (0.61,1) 1.53E-03 0.45 (0.28,0.74)

rs3762194 20 21074723 PLK1S1 A 1999 4.99E-06 0.69 (0.59,0.8) 8.82E-04 0.72 (0.59,0.87) 4.68E-02 0.78 (0.61,1) 1.53E-03 0.45 (0.28,0.74)

rs4815024 20 21086367 PLK1S1 C 1997 5.11E-06 0.69 (0.59,0.8) 9.03E-04 0.72 (0.59,0.87) 4.68E-02 0.78 (0.61,1) 1.53E-03 0.45 (0.28,0.74)

rs2093069 20 21088342 PLK1S1 C 1997 5.20E-06 0.69 (0.59,0.8) 9.19E-04 0.72 (0.59,0.87) 4.68E-02 0.78 (0.61,1) 1.53E-03 0.45 (0.28,0.74) rs6811337 4 172314454 T 1970 5.24E-06 0.7 (0.6,0.83) 1.40E-04 0.68 (0.56,0.83) 2.99E-02 0.74 (0.57,0.97) 1.68E-01 0.69 (0.41,1.17)

rs6047279 20 21090353 PLK1S1 T 1997 5.30E-06 0.69 (0.59,0.8) 9.37E-04 0.72 (0.59,0.88) 4.68E-02 0.78 (0.61,1) 1.53E-03 0.45 (0.28,0.74) rs4140624 6 19926539 T 1803 5.50E-06 0.65 (0.54,0.78) 1.25E-03 0.67 (0.53,0.85) 1.17E-03 0.63 (0.47,0.83)

rs17246620 4 172199835 LOC100506122 G 1981 5.59E-06 0.71 (0.6,0.83) 1.44E-04 0.68 (0.56,0.83) 3.09E-02 0.75 (0.57,0.97) 1.69E -01 0.69 (0.41,1.17)

rs3129943 6 32446673 C6orf10 G 1813 5.71E-06 1.44 (1.23,1.69) 4.19E-04 1.43 (1.17,1.75) 4.32E-03 1.45 (1.12,1.88)

rs11157764 14 50320087 NIN A 1773 6.32E-06 1.67 (1.34,2.1) 2.04E-04 1.74 (1.3,2.33) 9.96E-03 1.59 (1.12,2.27) rs1396323 4 172142182 A 1970 6.45E-06 0.71 (0.61,0.84) 9.56E-05 0.68 (0.55,0.82) 4.32E-02 0.76 (0.59,0.99) 2.06E -01 0.71 (0.42,1.2) rs7681844 4 172142671 C 1970 6.53E-06 0.71 (0.61,0.84) 9.63E-05 0.68 (0.55,0.82) 4.34E-02 0.76 (0.59,0.99) 2.06E-01 0.71 (0.42,1.2) rs13148831 4 172146081 T 1970 6.63E-06 0.71 (0.61,0.84) 9.78E-05 0.68 (0.56,0.82) 4.34E-02 0.76 (0.59,0.99) 2.06E-01 0.71 (0.42,1.2) rs2332086 4 172147756 G 1970 6.65E-06 0.71 (0.61,0.84) 9.82E-05 0.68 (0.56,0.82) 4.34E-02 0.76 (0.59,0.99) 2.06E-01 0.71 (0.42,1.2)

rs6047293 20 21102487 PLK1S1 G 1997 6.67E-06 0.69 (0.59,0.8) 1.19E-03 0.73 (0.6,0.88) 4.63E-02 0.78 (0.61,1) 1.53E-03 0.45 (0.28,0.74)

rs6082339 20 21100742 PLK1S1 G 1997 6.67E-06 0.69 (0.59,0.8) 1.19E-03 0.73 (0.6,0.88) 4.63E-02 0.78 (0.61,1) 1.53E-03 0.45 (0.28,0.74)

rs910975 20 21104169 PLK1S1 A 1997 6.67E-06 0.69 (0.59,0.8) 1.19E-03 0.73 (0.6,0.88) 4.63E-02 0.78 (0.61,1) 1.53E-03 0.45 (0.28,0.74)

rs2093070 20 21105510 PLK1S1 T 1997 6.67E-06 0.69 (0.59,0.8) 1.19E-03 0.73 (0.6,0.88) 4.63E-02 0.78 (0.61,1) 1.53E-03 0.45 (0.28,0.74)

rs6515144 20 21105565 PLK1S1 T 1997 6.67E-06 0.69 (0.59,0.8) 1.19E-03 0.73 (0.6,0.88) 4.63E-02 0.78 (0.61,1) 1.53E-03 0.45 (0.28,0.74)

rs6035795 20 21093885 PLK1S1 A 1997 6.69E-06 0.69 (0.59,0.8) 1.18E-03 0.73 (0.6,0.88) 4.68E-02 0.78 (0.61,1) 1.53E-03 0.45 (0.28,0.74)

rs6047281 20 21094287 PLK1S1 A 1998 6.72E-06 0.69 (0.59,0.8) 1.18E-03 0.73 (0.6,0.88) 4.68E-02 0.78 (0.61,1) 1.53E-03 0.45 (0.28,0.74) rs7682721 4 172151045 T 1970 6.73E-06 0.71 (0.61,0.84) 9.97E-05 0.68 (0.56,0.82) 4.34E-02 0.76 (0.59,0.99) 2.06E-01 0.71 (0.42,1.2) rs6827582 4 172179792 A 1982 6.87E-06 0.71 (0.6,0.83) 1.81E-04 0.68 (0.56,0.83) 3.10E-02 0.75 (0.57,0.97) 1.69E-01 0.69 (0.41,1.17) rs6811103 4 172176175 T 1984 6.90E-06 0.71 (0.6,0.83) 2.09E-04 0.69 (0.56,0.84) 2.99E-02 0.74 (0.57,0.97) 1.49E-01 0.68 (0.4,1.15) rs11735676 4 172177663 T 1983 7.11E-06 0.71 (0.6,0.83) 1.97E-04 0.69 (0.56,0.84) 2.99E-02 0.74 (0.57,0.97) 1.68E-01 0.69 (0.41,1.17) rs10012648 4 172177040 C 1983 7.12E-06 0.71 (0.6,0.83) 1.98E-04 0.69 (0.56,0.84) 2.99E-02 0.74 (0.57,0.97) 1.68E-01 0.69 (0.41,1.17) rs13151801 4 172176859 T 1983 7.12E-06 0.71 (0.6,0.83) 1.98E-04 0.69 (0.56,0.84) 2.99E-02 0.74 (0.57,0.97) 1.68E-01 0.69 (0.41,1.17) rs7673070 4 172176632 C 1983 7.14E-06 0.71 (0.6,0.83) 1.97E-04 0.69 (0.56,0.84) 3.01E-02 0.74 (0.57,0.97) 1.68E-01 0.69 (0.41,1.17) rs6812562 4 172177061 A 1983 7.14E-06 0.71 (0.6,0.83) 1.97E-04 0.69 (0.56,0.84) 3.01E-02 0.74 (0.57,0.97) 1.68E-01 0.69 (0.41,1.17) rs13138342 4 172177180 C 1983 7.14E-06 0.71 (0.6,0.83) 1.97E-04 0.69 (0.56,0.84) 3.01E-02 0.74 (0.57,0.97) 1.68E-01 0.69 (0.41,1.17) rs6553556 4 172176526 A 1983 7.14E-06 0.71 (0.6,0.83) 1.97E-04 0.69 (0.56,0.84) 3.01E-02 0.74 (0.57,0.97) 1.68E-01 0.69 (0.41,1.17) rs12648447 4 172175669 T 1985 7.45E-06 0.71 (0.6,0.83) 2.09E-04 0.69 (0.56,0.84) 2.99E-02 0.74 (0.57,0.97) 1.67E-01 0.7 (0.42,1.16) rs25511 4 172175559 T 1985 7.49E-06 0.71 (0.6,0.83) 2.09E-04 0.69 (0.56,0.84) 2.99E-02 0.74 (0.57,0.97) 1.68E-01 0.69 (0.41,1.17) rs9968437 4 172173406 T 1985 7.49E-06 0.71 (0.6,0.83) 2.09E-04 0.69 (0.56,0.84) 2.99E-02 0.74 (0.57,0.97) 1.68E-01 0.69 (0.41,1.17) rs1605651 4 172162912 A 1985 7.50E-06 0.71 (0.6,0.83) 2.08E-04 0.69 (0.56,0.84) 3.01E-02 0.74 (0.57,0.97) 1.68E-01 0.69 (0.41,1.17) rs11132865 4 172164946 C 1985 7.50E-06 0.71 (0.6,0.83) 2.09E-04 0.69 (0.56,0.84) 2.99E-02 0.74 (0.57,0.97) 1.68E-01 0.69 (0.41,1.17) rs13115632 4 172164388 G 1985 7.50E-06 0.71 (0.6,0.83) 2.09E-04 0.69 (0.56,0.84) 2.99E-02 0.74 (0.57,0.97) 1.68E-01 0.69 (0.41,1.17) rs1396325 4 172167776 G 1985 7.50E-06 0.71 (0.6,0.83) 2.09E-04 0.69 (0.56,0.84) 2.99E-02 0.74 (0.57,0.97) 1.68E-01 0.69 (0.41,1.17) rs4692627 4 172165637 T 1985 7.50E-06 0.71 (0.6,0.83) 2.09E-04 0.69 (0.56,0.84) 2.99E-02 0.74 (0.57,0.97) 1.68E-01 0.69 (0.41,1.17) rs1508507 4 172172780 A 1985 7.54E-06 0.71 (0.6,0.83) 2.09E-04 0.69 (0.56,0.84) 3.01E-02 0.74 (0.57,0.97) 1.68E-01 0.69 (0.41,1.17) rs25510 4 172175579 A 1985 7.54E-06 0.71 (0.6,0.83) 2.09E-04 0.69 (0.56,0.84) 3.01E-02 0.74 (0.57,0.97) 1.68E-01 0.69 (0.41,1.17) rs25512 4 172175532 G 1985 7.54E-06 0.71 (0.6,0.83) 2.09E-04 0.69 (0.56,0.84) 3.01E-02 0.74 (0.57,0.97) 1.68E-01 0.69 (0.41,1.17) rs6849128 4 172176001 A 1985 7.54E-06 0.71 (0.6,0.83) 2.09E-04 0.69 (0.56,0.84) 3.01E-02 0.74 (0.57,0.97) 1.68E-01 0.69 (0.41,1.17) rs6858075 4 172172043 A 1985 7.54E-06 0.71 (0.6,0.83) 2.09E-04 0.69 (0.56,0.84) 3.01E-02 0.74 (0.57,0.97) 1.68E-01 0.69 (0.41,1.17)

rs8120293 20 21116395 PLK1S1 T 1991 7.63E-06 0.69 (0.59,0.8) 1.36E-03 0.73 (0.6,0.88) 4.63E-02 0.78 (0.61,1) 1.53E-03 0.45 (0.28,0.74)

rs8120377 20 21116361 PLK1S1 T 1991 7.63E-06 0.69 (0.59,0.8) 1.36E-03 0.73 (0.6,0.88) 4.63E-02 0.78 (0.61,1) 1.53E-03 0.45 (0.28,0.74)

rs765585 20 21119172 PLK1S1 T 1991 7.63E-06 0.69 (0.59,0.8) 1.36E-03 0.73 (0.6,0.88) 4.63E-02 0.78 (0.61,1) 1.53E-03 0.45 (0.28,0.74)

rs17187123 4 172344509 LOC100506122 A 1935 8.00E-06 0.71 (0.61,0.84) 1.68E-04 0.68 (0.56,0.83) 3.35E-02 0.75 (0.57,0.98) 2.08E-01 0.72 (0.43,1.2)

rs17246878 4 172208800 LOC100506122 T 1935 8.19E-06 0.71 (0.61,0.84) 1.72E-04 0.68 (0.56,0.83) 3.35E-02 0.75 (0.57,0.98) 2.08E-01 0.72 (0.43,1.2)

rs879064 20 21123550 PLK1S1 C 1991 8.55E-06 0.69 (0.59,0.8) 1.36E-03 0.73 (0.6,0.88) 4.63E-02 0.78 (0.61,1) 2.05E-03 0.46 (0.28,0.75)

rs1508296 4 172208949 LOC100506122 C 1976 8.76E-06 0.71 (0.61,0.83) 1.91E-04 0.69 (0.56,0.84) 3.71E-02 0.75 (0.58,0.98) 1.67E-01 0.69 (0.41,1.17)

rs13110268 4 172211262 LOC100506122 G 1976 8.82E-06 0.71 (0.61,0.83) 1.93E-04 0.69 (0.56,0.84) 3.69E-02 0.75 (0.58,0.98) 1.68E-01 0.69 (0.41,1.17) rs7340816 4 172179585 A 1944 8.87E-06 0.71 (0.6,0.83) 2.27E-04 0.69 (0.56,0.84) 3.30E-02 0.75 (0.57,0.98) 1.62E-01 0.69 (0.41,1.16)

Supplemental Table S2. Top HLA region associations (genomic control adjusted P-values, not adjusted for HLA-risk haplotype tagging SNPs) for P<10-4.

Meta Set I P- best P- value Set II P- Set II OR Set III P- Set III Marker Position Gene Name RA Mode value Meta OR adj Set I OR value adj (95%CI) value adj OR(95%CI) rs2647012 32772436 C A 2.64E-07 0.66(0.57,0.77) 1.23E-03 0.73(0.6,0.88) 7.22E-04 0.66(0.52,0.84) 5.84E-03 0.52(0.32,0.82) rs2647003 32772859 G A 3.62E-07 0.67(0.58,0.77) 1.24E-03 0.73(0.6,0.88) 1.03E-03 0.67(0.53,0.85) 5.83E-03 0.52(0.32,0.82) rs2647040 32775259 G A 6.09E-07 0.67(0.58,0.78) 1.62E-03 0.73(0.6,0.89) 1.38E-03 0.68(0.54,0.86) 5.24E-03 0.51(0.32,0.82) rs2858310 32776302 A A 7.67E-07 0.67(0.58,0.78) 1.95E-03 0.74(0.61,0.89) 1.42E-03 0.68(0.54,0.86) 5.24E-03 0.52(0.32,0.82) rs2647046 32776315 C A 8.04E-07 0.67(0.58,0.78) 1.95E-03 0.74(0.61,0.89) 1.44E-03 0.68(0.54,0.86) 5.57E-03 0.52(0.32,0.82) rs9275521 32782931 C A 1.28E-06 0.68(0.59,0.78) 2.19E-03 0.74(0.61,0.89) 1.96E-03 0.69(0.54,0.87) 5.95E-03 0.52(0.32,0.83) rs9267972 32325210 A D 1.49E-06 1.85(1.46,2.33) 4.25E-03 1.52(1.15,2.02) 7.31E-04 1.96(1.33,2.89) 1.03E-02 2.78(1.28,6.04) rs9275517 32782628 G A 1.92E-06 0.68(0.59,0.79) 2.05E-03 0.74(0.61,0.89) 3.41E-03 0.7(0.56,0.89) 5.93E-03 0.52(0.32,0.83) rs9275596 32789610 C A 2.01E-06 1.48(1.28,1.72) 2.75E-03 1.35(1.11,1.64) 3.05E-03 1.45(1.14,1.85) 3.66E-03 2.02(1.26,3.25) rs9275524 32783087 C A 2.09E-06 0.68(0.59,0.79) 2.20E-03 0.74(0.61,0.9) 3.40E-03 0.7(0.56,0.89) 6.08E-03 0.52(0.32,0.83) rs3998157 32786456 A A 2.09E-06 0.68(0.59,0.79) 2.20E-03 0.74(0.61,0.9) 3.40E-03 0.7(0.56,0.89) 6.10E-03 0.52(0.32,0.83) rs9394114 32785917 C A 2.09E-06 0.68(0.59,0.79) 2.20E-03 0.74(0.61,0.9) 3.40E-03 0.7(0.56,0.89) 6.10E-03 0.52(0.32,0.83) rs9380318 32785648 T A 2.11E-06 0.68(0.59,0.79) 2.20E-03 0.74(0.61,0.9) 3.41E-03 0.7(0.56,0.89) 6.10E-03 0.52(0.32,0.83) rs9275572 32786977 G A 2.45E-06 0.69(0.59,0.79) 2.42E-03 0.74(0.62,0.9) 3.41E-03 0.7(0.56,0.89) 6.83E-03 0.52(0.33,0.83) rs6936204 32325070 T A 2.92E-06 1.46(1.26,1.69) 1.95E-03 1.36(1.12,1.65) 7.55E-03 1.38(1.09,1.75) 3.56E-03 1.99(1.26,3.16) rs3129943 32446673 C6orf10 G D 3.60E-06 1.58(1.29,1.95) 7.80E-04 1.58(1.21,2.06) 7.26E-04 1.79(1.28,2.51) 6.17E-01 1.2(0.61,2.34) rs3130316 32329206 T A 3.93E-06 1.45(1.25,1.68) 3.14E-03 1.34(1.11,1.62) 4.99E-03 1.4(1.11,1.78) 4.55E-03 1.96(1.23,3.12) rs3115571 32328896 A A 3.93E-06 1.45(1.25,1.68) 3.13E-03 1.34(1.11,1.62) 4.99E-03 1.4(1.11,1.78) 4.55E-03 1.96(1.23,3.12) rs3096700 32329760 A A 4.01E-06 1.45(1.25,1.68) 3.20E-03 1.34(1.11,1.62) 4.99E-03 1.4(1.11,1.78) 4.57E-03 1.96(1.23,3.12) rs521828 32399621 C6orf10 T D 4.45E-06 1.59(1.29,1.95) 1.93E-03 1.52(1.17,1.98) 3.26E-04 1.87(1.33,2.63) 5.21E-01 1.25(0.65,2.43) rs3130309 32323450 A A 4.83E-06 1.45(1.25,1.67) 3.78E-03 1.33(1.1,1.61) 4.99E-03 1.4(1.11,1.78) 4.55E-03 1.96(1.23,3.12) rs2647044 32775888 A D 7.75E-06 1.61(1.29,2) 9.29E-04 1.62(1.22,2.15) 2.08E-03 1.75(1.23,2.5) 4.61E-01 1.31(0.65,2.64) rs9275576 32787305 T D 8.33E-06 1.62(1.3,2.02) 9.86E-04 1.63(1.22,2.17) 2.09E-03 1.76(1.23,2.52) 4.67E-01 1.31(0.65,2.66) rs2856674 32767623 G D 8.79E-06 1.6(1.29,1.99) 9.79E-04 1.61(1.22,2.14) 2.02E-03 1.75(1.23,2.49) 5.12E-01 1.27(0.63,2.57) rs9268177 32382861 C6orf10 A D 9.08E-06 1.64(1.31,2.04) 3.74E-04 1.7(1.27,2.26) 1.89E-02 1.53(1.08,2.18) 1.36E-01 1.71(0.85,3.46) rs3130320 32331236 T D 9.30E-06 1.71(1.36,2.15) 5.90E-03 1.49(1.13,1.96) 1.32E-03 1.89(1.28,2.77) 6.29E-02 2.06(0.97,4.37) rs9268208 32388570 C6orf10 C D 9.40E-06 1.64(1.31,2.04) 3.75E-04 1.7(1.27,2.26) 1.92E-02 1.53(1.08,2.18) 1.38E-01 1.71(0.85,3.44) rs9268219 32392087 C6orf10 G D 9.83E-06 1.63(1.31,2.03) 3.77E-04 1.69(1.27,2.26) 1.95E-02 1.53(1.08,2.18) 1.43E-01 1.7(0.84,3.41) rs9268235 32398186 C6orf10 T D 1.03E-05 1.63(1.31,2.03) 3.91E-04 1.69(1.27,2.26) 1.96E-02 1.53(1.08,2.17) 1.43E-01 1.69(0.84,3.4) rs9268144 32365178 C D 1.11E-05 1.63(1.31,2.03) 4.54E-04 1.68(1.26,2.24) 1.91E-02 1.53(1.08,2.18) 1.36E-01 1.71(0.85,3.46) rs9296032 32526688 C D 1.13E-05 1.78(1.42,2.23) 1.59E-02 1.42(1.07,1.87) 4.63E-03 1.75(1.19,2.56) 5.79E-04 3.52(1.72,7.2) rs7775397 32369231 C6orf10 G D 1.16E-05 1.63(1.31,2.03) 4.77E-04 1.67(1.26,2.23) 1.91E-02 1.53(1.08,2.18) 1.36E-01 1.71(0.85,3.46) rs2395149 32433540 C6orf10 A D 1.22E-05 1.62(1.3,2.02) 4.43E-04 1.68(1.26,2.24) 2.06E-02 1.52(1.07,2.16) 1.46E-01 1.69(0.84,3.38) rs3129927 32441805 C6orf10 C D 1.24E-05 1.62(1.3,2.02) 4.62E-04 1.68(1.26,2.23) 2.01E-02 1.53(1.07,2.17) 1.47E-01 1.68(0.84,3.38) rs3129949 32406792 C6orf10 A D 1.36E-05 1.55(1.26,1.91) 5.06E-03 1.47(1.13,1.91) 3.23E-04 1.86(1.33,2.6) 5.55E-01 1.23(0.64,2.37) rs2040410 32710677 T D 1.67E-05 1.57(1.26,1.94) 1.57E-03 1.57(1.19,2.08) 2.70E-03 1.7(1.21,2.4) 4.81E-01 1.29(0.65,2.57) rs1003878 32407800 C6orf10 A D 1.72E-05 1.54(1.26,1.9) 5.02E-03 1.47(1.13,1.91) 4.58E-04 1.83(1.31,2.56) 5.55E-01 1.23(0.64,2.37) rs9368716 32414069 C6orf10 A A 2.21E-05 0.72(0.62,0.83) 1.06E-03 0.73(0.6,0.88) 2.89E-02 0.76(0.59,0.97) 5.36E-02 0.62(0.39,1) rs1150754 32158736 TNXB T D 2.30E-05 1.58(1.27,1.96) 3.91E-04 1.66(1.26,2.19) 3.73E-02 1.46(1.03,2.07) 1.76E-01 1.61(0.81,3.2) rs1150755 32146528 TNXB T D 2.31E-05 1.58(1.27,1.96) 4.01E-04 1.66(1.26,2.19) 3.66E-02 1.46(1.03,2.07) 1.77E-01 1.61(0.81,3.2) rs9268209 32388599 C6orf10 C D 2.52E-05 1.58(1.28,1.95) 2.06E-03 1.53(1.17,2) 9.48E-03 1.58(1.12,2.23) 1.32E-01 1.71(0.86,3.38) rs9276665 32855480 G D 2.55E-05 1.61(1.29,2.02) 6.88E-04 1.68(1.25,2.26) 2.26E-02 1.53(1.07,2.19) 2.03E-01 1.61(0.78,3.3) rs1794282 32774504 T D 2.77E-05 1.6(1.28,2.01) 7.16E-04 1.68(1.25,2.25) 2.19E-02 1.53(1.07,2.19) 2.25E-01 1.57(0.77,3.2) rs9276731 32873564 T D 3.04E-05 1.6(1.28,2.01) 9.20E-04 1.66(1.23,2.22) 2.06E-02 1.54(1.07,2.2) 1.99E-01 1.61(0.78,3.32) rs2894254 32453668 G D 3.25E-05 1.58(1.27,1.97) 1.67E-03 1.59(1.2,2.12) 1.09E-02 1.59(1.12,2.25) 2.28E-01 1.55(0.77,3.14) rs9268207 32388440 C6orf10 T D 3.25E-05 1.54(1.26,1.9) 1.77E-03 1.54(1.18,2) 1.11E-02 1.55(1.11,2.17) 2.03E-01 1.55(0.8,3.01) rs7341328 32383172 C6orf10 A D 3.32E-05 1.54(1.25,1.9) 1.77E-03 1.54(1.18,2) 1.11E-02 1.55(1.11,2.17) 2.10E-01 1.53(0.79,2.97) rs9268181 32383987 C6orf10 C D 3.32E-05 1.54(1.25,1.9) 1.77E-03 1.54(1.18,2) 1.11E-02 1.55(1.11,2.17) 2.10E-01 1.53(0.79,2.97) rs9268182 32384005 C6orf10 G D 3.32E-05 1.54(1.25,1.9) 1.77E-03 1.54(1.18,2) 1.11E-02 1.55(1.11,2.17) 2.10E-01 1.53(0.79,2.97) rs9268197 32385912 C6orf10 A D 3.32E-05 1.54(1.25,1.9) 1.77E-03 1.54(1.18,2) 1.11E-02 1.55(1.11,2.17) 2.10E-01 1.53(0.79,2.97) rs9268201 32387262 C6orf10 A D 3.32E-05 1.54(1.25,1.9) 1.77E-03 1.54(1.18,2) 1.11E-02 1.55(1.11,2.17) 2.10E-01 1.53(0.79,2.97) rs3864302 32386770 C6orf10 T D 3.32E-05 1.54(1.25,1.9) 1.77E-03 1.54(1.18,2) 1.11E-02 1.55(1.11,2.17) 2.10E-01 1.53(0.79,2.97) rs6934429 32387600 C6orf10 T D 3.32E-05 1.54(1.25,1.9) 1.77E-03 1.54(1.18,2) 1.11E-02 1.55(1.11,2.17) 2.10E-01 1.53(0.79,2.97) rs7341300 32383005 C6orf10 T D 3.32E-05 1.54(1.25,1.9) 1.77E-03 1.54(1.18,2) 1.11E-02 1.55(1.11,2.17) 2.10E-01 1.53(0.79,2.97) rs9268200 32386648 C6orf10 T D 3.32E-05 1.54(1.25,1.9) 1.77E-03 1.54(1.18,2) 1.11E-02 1.55(1.11,2.17) 2.10E-01 1.53(0.79,2.97) rs9268202 32387318 C6orf10 T D 3.32E-05 1.54(1.25,1.9) 1.77E-03 1.54(1.18,2) 1.11E-02 1.55(1.11,2.17) 2.10E-01 1.53(0.79,2.97) rs9268204 32387478 C6orf10 T D 3.32E-05 1.54(1.25,1.9) 1.77E-03 1.54(1.18,2) 1.11E-02 1.55(1.11,2.17) 2.10E-01 1.53(0.79,2.97) rs3864300 32379785 C6orf10 T D 3.40E-05 1.54(1.25,1.89) 1.77E-03 1.54(1.18,2) 1.14E-02 1.55(1.11,2.17) 2.10E-01 1.53(0.79,2.97) rs3864301 32379933 C6orf10 T D 3.40E-05 1.54(1.25,1.89) 1.77E-03 1.54(1.18,2) 1.14E-02 1.55(1.11,2.17) 2.10E-01 1.53(0.79,2.97) rs9268170 32380689 C6orf10 G D 3.40E-05 1.54(1.25,1.89) 1.77E-03 1.54(1.18,2) 1.14E-02 1.55(1.11,2.17) 2.10E-01 1.53(0.79,2.97) rs6935269 32368328 C D 3.43E-05 1.54(1.25,1.89) 1.79E-03 1.54(1.18,2.01) 1.14E-02 1.55(1.11,2.17) 2.10E-01 1.53(0.79,2.97) rs9268402 32449332 C6orf10 A A 3.47E-05 0.7(0.6,0.81) 3.26E-02 0.81(0.66,0.98) 2.08E-03 0.68(0.53,0.87) 6.10E-03 0.51(0.32,0.83) rs9268163 32378853 C6orf10 T D 3.57E-05 1.54(1.25,1.89) 1.87E-03 1.53(1.18,2) 1.14E-02 1.55(1.11,2.17) 2.10E-01 1.53(0.79,2.97) rs2858330 32766694 C A 3.59E-05 0.71(0.61,0.82) 2.56E-03 0.74(0.61,0.9) 8.34E-02 0.8(0.63,1.02) 1.25E-03 0.46(0.29,0.74) rs7762279 32863269 C D 3.72E-05 1.6(1.28,2) 1.02E-03 1.65(1.23,2.23) 2.23E-02 1.53(1.07,2.18) 2.05E-01 1.6(0.78,3.3) rs7775592 32378261 C6orf10 A D 3.76E-05 1.54(1.25,1.89) 1.96E-03 1.53(1.17,2) 1.14E-02 1.55(1.11,2.17) 2.10E-01 1.53(0.79,2.97) rs6909427 32376679 C6orf10 G D 3.77E-05 1.54(1.25,1.89) 1.97E-03 1.53(1.17,2) 1.14E-02 1.55(1.11,2.17) 2.10E-01 1.53(0.79,2.97) rs7750783 32376058 C6orf10 T D 3.77E-05 1.54(1.25,1.89) 1.97E-03 1.53(1.17,2) 1.14E-02 1.55(1.11,2.17) 2.10E-01 1.53(0.79,2.97) rs9267084 31517585 A D 3.89E-05 0.55(0.42,0.7) 7.76E-03 0.64(0.47,0.89) 3.10E-02 0.62(0.4,0.95) 1.12E-03 0.26(0.11,0.58) rs1018434 32389338 C6orf10 C D 3.96E-05 1.54(1.25,1.89) 2.15E-03 1.53(1.17,1.99) 1.07E-02 1.56(1.11,2.18) 2.15E-01 1.53(0.79,2.97) rs2069026 32389937 C6orf10 T D 4.05E-05 1.54(1.25,1.89) 2.20E-03 1.53(1.17,1.99) 1.06E-02 1.56(1.11,2.19) 2.16E-01 1.53(0.79,2.97) rs1018430 32389666 C6orf10 T D 4.08E-05 1.54(1.25,1.89) 2.20E-03 1.53(1.17,1.99) 1.06E-02 1.56(1.11,2.18) 2.16E-01 1.53(0.79,2.97) rs3864303 32389600 C6orf10 G D 4.08E-05 1.54(1.25,1.89) 2.20E-03 1.53(1.17,1.99) 1.07E-02 1.56(1.11,2.18) 2.16E-01 1.53(0.79,2.97) rs6903871 32389998 C6orf10 C D 4.08E-05 1.54(1.25,1.89) 2.20E-03 1.53(1.17,1.99) 1.06E-02 1.56(1.11,2.19) 2.16E-01 1.53(0.79,2.97) rs1018431 32389654 C6orf10 A D 4.08E-05 1.54(1.25,1.89) 2.19E-03 1.53(1.17,1.99) 1.07E-02 1.56(1.11,2.18) 2.16E-01 1.53(0.79,2.97) rs6909790 32390958 C6orf10 G D 4.22E-05 1.54(1.25,1.89) 2.27E-03 1.52(1.17,1.99) 1.07E-02 1.56(1.11,2.19) 2.18E-01 1.53(0.79,2.97) rs3749966 32369486 C6orf10 C D 4.30E-05 1.53(1.25,1.89) 2.24E-03 1.52(1.17,1.99) 1.14E-02 1.55(1.11,2.17) 2.10E-01 1.53(0.79,2.97) rs3130322 32331903 C D 4.39E-05 1.54(1.25,1.89) 2.70E-03 1.51(1.16,1.97) 9.04E-03 1.58(1.12,2.21) 2.20E-01 1.52(0.78,2.95) rs3115569 32332117 A D 4.40E-05 1.54(1.25,1.89) 2.70E-03 1.51(1.16,1.97) 9.10E-03 1.58(1.12,2.21) 2.20E-01 1.52(0.78,2.95) rs6908927 32332468 A D 4.40E-05 1.54(1.25,1.89) 2.70E-03 1.51(1.16,1.97) 9.10E-03 1.58(1.12,2.21) 2.20E-01 1.52(0.78,2.95) rs6927098 32335484 T D 4.42E-05 1.54(1.25,1.89) 2.70E-03 1.51(1.16,1.97) 9.13E-03 1.58(1.12,2.21) 2.20E-01 1.52(0.78,2.96) rs3115568 32332297 T D 4.42E-05 1.54(1.25,1.89) 2.70E-03 1.51(1.16,1.97) 9.13E-03 1.58(1.12,2.21) 2.20E-01 1.52(0.78,2.95) rs9268218 32391678 C6orf10 G D 4.51E-05 1.54(1.25,1.89) 2.42E-03 1.52(1.16,1.98) 1.07E-02 1.56(1.11,2.19) 2.18E-01 1.53(0.79,2.97) rs3115553 32353805 T D 4.91E-05 1.53(1.25,1.88) 2.69E-03 1.51(1.16,1.97) 1.08E-02 1.55(1.11,2.17) 2.10E-01 1.53(0.79,2.97) rs9268176 32382058 C6orf10 T D 4.95E-05 1.53(1.24,1.89) 1.76E-03 1.56(1.18,2.04) 1.32E-02 1.55(1.1,2.18) 2.98E-01 1.44(0.74,2.8) rs3130340 32352605 C D 5.15E-05 1.53(1.24,1.88) 2.69E-03 1.51(1.16,1.97) 1.14E-02 1.55(1.11,2.17) 2.10E-01 1.53(0.79,2.97) rs9268143 32364452 G D 5.19E-05 1.53(1.24,1.88) 2.70E-03 1.51(1.16,1.97) 1.14E-02 1.55(1.11,2.17) 2.10E-01 1.53(0.79,2.97) rs9268142 32364397 C D 5.19E-05 1.53(1.24,1.88) 2.70E-03 1.51(1.16,1.97) 1.14E-02 1.55(1.11,2.17) 2.10E-01 1.53(0.79,2.97) rs1559874 32351133 A D 5.22E-05 1.53(1.24,1.88) 2.76E-03 1.51(1.16,1.97) 1.14E-02 1.55(1.11,2.17) 2.06E-01 1.54(0.8,2.97) rs3129856 32507316 C D 5.27E-05 1.58(1.27,1.97) 1.64E-03 1.6(1.2,2.13) 3.04E-02 1.48(1.04,2.11) 1.09E-01 1.77(0.88,3.53) rs1559873 32351107 C D 5.29E-05 1.53(1.24,1.88) 2.76E-03 1.51(1.16,1.97) 1.14E-02 1.55(1.11,2.17) 2.10E-01 1.53(0.79,2.97) rs3117099 32466248 A D 5.44E-05 1.53(1.24,1.89) 4.56E-03 1.48(1.13,1.94) 5.86E-03 1.62(1.15,2.27) 2.42E-01 1.5(0.77,2.95) rs3132931 32343873 G D 5.73E-05 1.52(1.24,1.87) 2.75E-03 1.51(1.16,1.97) 1.14E-02 1.55(1.11,2.17) 2.36E-01 1.5(0.77,2.91) rs3115560 32344120 A D 5.75E-05 1.52(1.24,1.87) 2.75E-03 1.51(1.16,1.97) 1.14E-02 1.55(1.11,2.17) 2.36E-01 1.5(0.77,2.91) rs3096673 32345991 C D 5.76E-05 1.52(1.24,1.87) 2.76E-03 1.51(1.16,1.97) 1.14E-02 1.55(1.11,2.17) 2.36E-01 1.5(0.77,2.91) rs3132945 32346658 G D 5.76E-05 1.52(1.24,1.87) 2.76E-03 1.51(1.16,1.97) 1.14E-02 1.55(1.11,2.17) 2.36E-01 1.5(0.77,2.91) rs9469220 32766288 A R 6.02E-05 0.55(0.41,0.73) 1.96E-03 0.58(0.41,0.81) 7.41E-03 0.51(0.32,0.83) rs6901158 32313921 T D 6.12E-05 1.55(1.25,1.93) 1.47E-04 1.71(1.3,2.24) 8.44E-02 1.37(0.97,1.94) rs9268473 32463662 G A 6.24E-05 0.72(0.62,0.83) 2.39E-02 0.8(0.66,0.97) 2.49E-03 0.68(0.54,0.87) 3.75E-02 0.58(0.35,0.97) rs2076533 32471506 BTNL2 T A 6.60E-05 0.72(0.62,0.83) 2.48E-02 0.8(0.66,0.97) 2.53E-03 0.69(0.54,0.87) 3.75E-02 0.58(0.35,0.97) rs6457536 32381744 C6orf10 G D 6.68E-05 1.52(1.24,1.87) 3.20E-03 1.5(1.15,1.96) 1.25E-02 1.55(1.1,2.17) 2.10E-01 1.53(0.79,2.97) rs3129858 32508498 A D 6.70E-05 1.57(1.28,1.94) 4.79E-03 1.47(1.13,1.91) 3.01E-02 1.47(1.04,2.06) 2.02E-02 2.22(1.14,4.32) rs6457617 32771829 T A 6.73E-05 0.72(0.62,0.84) 2.26E-02 0.8(0.66,0.96) 2.75E-03 0.69(0.54,0.88) 4.23E-02 0.61(0.38,0.98) rs9275141 32759096 G A 6.80E-05 0.71(0.61,0.83) 2.81E-03 0.74(0.61,0.9) 1.02E-01 0.81(0.64,1.04) 2.42E-03 0.47(0.28,0.76) rs2395172 32507820 C D 6.80E-05 1.57(1.28,1.94) 4.85E-03 1.47(1.13,1.91) 3.03E-02 1.47(1.04,2.06) 2.01E-02 2.22(1.14,4.33) rs3135394 32516475 HLA-DRA G D 7.11E-05 1.57(1.26,1.96) 2.16E-03 1.58(1.18,2.1) 3.12E-02 1.48(1.04,2.11) 1.11E-01 1.76(0.88,3.52) rs4988822 32506953 T D 7.21E-05 1.57(1.28,1.94) 5.15E-03 1.47(1.13,1.91) 3.02E-02 1.47(1.04,2.06) 2.00E-02 2.22(1.14,4.33) rs3135340 32506850 G D 7.21E-05 1.57(1.28,1.94) 5.15E-03 1.47(1.13,1.91) 3.02E-02 1.47(1.04,2.06) 2.00E-02 2.22(1.14,4.33) rs9275224 32767856 G A 7.23E-05 0.73(0.63,0.84) 2.11E-02 0.8(0.66,0.96) 3.40E-03 0.7(0.55,0.89) 4.24E-02 0.61(0.38,0.98) rs3135342 32504593 T D 7.24E-05 1.57(1.28,1.94) 5.20E-03 1.47(1.13,1.91) 3.02E-02 1.47(1.04,2.06) 1.98E-02 2.22(1.14,4.33) rs3129847 32504484 G D 7.28E-05 1.57(1.28,1.94) 5.21E-03 1.47(1.13,1.91) 3.02E-02 1.47(1.04,2.06) 1.98E-02 2.22(1.14,4.33) rs9275295 32771370 G A 7.29E-05 0.72(0.63,0.84) 2.27E-02 0.8(0.66,0.96) 3.03E-03 0.69(0.55,0.88) 4.23E-02 0.61(0.38,0.98) rs9275292 32771268 A A 7.29E-05 0.72(0.63,0.84) 2.26E-02 0.8(0.66,0.96) 3.05E-03 0.69(0.55,0.88) 4.23E-02 0.61(0.38,0.98) rs4424066 32462407 G A 7.34E-05 0.72(0.62,0.83) 2.83E-02 0.8(0.66,0.97) 2.44E-03 0.68(0.53,0.87) 3.75E-02 0.58(0.35,0.97) rs983561 32511633 G D 7.62E-05 1.56(1.27,1.92) 4.76E-03 1.47(1.13,1.92) 3.15E-02 1.46(1.04,2.05) 2.46E-02 2.15(1.11,4.19) rs9276689 32859941 T D 7.89E-05 1.59(1.26,1.99) 1.42E-03 1.64(1.21,2.21) 4.64E-02 1.45(1.01,2.08) 1.29E-01 1.77(0.85,3.68) rs4947349 32855769 T D 7.91E-05 1.59(1.26,1.99) 1.43E-03 1.64(1.21,2.21) 4.63E-02 1.45(1.01,2.08) 1.29E-01 1.77(0.85,3.68) rs5000563 32512113 G D 7.94E-05 1.56(1.27,1.92) 4.79E-03 1.47(1.13,1.91) 3.19E-02 1.46(1.04,2.05) 2.59E-02 2.14(1.1,4.16) rs4713583 32768132 G A 7.97E-05 0.73(0.63,0.84) 2.27E-02 0.8(0.66,0.96) 3.39E-03 0.7(0.55,0.88) 4.24E-02 0.61(0.38,0.98) rs4713582 32768029 C A 7.99E-05 0.73(0.63,0.84) 2.27E-02 0.8(0.66,0.96) 3.40E-03 0.7(0.55,0.89) 4.24E-02 0.61(0.38,0.98) rs3132928 32341993 A D 7.99E-05 1.5(1.22,1.84) 2.74E-03 1.51(1.16,1.97) 1.14E-02 1.55(1.11,2.17) 3.71E-01 1.36(0.7,2.63) rs5002702 32767137 A A 8.16E-05 0.73(0.63,0.84) 2.29E-02 0.8(0.66,0.96) 3.44E-03 0.7(0.55,0.89) 4.24E-02 0.61(0.38,0.98) rs6915455 32391473 C6orf10 A D 8.16E-05 1.52(1.23,1.88) 2.82E-03 1.52(1.16,1.99) 1.72E-02 1.53(1.08,2.16) 2.22E-01 1.53(0.78,3) rs1150752 32172704 TNXB C D 8.30E-05 1.54(1.23,1.92) 1.13E-03 1.63(1.22,2.18) 2.84E-02 1.5(1.05,2.14) 3.82E-01 1.38(0.68,2.79) rs3793126 32479598 BTNL2 G D 8.33E-05 0.63(0.51,0.78) 7.25E-03 0.69(0.53,0.9) 3.77E-02 0.69(0.49,0.97) 6.93E-03 0.4(0.2,0.77) rs1150753 32167845 TNXB G D 8.42E-05 1.54(1.23,1.92) 1.14E-03 1.63(1.22,2.18) 2.89E-02 1.5(1.05,2.13) 3.81E-01 1.38(0.68,2.78) rs2395174 32512856 G D 8.65E-05 1.56(1.27,1.91) 4.90E-03 1.47(1.13,1.91) 3.32E-02 1.46(1.04,2.05) 2.75E-02 2.12(1.09,4.11) rs433061 32122807 TNXB A D 9.08E-05 1.53(1.23,1.91) 1.02E-03 1.64(1.22,2.19) 3.41E-02 1.48(1.04,2.11) 3.87E-01 1.37(0.68,2.78) rs9268493 32483309 BTNL2 A D 9.20E-05 0.63(0.51,0.78) 8.70E-03 0.7(0.53,0.91) 3.43E-02 0.69(0.49,0.97) 7.02E-03 0.4(0.2,0.77) rs9268494 32483331 BTNL2 C D 9.25E-05 0.63(0.51,0.78) 8.72E-03 0.7(0.53,0.91) 3.43E-02 0.69(0.49,0.97) 7.02E-03 0.4(0.2,0.77) rs9268499 32483674 BTNL2 A D 9.49E-05 0.63(0.51,0.78) 8.97E-03 0.7(0.53,0.91) 3.42E-02 0.69(0.49,0.97) 7.02E-03 0.39(0.2,0.77) rs3132956 32287416 NOTCH4 A D 9.62E-05 1.49(1.21,1.85) 1.57E-04 1.72(1.3,2.28) 1.41E-01 1.3(0.93,1.83) 4.21E-01 1.34(0.67,2.7) rs389884 32048877 DOM3Z,STK19 G D 9.98E-05 1.53(1.22,1.9) 8.98E-04 1.64(1.23,2.2) 4.17E-02 1.46(1.02,2.08) 3.97E-01 1.37(0.68,2.77)

Supplemental Table S3: Top HLA region associations after adjusting for HLA-DRB1*1501 and HLA-DRB1*0301 tag SNPs via logistic regression (P- value genomic control adjusted, associations with P<10-2).

Meta Set I Set II Set III Gene Best P- Meta Best OR adjusted adjusted Set II OR adjusted Marker Position Name Mode N RA value (95%CI) P-value Set I OR (95%CI) P-value (95%CI) P-value Set III OR (95%CI) rs9263871 31278508 HCG27 D 1999 G 8.53E-06 1.7(1.35,2.13) 7.56E-03 1.47(1.11,1.94) 5.62E-04 1.96(1.34,2.87) 1.10E-01 1.85(0.88,3.89) rs4713447 31270942 D 1994 G 1.44E-04 1.55(1.22,1.96) 6.76E-03 1.5(1.12,1.99) 6.44E-03 1.73(1.17,2.55) 4.62E-01 1.36(0.61,3) rs2523589 31435313 D 1723 T 1.77E-04 1.69(1.31,2.19) 3.11E-02 1.44(1.04,1.98) 6.15E-04 2.08(1.37,3.16) rs9404982 31274518 HCG27 D 2021 G 1.90E-04 1.54(1.22,1.95) 9.00E-03 1.47(1.11,1.95) 6.42E-03 1.73(1.17,2.55) 4.50E-01 1.37(0.62,3.04) rs3868075 31275794 HCG27 D 2021 G 2.23E-04 1.54(1.22,1.95) 1.06E-02 1.46(1.1,1.94) 6.47E-03 1.73(1.17,2.54) 4.39E-01 1.38(0.62,3.07) rs9263873 31278692 HCG27 D 2012 T 2.47E-04 1.54(1.21,1.95) 1.03E-02 1.46(1.1,1.94) 8.35E-03 1.7(1.15,2.51) 3.98E-01 1.42(0.64,3.17) rs2074488 31348410 D 2018 T 2.58E-04 1.61(1.21,2.13) 8.50E-03 1.58(1.13,2.22) 4.11E-03 1.98(1.25,3.14) 9.28E-01 1.06(0.4,2.84) rs11966332 31337680 D 2017 T 2.77E-04 1.6(1.21,2.12) 7.24E-03 1.6(1.14,2.23) 5.53E-03 1.93(1.22,3.04) 9.32E-01 1.06(0.4,2.83) rs11966319 31337657 D 2017 T 2.79E-04 1.6(1.21,2.12) 7.25E-03 1.6(1.14,2.23) 5.53E-03 1.93(1.22,3.04) 9.32E-01 1.06(0.4,2.83) rs2074489 31348107 D 2026 T 4.40E-04 1.54(1.22,1.95) 2.51E-02 1.38(1.05,1.83) 9.17E-03 1.7(1.15,2.53) 2.06E-01 1.67(0.76,3.69) rs2394963 31359441 D 2020 T 5.63E-04 1.54(1.22,1.95) 6.43E-02 1.31(0.99,1.72) 3.36E-03 1.81(1.22,2.67) 1.65E-01 1.73(0.8,3.74) rs3819294 31430466 HLA-B D 1827 G 5.90E-04 2(1.4,2.87) 8.71E-02 1.49(0.96,2.31) 5.13E-04 2.89(1.59,5.24) rs9378249 31435680 D 1833 T 6.19E-04 1.98(1.39,2.84) 8.49E-02 1.49(0.96,2.29) 5.66E-04 2.85(1.58,5.16) rs4628144 31365083 D 2034 T 6.19E-04 1.53(1.22,1.93) 6.11E-02 1.31(1,1.73) 4.01E-03 1.78(1.21,2.62) 1.77E-01 1.71(0.79,3.7) rs3906269 31366947 D 2034 G 6.21E-04 1.53(1.22,1.93) 6.07E-02 1.31(1,1.73) 4.01E-03 1.78(1.21,2.62) 1.81E-01 1.7(0.79,3.68) rs3873379 31370148 D 2033 T 6.21E-04 1.53(1.22,1.93) 5.96E-02 1.31(1,1.73) 4.02E-03 1.78(1.21,2.62) 1.88E-01 1.69(0.78,3.65) rs9468920 31362915 D 2032 G 6.26E-04 1.53(1.22,1.93) 6.25E-02 1.31(1,1.73) 4.02E-03 1.78(1.21,2.62) 1.72E-01 1.72(0.8,3.71) rs7754443 31362242 D 2032 G 6.34E-04 1.53(1.22,1.93) 6.36E-02 1.31(0.99,1.73) 4.02E-03 1.78(1.21,2.62) 1.71E-01 1.72(0.8,3.72) rs6921663 31262599 D 2003 T 9.83E-04 1.52(1.21,1.91) 1.48E-01 1.25(0.94,1.65) 1.20E-03 1.88(1.29,2.76) 2.13E-01 1.63(0.76,3.49) rs16899207 31374366 D 2014 G 1.01E-03 1.51(1.2,1.9) 7.26E-02 1.3(0.99,1.71) 4.96E-03 1.76(1.19,2.59) 2.21E-01 1.63(0.75,3.53) rs16899205 31374340 D 2014 G 1.02E-03 1.51(1.2,1.9) 7.30E-02 1.3(0.99,1.71) 4.95E-03 1.76(1.19,2.59) 2.21E-01 1.63(0.75,3.53) rs16899213 31376121 D 2014 T 1.06E-03 1.51(1.2,1.9) 7.51E-02 1.3(0.98,1.71) 5.14E-03 1.75(1.19,2.59) 2.15E-01 1.64(0.76,3.56) rs9267084 31517585 D 1938 G 1.09E-03 0.58(0.44,0.76) 2.61E-02 0.68(0.49,0.95) 2.10E-01 0.74(0.46,1.17) 6.77E-04 0.2(0.08,0.51) rs4713964 36437397 A 1739 C 1.15E-03 1.43(1.17,1.74) 7.28E-02 1.26(0.99,1.61) 2.06E-03 1.67(1.21,2.3) rs9461681 31359019 D 2024 G 1.21E-03 1.51(1.19,1.9) 8.20E-02 1.29(0.98,1.7) 5.59E-03 1.74(1.18,2.57) 2.01E-01 1.69(0.76,3.73) rs3873375 31359339 D 2024 T 1.22E-03 1.51(1.19,1.9) 8.21E-02 1.29(0.98,1.7) 5.61E-03 1.74(1.18,2.57) 2.02E-01 1.69(0.76,3.73) rs744848 36444066 ETV7 A 1764 G 1.28E-03 1.44(1.17,1.76) 6.23E-02 1.28(1,1.65) 3.38E-03 1.65(1.18,2.3) rs1052989 31254382 D 2024 T 1.39E-03 1.51(1.18,1.94) 4.06E-02 1.38(1.02,1.87) 1.20E-02 1.71(1.13,2.58) 3.91E-01 1.46(0.63,3.43) rs7745906 31311988 D 2029 G 1.45E-03 1.51(1.16,1.96) 5.99E-02 1.37(1,1.88) 3.48E-03 1.9(1.24,2.92) 7.19E-01 1.19(0.49,2.87) rs9366778 31377152 D 2020 G 1.45E-03 1.46(1.15,1.85) 3.31E-02 1.37(1.03,1.82) 1.24E-02 1.66(1.12,2.45) 5.40E-01 1.3(0.58,2.88) rs4543367 31374746 D 1942 G 1.57E-03 1.49(1.18,1.88) 8.40E-02 1.29(0.98,1.71) 5.71E-03 1.76(1.18,2.61) 2.85E-01 1.55(0.7,3.4) rs11967472 31379264 D 2002 G 1.70E-03 1.5(1.18,1.89) 7.25E-02 1.3(0.99,1.71) 1.21E-02 1.67(1.12,2.47) 1.68E-01 1.77(0.79,3.95) rs6899874 31270308 D 2034 C 1.77E-03 1.49(1.18,1.87) 2.01E-01 1.22(0.92,1.61) 1.31E-03 1.87(1.28,2.74) 2.45E-01 1.57(0.74,3.34) rs12111032 31350170 A 1832 G 1.80E-03 1.41(1.14,1.74) 6.86E-03 1.41(1.1,1.8) 7.88E-02 1.4(0.97,2.03) rs4394275 31426157 D 1764 G 1.85E-03 1.51(1.19,1.92) 4.66E-02 1.35(1.01,1.81) 8.12E-03 1.73(1.16,2.59) rs4122189 31275907 HCG27 D 2034 T 1.89E-03 1.49(1.18,1.87) 2.04E-01 1.21(0.92,1.61) 1.65E-03 1.85(1.26,2.69) 2.07E-01 1.64(0.77,3.52) rs6908994 31306689 D 2033 T 1.94E-03 1.5(1.15,1.94) 7.41E-02 1.35(0.98,1.85) 3.67E-03 1.9(1.24,2.91) 7.19E-01 1.19(0.49,2.87) rs9295957 31265573 D 2002 G 1.96E-03 1.5(1.17,1.93) 5.32E-02 1.37(1.01,1.86) 1.28E-02 1.71(1.13,2.6) 3.92E-01 1.46(0.62,3.4) rs3905495 31373518 D 2021 G 2.07E-03 1.44(1.14,1.81) 5.94E-02 1.31(1,1.73) 8.68E-03 1.69(1.15,2.5) 5.16E-01 1.3(0.6,2.82) rs7768431 31310644 D 2035 G 2.07E-03 1.49(1.15,1.94) 7.73E-02 1.34(0.98,1.84) 3.77E-03 1.89(1.23,2.91) 7.19E-01 1.19(0.49,2.87) rs6921948 31279236 HCG27 D 2016 C 2.11E-03 1.45(1.14,1.85) 1.03E-01 1.29(0.96,1.74) 1.66E-03 1.91(1.28,2.85) 8.76E-01 1.08(0.48,2.46) rs3130216 33185249 D 1717 G 2.16E-03 0.67(0.52,0.85) 2.48E-02 0.71(0.52,0.95) 2.43E-02 0.62(0.41,0.94) rs7451190 31282506 D 2017 G 2.19E-03 1.45(1.14,1.85) 1.05E-01 1.29(0.96,1.74) 1.69E-03 1.91(1.28,2.85) 8.73E-01 1.08(0.48,2.47) rs3131621 31533478 A 2002 G 2.94E-03 0.72(0.6,0.87) 1.21E-01 0.83(0.66,1.04) 3.13E-02 0.71(0.52,0.96) 2.77E-02 0.52(0.29,0.93) rs3873380 31370417 D 2030 T 3.09E-03 1.41(1.12,1.77) 5.96E-02 1.31(1,1.73) 1.18E-02 1.65(1.12,2.44) 6.67E-01 1.2(0.56,2.57) rs9266336 31439114 A 1877 G 3.47E-03 1.39(1.13,1.72) 3.32E-02 1.31(1.03,1.67) 2.99E-02 1.51(1.05,2.17) rs2180106 38668193 BTBD9 D 2021 T 3.57E-03 1.46(1.18,1.82) 1.14E-01 1.25(0.96,1.63) 4.25E-02 1.45(1.02,2.08) 2.61E-02 2.33(1.11,4.89) rs9266359 31440718 A 1884 T 3.89E-03 1.38(1.12,1.71) 3.32E-02 1.31(1.03,1.67) 3.46E-02 1.48(1.04,2.12) rs9461688 31379695 D 2013 G 3.93E-03 1.45(1.15,1.84) 1.09E-01 1.27(0.96,1.67) 1.61E-02 1.63(1.1,2.41) 2.25E-01 1.67(0.74,3.75) rs9266375 31441854 A 1884 G 3.96E-03 1.38(1.12,1.7) 3.34E-02 1.31(1.03,1.67) 3.49E-02 1.48(1.03,2.12) rs9266379 31442160 A 1884 T 4.00E-03 1.38(1.12,1.7) 3.38E-02 1.31(1.03,1.67) 3.49E-02 1.48(1.03,2.12) rs3129943 32446673 C6orf10 D 1986 G 4.01E-03 1.56(1.16,2.09) 3.20E-02 1.49(1.04,2.12) 7.50E-02 1.58(0.97,2.6) 2.89E-01 1.7(0.65,4.43) rs9266381 31442771 A 1884 T 4.03E-03 1.38(1.12,1.7) 3.40E-02 1.31(1.03,1.67) 3.49E-02 1.48(1.03,2.12) rs9266382 31442856 A 1884 C 4.03E-03 1.38(1.12,1.7) 3.40E-02 1.31(1.03,1.67) 3.50E-02 1.48(1.03,2.12) rs9266386 31443061 A 1884 T 4.05E-03 1.38(1.12,1.7) 3.40E-02 1.31(1.03,1.67) 3.50E-02 1.48(1.03,2.12) rs9266387 31443195 A 1884 T 4.05E-03 1.38(1.12,1.7) 3.41E-02 1.31(1.03,1.67) 3.50E-02 1.48(1.03,2.12) rs9266392 31443382 A 1884 G 4.08E-03 1.38(1.12,1.7) 3.43E-02 1.31(1.03,1.67) 3.50E-02 1.48(1.03,2.12) rs9266404 31444202 A 1886 T 4.15E-03 1.38(1.12,1.7) 3.48E-02 1.31(1.03,1.66) 3.51E-02 1.48(1.03,2.12) rs9266406 31444398 A 1886 G 4.15E-03 1.38(1.12,1.7) 3.48E-02 1.31(1.03,1.66) 3.51E-02 1.48(1.03,2.12) rs9266429 31445235 A 1886 T 4.20E-03 1.38(1.12,1.7) 3.49E-02 1.31(1.03,1.66) 3.54E-02 1.48(1.03,2.12) rs9266409 31444548 A 1884 T 4.32E-03 1.38(1.12,1.7) 3.62E-02 1.3(1.02,1.66) 3.51E-02 1.48(1.03,2.12) rs9368687 31448137 A 1879 G 4.56E-03 1.38(1.12,1.7) 3.53E-02 1.31(1.03,1.66) 3.86E-02 1.47(1.03,2.11) rs7755619 38642912 BTBD9 D 1932 T 4.68E-03 0.69(0.55,0.86) 1.66E-01 0.82(0.62,1.07) 2.25E-02 0.65(0.45,0.94) 5.79E-02 0.48(0.23,1.02) rs6933050 31451612 A 1877 T 4.74E-03 1.38(1.12,1.7) 3.65E-02 1.3(1.02,1.66) 3.87E-02 1.47(1.03,2.11) rs6910516 31451807 A 1877 G 4.83E-03 1.38(1.12,1.7) 3.68E-02 1.3(1.02,1.66) 3.92E-02 1.47(1.03,2.11) rs4076112 21228748 CDKAL1 D 1983 G 4.95E-03 1.44(1.15,1.8) 1.16E-01 1.26(0.96,1.66) 3.99E-02 1.48(1.02,2.14) 7.33E-02 2(0.94,4.23) rs849870 22391865 D 1864 T 5.02E-03 0.69(0.54,0.88) 2.88E-02 0.71(0.53,0.96) 5.52E-02 0.66(0.44,1) rs521828 32399621 C6orf10 D 2013 T 5.15E-03 1.54(1.15,2.05) 6.79E-02 1.4(0.99,1.98) 3.68E-02 1.7(1.04,2.76) 3.23E-01 1.63(0.63,4.18) rs9466619 23207198 D 1950 G 5.20E-03 1.52(1.21,1.9) 3.75E-01 1.15(0.87,1.5) 2.05E-02 1.56(1.08,2.25) 2.96E-03 3.13(1.48,6.63) rs4713113 27663105 R 1873 G 5.20E-03 2.17(1.3,3.6) 5.09E-02 2(1.02,3.93) 2.86E-02 2.39(1.11,5.17) rs7774939 27655771 R 1883 C 5.37E-03 2.15(1.3,3.54) 5.22E-02 1.97(1.02,3.81) 2.86E-02 2.39(1.11,5.17) rs9295856 30488718 R 1832 T 5.37E-03 1.64(1.15,2.35) 2.92E-03 1.94(1.26,2.98) 3.92E-01 1.32(0.72,2.42) rs4713324 30488252 R 1832 T 5.44E-03 1.64(1.15,2.35) 2.92E-03 1.94(1.26,2.98) 3.96E-01 1.32(0.72,2.42) rs9461583 not found R 1834 T 5.47E-03 1.64(1.15,2.34) 2.92E-03 1.94(1.26,2.98) 3.97E-01 1.32(0.72,2.41) rs13208193 23185431 D 2034 T 5.64E-03 1.51(1.21,1.88) 4.22E-01 1.13(0.87,1.48) 1.79E-02 1.55(1.08,2.23) 2.50E-03 3.17(1.5,6.7) rs13213112 38653970 BTBD9 D 2024 G 5.68E-03 1.44(1.16,1.79) 1.40E-01 1.23(0.95,1.61) 5.54E-02 1.42(1,2.03) 2.61E-02 2.33(1.11,4.89) rs4713327 30491747 R 1862 G 5.70E-03 1.66(1.14,2.4) 3.18E-03 1.94(1.26,2.99) 3.87E-01 1.35(0.71,2.57) rs4345386 23185103 D 2034 T 5.80E-03 1.51(1.21,1.88) 4.27E-01 1.13(0.86,1.48) 1.80E-02 1.55(1.08,2.22) 2.50E-03 3.17(1.5,6.7) rs9369022 37869542 D 1717 T 5.92E-03 1.4(1.12,1.76) 3.31E-02 1.37(1.03,1.81) 5.70E-02 1.45(1,2.11) rs6903004 38644425 BTBD9 D 2008 G 5.95E-03 0.69(0.56,0.86) 1.74E-01 0.82(0.63,1.07) 3.42E-02 0.67(0.47,0.97) 4.24E-02 0.46(0.22,0.97) rs2523663 31547720 R 1866 T 6.00E-03 0.54(0.36,0.81) 4.94E-02 0.61(0.38,0.98) 3.50E-02 0.46(0.23,0.94) rs9261763 30481463 R 1852 G 6.02E-03 1.63(1.14,2.32) 3.47E-03 1.91(1.25,2.94) 3.75E-01 1.33(0.74,2.39) rs2523715 30279263 TRIM26 D 2019 T 6.10E-03 0.7(0.54,0.9) 1.50E-02 0.68(0.5,0.92) 2.37E-01 0.76(0.49,1.17) 2.77E-01 0.62(0.27,1.45) rs2517612 30277071 TRIM26 D 2019 G 6.12E-03 0.7(0.54,0.9) 1.50E-02 0.68(0.5,0.92) 2.37E-01 0.76(0.49,1.17) 2.77E-01 0.62(0.27,1.45) rs2523719 30276298 TRIM26 D 2019 T 6.12E-03 0.7(0.54,0.9) 1.50E-02 0.68(0.5,0.92) 2.37E-01 0.76(0.49,1.17) 2.77E-01 0.62(0.27,1.45) rs12523660 23197478 D 1984 T 6.22E-03 1.51(1.21,1.89) 4.04E-01 1.14(0.87,1.49) 2.05E-02 1.56(1.08,2.25) 3.02E-03 3.12(1.47,6.61) rs12524966 23196557 D 1987 T 6.26E-03 1.51(1.21,1.89) 4.06E-01 1.14(0.87,1.49) 2.04E-02 1.56(1.08,2.25) 3.00E-03 3.12(1.47,6.61) rs10806982 24188385 R 1884 G 6.39E-03 1.65(1.17,2.34) 1.90E-02 1.66(1.1,2.52) 1.11E-01 1.64(0.91,2.95) rs9266604 31453048 D 1745 T 6.53E-03 1.39(1.1,1.77) 8.34E-03 1.48(1.11,1.96) 2.23E-01 1.3(0.87,1.94) rs9461680 31351327 A 1821 T 6.66E-03 1.39(1.11,1.74) 5.38E-02 1.3(1,1.68) 3.59E-02 1.53(1.03,2.25) rs543532 24029596 D 1866 T 6.75E-03 1.5(1.13,1.99) 1.91E-02 1.51(1.08,2.1) 1.17E-01 1.49(0.92,2.43) rs3873386 31381725 D 1826 T 6.80E-03 1.4(1.1,1.77) 1.30E-02 1.44(1.09,1.92) 1.66E-01 1.34(0.9,1.99) rs12182794 31377863 D 2006 T 6.89E-03 1.4(1.11,1.77) 2.78E-02 1.38(1.04,1.82) 1.83E-01 1.32(0.89,1.97) 2.09E-01 1.65(0.76,3.58) rs545967 24032285 D 1863 T 6.90E-03 1.5(1.13,1.99) 1.94E-02 1.5(1.08,2.1) 1.19E-01 1.49(0.91,2.43) rs482180 24033759 D 1863 T 6.95E-03 1.5(1.13,1.99) 1.95E-02 1.51(1.08,2.1) 1.19E-01 1.49(0.91,2.43) rs556835 24035362 D 1863 G 6.97E-03 1.5(1.13,2) 1.95E-02 1.51(1.08,2.1) 1.19E-01 1.5(0.92,2.44) rs2523720 30274865 TRIM26 D 2003 T 6.97E-03 0.7(0.54,0.9) 1.74E-02 0.68(0.5,0.93) 2.37E-01 0.76(0.49,1.17) 2.77E-01 0.62(0.27,1.45) rs2517613 30273641 TRIM26 D 2003 G 7.00E-03 0.7(0.54,0.9) 1.75E-02 0.68(0.5,0.93) 2.37E-01 0.76(0.49,1.17) 2.77E-01 0.62(0.27,1.45) rs481372 24033805 D 1863 G 7.00E-03 1.5(1.13,1.99) 1.94E-02 1.51(1.08,2.1) 1.20E-01 1.49(0.91,2.43) rs7775817 27656071 R 1873 G 7.02E-03 2.11(1.27,3.48) 6.68E-02 1.9(0.98,3.7) 2.86E-02 2.39(1.11,5.17) rs488037 24034055 D 1863 T 7.04E-03 1.5(1.13,1.99) 1.95E-02 1.5(1.08,2.1) 1.20E-01 1.49(0.91,2.43) rs17543429 38664619 BTBD9 D 2021 T 7.06E-03 0.7(0.56,0.87) 1.86E-01 0.82(0.63,1.08) 4.03E-02 0.69(0.48,0.98) 3.84E-02 0.46(0.22,0.95) rs12206218 38666469 BTBD9 D 2019 T 7.12E-03 0.7(0.56,0.87) 1.87E-01 0.82(0.63,1.08) 4.03E-02 0.69(0.48,0.98) 3.84E-02 0.46(0.22,0.95) rs6457422 31524135 A 1962 G 7.14E-03 1.26(1.07,1.48) 1.93E-02 1.27(1.04,1.55) 2.15E-01 1.2(0.91,1.6) 3.10E-01 1.33(0.77,2.3) rs12208087 38667467 BTBD9 D 2019 T 7.17E-03 0.7(0.56,0.87) 1.88E-01 0.83(0.63,1.08) 4.03E-02 0.69(0.48,0.98) 3.84E-02 0.46(0.22,0.95) rs10484856 38667641 BTBD9 D 2019 T 7.17E-03 0.7(0.56,0.87) 1.88E-01 0.83(0.63,1.08) 4.03E-02 0.69(0.48,0.98) 3.84E-02 0.46(0.22,0.95) rs3131622 31528479 A 1966 T 7.28E-03 0.78(0.66,0.93) 3.02E-02 0.79(0.64,0.97) 1.92E-01 0.82(0.62,1.09) 1.83E-01 0.68(0.39,1.19) rs10946938 27658775 R 1856 C 7.38E-03 1.97(1.24,3.14) 5.46E-02 1.86(1.01,3.42) 4.00E-02 2.13(1.05,4.33) rs1406841 38684695 BTBD9 D 1962 C 7.48E-03 0.7(0.56,0.87) 1.83E-01 0.82(0.62,1.08) 4.39E-02 0.69(0.48,0.98) 4.01E-02 0.46(0.22,0.96) rs2523713 30281309 TRIM26 D 1992 G 7.57E-03 0.72(0.57,0.92) 3.51E-02 0.73(0.55,0.97) 1.09E-01 0.71(0.48,1.07) 4.18E-01 0.72(0.33,1.56) rs1117490 30278489 TRIM26 D 1992 T 7.58E-03 0.72(0.57,0.92) 3.51E-02 0.73(0.55,0.97) 1.09E-01 0.71(0.48,1.07) 4.18E-01 0.72(0.33,1.56) rs2021722 30282110 TRIM26 D 1992 T 7.58E-03 0.72(0.57,0.92) 3.51E-02 0.73(0.55,0.97) 1.09E-01 0.71(0.48,1.07) 4.18E-01 0.72(0.33,1.56) rs2517611 30277306 TRIM26 D 1992 G 7.58E-03 0.72(0.57,0.92) 3.51E-02 0.73(0.55,0.97) 1.09E-01 0.71(0.48,1.07) 4.18E-01 0.72(0.33,1.56) rs2523716 30278504 TRIM26 D 1992 T 7.58E-03 0.72(0.57,0.92) 3.51E-02 0.73(0.55,0.97) 1.09E-01 0.71(0.48,1.07) 4.18E-01 0.72(0.33,1.56) rs971570 30280492 TRIM26 D 1992 C 7.58E-03 0.72(0.57,0.92) 3.51E-02 0.73(0.55,0.97) 1.09E-01 0.71(0.48,1.07) 4.18E-01 0.72(0.33,1.56) rs9468926 31368197 D 1875 T 7.96E-03 1.44(1.13,1.83) 1.98E-01 1.22(0.92,1.62) 1.66E-02 1.65(1.1,2.47) 2.07E-01 1.68(0.76,3.74) rs13206291 23176183 D 2029 G 8.02E-03 1.48(1.19,1.85) 4.48E-01 1.13(0.86,1.47) 2.05E-02 1.54(1.07,2.2) 4.57E-03 2.96(1.4,6.24) rs474923 24023879 D 1771 T 8.08E-03 1.53(1.15,2.05) 7.38E-02 1.39(0.98,1.97) 2.90E-02 1.74(1.07,2.84) rs1277137 24182956 R 1884 G 8.18E-03 1.63(1.15,2.31) 2.48E-02 1.63(1.07,2.46) 1.11E-01 1.64(0.91,2.95) rs1290088 24184654 R 1884 T 8.18E-03 1.63(1.15,2.31) 2.48E-02 1.63(1.07,2.46) 1.11E-01 1.64(0.91,2.95) rs2683639 24186258 R 1884 G 8.18E-03 1.63(1.15,2.31) 2.48E-02 1.63(1.07,2.46) 1.11E-01 1.63(0.91,2.95) rs2064364 23165852 D 2029 G 8.19E-03 1.48(1.19,1.85) 4.54E-01 1.13(0.86,1.47) 2.05E-02 1.54(1.07,2.2) 4.57E-03 2.96(1.4,6.24) rs1277136 24182859 R 1884 G 8.25E-03 1.63(1.15,2.31) 2.51E-02 1.63(1.07,2.46) 1.11E-01 1.63(0.91,2.95) rs885912 30282612 TRIM26 D 1984 C 8.25E-03 0.72(0.57,0.92) 3.74E-02 0.73(0.55,0.97) 1.12E-01 0.71(0.47,1.07) 4.16E-01 0.72(0.33,1.57) rs2523721 30274245 TRIM26 D 1974 T 8.26E-03 0.72(0.57,0.92) 3.85E-02 0.73(0.55,0.98) 1.09E-01 0.71(0.48,1.07) 4.18E-01 0.72(0.33,1.56) rs2517614 30271934 TRIM26 D 1974 G 8.26E-03 0.72(0.57,0.92) 3.86E-02 0.73(0.55,0.98) 1.08E-01 0.71(0.48,1.07) 4.18E-01 0.72(0.33,1.56) rs2523722 30273252 TRIM26 D 1974 T 8.28E-03 0.72(0.57,0.92) 3.86E-02 0.73(0.55,0.98) 1.09E-01 0.71(0.48,1.07) 4.18E-01 0.72(0.33,1.56) rs9295576 23163490 D 2028 T 8.62E-03 1.48(1.19,1.84) 4.54E-01 1.13(0.86,1.47) 2.05E-02 1.54(1.07,2.2) 5.39E-03 2.91(1.37,6.15) rs3129881 32517462 HLA-DRA R 1876 T 8.67E-03 0.56(0.38,0.81) 3.25E-01 0.77(0.48,1.24) 1.75E-03 0.37(0.2,0.69) rs11967684 31307745 D 1944 G 8.69E-03 1.35(1.07,1.71) 6.36E-02 1.32(0.99,1.75) 3.17E-02 1.56(1.05,2.32) 8.91E-01 1.07(0.49,2.33) rs9689955 24188350 R 1874 T 8.72E-03 1.63(1.15,2.3) 2.68E-02 1.62(1.07,2.45) 1.10E-01 1.64(0.91,2.95) rs2596450 31546222 R 1871 G 9.38E-03 0.54(0.35,0.84) 5.58E-02 0.61(0.38,1) 5.23E-02 0.47(0.22,0.99) rs9393831 27696706 R 1864 C 9.38E-03 2.12(1.26,3.59) 7.70E-02 1.88(0.96,3.69) 3.41E-02 2.48(1.08,5.66) rs2517618 30266106 TRIM26 D 2000 G 9.42E-03 0.71(0.55,0.91) 2.46E-02 0.7(0.51,0.95) 2.37E-01 0.76(0.49,1.17) 2.77E-01 0.62(0.27,1.45) rs9460965 24186238 R 1874 T 9.47E-03 1.62(1.14,2.29) 2.91E-02 1.61(1.06,2.43) 1.11E-01 1.63(0.91,2.95) rs2395171 32502515 R 1872 T 9.47E-03 0.5(0.3,0.82) 3.14E-02 0.48(0.25,0.92) 1.02E-01 0.52(0.24,1.12) rs6457577 32499494 R 1872 G 9.47E-03 0.5(0.3,0.82) 3.16E-02 0.48(0.25,0.92) 1.02E-01 0.52(0.24,1.12) rs2064193 22502049 D 2021 T 9.69E-03 0.66(0.5,0.86) 1.28E-02 0.64(0.46,0.9) 7.91E-01 0.92(0.6,1.43) 1.90E-02 0.33(0.13,0.83) rs3135353 32500855 R 1852 T 9.71E-03 0.48(0.28,0.81) 3.10E-02 0.46(0.23,0.91) 1.07E-01 0.5(0.22,1.14) rs12110752 22501454 D 2034 T 9.96E-03 0.67(0.51,0.87) 1.14E-02 0.64(0.45,0.9) 7.91E-01 0.92(0.6,1.43) 2.83E-02 0.36(0.15,0.89)

Supplemental Table S4. Association results for non-HLA associations using best genetic model for lupus nephritis(LN) contrasting LN cases with lupus cases without nephritis (P<10-4).

Meta Best Meta Best Set I P- Set II P- Set II OR(95% Set III P- Set III OR(95 % Marker Chr Position Gene Name RA N Mode P-value OR(95%CI) value Set I OR(95% CI) value CI) value CI) rs1364989 4 54706526 T 1827 R 4.52E-07 3.41(2.1,5.54) 1.30E-06 4.57(2.48,8.42) 3.91E-02 2.32(1.06,5.08) rs274068 16 24806473 SLC5A11 C 1838 R 5.08E-07 2.85(1.93,4.22) 1.40E-03 2.26(1.38,3.7) 2.91E-05 3.87(2.06,7.29) rs8012283 14 50303911 NIN G 1807 A 5.27E-07 1.64(1.35,1.98) 3.84E-05 1.68(1.31,2.14) 2.94E-03 1.59(1.17,2.14) rs7773456 6 19931217 G 1743 D 7.36E-07 0.57(0.46,0.7) 1.02E-03 0.63(0.48,0.83) 7.98E-05 0.49(0.35,0.7) rs274069 16 24806651 SLC5A11 T 1841 R 8.50E-07 2.78(1.88,4.11) 1.40E-03 2.26(1.38,3.7) 5.88E-05 3.64(1.95,6.82) rs7834765 8 122345087 T 1769 R 1.06E-06 3.15(1.97,5.03) 7.39E-06 3.79(2.13,6.76) 2.29E-02 2.48(1.15,5.35) rs7834648 8 122345164 T 1768 R 1.07E-06 3.15(1.97,5.03) 7.42E-06 3.79(2.13,6.77) 2.30E-02 2.47(1.15,5.35) rs1017280 4 54705880 T 1828 R 1.24E-06 3.23(1.99,5.22) 4.40E-06 4.14(2.27,7.55) 3.88E-02 2.32(1.06,5.1) rs6910773 6 19928637 C 1826 D 1.42E-06 0.58(0.47,0.72) 2.95E-03 0.66(0.51,0.87) 3.55E-05 0.49(0.35,0.69) rs601162 9 29622142 A 1824 R 1.42E-06 3.11(1.99,4.88) 5.94E-04 2.85(1.58,5.16) 4.02E-04 3.49(1.75,6.94) rs12507253 4 54711576 T 1821 R 1.63E-06 3.13(1.95,5.03) 4.69E-06 4.06(2.24,7.36) 4.45E-02 2.23(1.03,4.82) rs602469 9 29622433 C 1834 R 1.69E-06 3.08(1.97,4.82) 6.51E-04 2.82(1.57,5.09) 4.35E-04 3.45(1.74,6.85) rs8015968 14 50308509 NIN A 1799 A 1.89E-06 1.72(1.38,2.15) 2.97E-05 1.85(1.39,2.46) 1.29E-02 1.57(1.11,2.23) rs4140624 6 19926539 T 1803 D 2.18E-06 0.58(0.47,0.72) 7.96E-04 0.61(0.46,0.81) 4.77E-04 0.54(0.38,0.76) rs752010 1 41865602 HIVEP3 C 1932 D 2.31E-06 0.57(0.45,0.71) 4.14E-04 0.59(0.44,0.79) 1.02E-02 0.61(0.42,0.89) 3.31E-02 0.43(0.2,0.93) rs2077172 1 41865927 HIVEP3 A 1932 D 2.31E-06 0.57(0.45,0.71) 4.16E-04 0.59(0.44,0.79) 1.01E-02 0.61(0.42,0.89) 3.31E-02 0.43(0.2,0.93) rs9368127 6 19919970 A 1821 D 2.41E-06 0.58(0.47,0.73) 7.82E-04 0.62(0.47,0.82) 5.19E-04 0.54(0.38,0.76) rs9350190 6 19919639 G 1820 D 2.47E-06 0.58(0.47,0.73) 7.84E-04 0.62(0.47,0.82) 5.29E-04 0.54(0.38,0.76) rs12500475 4 54665968 G 1743 R 2.64E-06 2.94(1.86,4.66) 1.26E-05 3.54(2.01,6.21) 3.39E-02 2.31(1.08,4.96) rs2038978 1 41867306 HIVEP3 A 1950 D 2.65E-06 0.57(0.45,0.72) 4.81E-04 0.59(0.44,0.79) 1.00E-02 0.61(0.42,0.89) 3.30E-02 0.43(0.2,0.93) rs967616 4 172124797 G 1920 A 2.86E-06 0.69(0.59,0.81) 5.34E-05 0.66(0.55,0.81) 3.24E-02 0.74(0.57,0.97) 1.29E-01 0.67(0.4,1.12) rs12206194 6 19927887 C 1845 D 3.15E-06 0.59(0.47,0.73) 9.91E-04 0.62(0.47,0.82) 5.35E-04 0.54(0.39,0.77) rs6538678 12 94785700 CCDC38 A 1832 A 3.33E-06 1.57(1.3,1.88) 3.55E-04 1.52(1.21,1.91) 2.04E-03 1.63(1.2,2.21) rs10041935 5 57250574 C 1849 R 3.47E-06 2.5(1.71,3.66) 3.86E-04 2.4(1.49,3.88) 1.94E-03 2.64(1.44,4.85) rs4337811 5 57249936 G 1851 R 3.71E-06 2.48(1.7,3.6) 4.20E-04 2.35(1.47,3.77) 1.90E-03 2.65(1.44,4.86) rs10027676 4 54740473 C 1736 R 3.91E-06 3.08(1.9,5) 1.11E-06 4.89(2.59,9.21) 1.71E-01 1.72(0.81,3.63) rs6664724 1 41866408 HIVEP3 G 1892 D 4.27E-06 0.57(0.45,0.72) 7.69E-04 0.6(0.45,0.81) 1.01E-02 0.61(0.42,0.89) 3.31E-02 0.43(0.2,0.93) rs2236178 20 21090813 PLK1S1 T 1985 A 4.69E-06 0.68(0.58,0.79) 4.87E-04 0.7(0.58,0.85) 5.64E-02 0.78(0.61,1) 1.67E-03 0.45(0.28,0.74) rs583110 9 29627044 A 1811 R 4.93E-06 2.96(1.89,4.64) 1.51E-03 2.66(1.47,4.83) 5.34E-04 3.39(1.71,6.75) rs2786111 1 195572722 CRB1 C 1824 R 5.32E-06 2.26(1.6,3.19) 1.10E-04 2.44(1.56,3.82) 1.10E-02 2.04(1.19,3.52) rs2478118 10 13690038 PRPF18 T 1959 D 5.44E-06 1.61(1.3,1.99) 1.43E-03 1.57(1.19,2.06) 1.00E-03 1.79(1.27,2.52) 3.82E-01 1.37(0.69,2.72) rs10141242 14 50297072 NIN C 1849 A 6.12E-06 1.6(1.3,1.97) 9.40E-06 1.82(1.4,2.37) 7.80E-02 1.36(0.97,1.89) rs4083593 1 41872170 HIVEP3 A 1894 D 6.77E-06 0.58(0.46,0.73) 1.40E-03 0.62(0.47,0.83) 8.23E-03 0.61(0.42,0.88) 3.53E-02 0.44(0.2,0.94) rs2786115 1 195569313 CRB1 A 1702 R 7.07E-06 2.25(1.59,3.18) 3.74E-04 2.19(1.43,3.37) 4.43E-03 2.31(1.3,4.11) rs13139444 4 172127251 A 1964 A 7.89E-06 0.7(0.6,0.82) 1.50E-04 0.68(0.56,0.83) 4.04E-02 0.75(0.58,0.98) 1.10E-01 0.65(0.39,1.1) rs2567952 4 172129725 C 1964 A 8.06E-06 0.7(0.6,0.82) 1.53E-04 0.68(0.56,0.83) 4.04E-02 0.75(0.58,0.98) 1.10E-01 0.65(0.39,1.1) rs2661917 4 172129968 C 1964 A 8.06E-06 0.7(0.6,0.82) 1.53E-04 0.68(0.56,0.83) 4.04E-02 0.75(0.58,0.98) 1.10E-01 0.65(0.39,1.1) rs2661923 4 172127242 C 1981 A 8.13E-06 0.7(0.6,0.82) 1.69E-04 0.68(0.56,0.83) 3.17E-02 0.74(0.57,0.97) 1.50E-01 0.68(0.4,1.14) rs2567956 4 172126317 C 1993 A 8.14E-06 0.7(0.6,0.83) 1.54E-04 0.68(0.56,0.83) 3.13E-02 0.74(0.57,0.97) 1.73E-01 0.69(0.41,1.17) rs1236448 4 172118655 C 1993 A 8.14E-06 0.7(0.6,0.83) 1.54E-04 0.68(0.56,0.83) 3.13E-02 0.74(0.57,0.97) 1.73E-01 0.69(0.41,1.17) rs17245674 4 172121285 A 1993 A 8.14E-06 0.7(0.6,0.83) 1.54E-04 0.68(0.56,0.83) 3.13E-02 0.74(0.57,0.97) 1.73E-01 0.69(0.41,1.17) rs2567960 4 172122108 T 1992 A 8.16E-06 0.7(0.6,0.83) 1.54E-04 0.68(0.56,0.83) 3.13E-02 0.74(0.57,0.97) 1.73E-01 0.69(0.41,1.17) rs17186543 4 172126746 T 1993 A 8.16E-06 0.7(0.6,0.83) 1.54E-04 0.68(0.56,0.83) 3.14E-02 0.74(0.57,0.97) 1.73E-01 0.69(0.41,1.17) rs12331863 4 172133772 G 1981 A 8.33E-06 0.7(0.6,0.82) 1.75E-04 0.68(0.56,0.83) 3.17E-02 0.74(0.57,0.97) 1.49E-01 0.68(0.4,1.14) rs13041255 20 21078707 PLK1S1 T 1999 A 8.42E-06 0.69(0.59,0.8) 1.02E-03 0.72(0.59,0.87) 5.10E-02 0.78(0.61,1) 1.58E-03 0.45(0.28,0.74) rs4813414 20 21081212 PLK1S1 A 1999 A 8.42E-06 0.69(0.59,0.8) 1.02E-03 0.72(0.59,0.87) 5.10E-02 0.78(0.61,1) 1.58E-03 0.45(0.28,0.74) rs4815022 20 21072872 PLK1S1 T 1999 A 8.42E-06 0.68(0.59,0.8) 1.02E-03 0.72(0.59,0.87) 5.10E-02 0.78(0.61,1) 1.58E-03 0.45(0.28,0.74) rs6047274 20 21083126 PLK1S1 T 1998 A 8.43E-06 0.69(0.59,0.8) 1.02E-03 0.72(0.59,0.87) 5.10E-02 0.78(0.61,1) 1.58E-03 0.45(0.28,0.74) rs1884763 20 21076127 PLK1S1 A 1999 A 8.43E-06 0.69(0.59,0.8) 1.02E-03 0.72(0.59,0.87) 5.10E-02 0.78(0.61,1) 1.58E-03 0.45(0.28,0.74) rs3762194 20 21074723 PLK1S1 A 1999 A 8.48E-06 0.69(0.59,0.8) 1.02E-03 0.72(0.59,0.87) 5.10E-02 0.78(0.61,1) 1.58E-03 0.45(0.28,0.74) rs4815024 20 21086367 PLK1S1 C 1997 A 8.69E-06 0.69(0.59,0.8) 1.05E-03 0.72(0.59,0.87) 5.10E-02 0.78(0.61,1) 1.58E-03 0.45(0.28,0.74) rs2093069 20 21088342 PLK1S1 C 1997 A 8.84E-06 0.69(0.59,0.8) 1.07E-03 0.72(0.59,0.87) 5.10E-02 0.78(0.61,1) 1.58E-03 0.45(0.28,0.74) rs6811337 4 172176299 T 1970 A 8.91E-06 0.7(0.6,0.83) 1.62E-04 0.68(0.56,0.83) 3.26E-02 0.74(0.57,0.97) 1.73E-01 0.69(0.41,1.17) rs6047279 20 21090353 PLK1S1 T 1997 A 9.01E-06 0.69(0.59,0.8) 1.09E-03 0.72(0.59,0.88) 5.10E-02 0.78(0.61,1) 1.58E-03 0.45(0.28,0.74) rs17246620 4 172199835 LOC100506122 G 1981 A 9.50E-06 0.71(0.6,0.83) 1.67E-04 0.68(0.56,0.83) 3.37E-02 0.75(0.57,0.97) 1.74E-01 0.69(0.41,1.17) rs11157764 14 50320087 NIN A 1773 A 1.07E-05 1.67(1.34,2.1) 2.37E-04 1.74(1.3,2.33) 1.09E-02 1.59(1.12,2.27) rs648705 13 109654154 COL4A1 A 1810 R 1.09E-05 0.48(0.34,0.66) 5.87E-05 0.42(0.28,0.64) 3.49E-02 0.57(0.34,0.95) rs1396323 4 172142182 A 1970 A 1.10E-05 0.71(0.61,0.84) 1.11E-04 0.68(0.55,0.82) 4.71E-02 0.76(0.59,0.99) 2.12E-01 0.71(0.42,1.2) rs7681844 4 172142671 C 1970 A 1.11E-05 0.71(0.61,0.84) 1.12E-04 0.68(0.55,0.82) 4.73E-02 0.76(0.59,0.99) 2.12E-01 0.71(0.42,1.2) rs4815021 20 21068543 PLK1S1 C 1895 A 1.12E-05 0.69(0.59,0.8) 1.12E-03 0.72(0.59,0.88) 6.04E-02 0.78(0.61,1.01) 1.67E-03 0.45(0.28,0.74) rs13148831 4 172146081 T 1970 A 1.13E-05 0.71(0.61,0.84) 1.13E-04 0.68(0.56,0.82) 4.73E-02 0.76(0.59,0.99) 2.12E-01 0.71(0.42,1.2) rs2332086 4 172147756 G 1970 A 1.13E-05 0.71(0.61,0.84) 1.14E-04 0.68(0.56,0.82) 4.73E-02 0.76(0.59,0.99) 2.12E-01 0.71(0.42,1.2) rs6047293 20 21102487 PLK1S1 G 1997 A 1.13E-05 0.69(0.59,0.8) 1.38E-03 0.73(0.6,0.88) 5.05E-02 0.78(0.61,1) 1.58E-03 0.45(0.28,0.74) rs6082339 20 21100742 PLK1S1 G 1997 A 1.13E-05 0.69(0.59,0.8) 1.38E-03 0.73(0.6,0.88) 5.05E-02 0.78(0.61,1) 1.58E-03 0.45(0.28,0.74) rs910975 20 21104169 PLK1S1 A 1997 A 1.13E-05 0.69(0.59,0.8) 1.38E-03 0.73(0.6,0.88) 5.05E-02 0.78(0.61,1) 1.58E-03 0.45(0.28,0.74) rs2093070 20 21105510 PLK1S1 T 1997 A 1.13E-05 0.69(0.59,0.8) 1.38E-03 0.73(0.6,0.88) 5.05E-02 0.78(0.61,1) 1.58E-03 0.45(0.28,0.74) rs6515144 20 21105565 PLK1S1 T 1997 A 1.13E-05 0.69(0.59,0.8) 1.38E-03 0.73(0.6,0.88) 5.05E-02 0.78(0.61,1) 1.58E-03 0.45(0.28,0.74) rs7834813 8 122345329 C 1736 R 1.14E-05 2.69(1.72,4.23) 2.74E-05 3.33(1.91,5.81) 6.42E-02 2.04(0.97,4.29) rs6035795 20 21093885 PLK1S1 A 1997 A 1.14E-05 0.69(0.59,0.8) 1.37E-03 0.73(0.6,0.88) 5.10E-02 0.78(0.61,1) 1.58E-03 0.45(0.28,0.74) rs6047281 20 21094287 PLK1S1 A 1998 A 1.14E-05 0.69(0.59,0.8) 1.37E-03 0.73(0.6,0.88) 5.10E-02 0.78(0.61,1) 1.58E-03 0.45(0.28,0.74) rs7682721 4 172151045 T 1970 A 1.14E-05 0.71(0.61,0.84) 1.16E-04 0.68(0.56,0.82) 4.73E-02 0.76(0.59,0.99) 2.12E-01 0.71(0.42,1.2) rs2399985 10 13685216 PRPF18 T 1785 D 1.16E-05 1.65(1.33,2.06) 1.64E-03 1.58(1.19,2.08) 1.42E-03 1.76(1.25,2.48) rs6827582 4 172179792 A 1982 A 1.17E-05 0.71(0.6,0.83) 2.10E-04 0.68(0.56,0.83) 3.38E-02 0.75(0.57,0.97) 1.74E-01 0.69(0.41,1.17) rs6811103 4 172176175 T 1984 A 1.17E-05 0.71(0.6,0.83) 2.42E-04 0.69(0.56,0.84) 3.26E-02 0.74(0.57,0.97) 1.53E-01 0.68(0.4,1.15) rs4901055 14 50296750 NIN G 1834 A 1.17E-05 1.58(1.29,1.95) 1.72E-05 1.79(1.38,2.34) 8.67E-02 1.35(0.97,1.87) rs402031 1 165217082 G 1722 R 1.18E-05 0.54(0.4,0.71) 3.07E-05 0.47(0.33,0.67) 6.09E-02 0.64(0.41,1.01) rs11735676 4 172177663 T 1983 A 1.21E-05 0.71(0.6,0.83) 2.29E-04 0.69(0.56,0.84) 3.26E-02 0.74(0.57,0.97) 1.73E-01 0.69(0.41,1.17) rs10012648 4 172177040 C 1983 A 1.21E-05 0.71(0.6,0.83) 2.30E-04 0.69(0.56,0.84) 3.26E-02 0.74(0.57,0.97) 1.73E-01 0.69(0.41,1.17) rs13151801 4 172176859 T 1983 A 1.21E-05 0.71(0.6,0.83) 2.30E-04 0.69(0.56,0.84) 3.26E-02 0.74(0.57,0.97) 1.73E-01 0.69(0.41,1.17) rs7673070 4 172176632 C 1983 A 1.21E-05 0.71(0.6,0.83) 2.29E-04 0.69(0.56,0.84) 3.28E-02 0.74(0.57,0.97) 1.73E-01 0.69(0.41,1.17) rs6812562 4 172177061 A 1983 A 1.21E-05 0.71(0.6,0.83) 2.29E-04 0.69(0.56,0.84) 3.28E-02 0.74(0.57,0.97) 1.73E-01 0.69(0.41,1.17) rs13138342 4 172177180 C 1983 A 1.21E-05 0.71(0.6,0.83) 2.29E-04 0.69(0.56,0.84) 3.28E-02 0.74(0.57,0.97) 1.73E-01 0.69(0.41,1.17) rs6553556 4 172176526 A 1983 A 1.21E-05 0.71(0.6,0.83) 2.29E-04 0.69(0.56,0.84) 3.28E-02 0.74(0.57,0.97) 1.73E-01 0.69(0.41,1.17) rs12648447 4 172175669 T 1985 A 1.27E-05 0.71(0.6,0.83) 2.42E-04 0.69(0.56,0.84) 3.26E-02 0.74(0.57,0.97) 1.72E-01 0.7(0.42,1.16) rs25511 4 172175559 T 1985 A 1.27E-05 0.71(0.6,0.83) 2.42E-04 0.69(0.56,0.84) 3.26E-02 0.74(0.57,0.97) 1.73E-01 0.69(0.41,1.17) rs9968437 4 172173406 T 1985 A 1.27E-05 0.71(0.6,0.83) 2.42E-04 0.69(0.56,0.84) 3.26E-02 0.74(0.57,0.97) 1.73E-01 0.69(0.41,1.17) rs1605651 4 172162912 A 1985 A 1.28E-05 0.71(0.6,0.83) 2.41E-04 0.69(0.56,0.84) 3.28E-02 0.74(0.57,0.97) 1.73E-01 0.69(0.41,1.17) rs11132865 4 172164946 C 1985 A 1.28E-05 0.71(0.6,0.83) 2.42E-04 0.69(0.56,0.84) 3.26E-02 0.74(0.57,0.97) 1.73E-01 0.69(0.41,1.17) rs13115632 4 172164388 G 1985 A 1.28E-05 0.71(0.6,0.83) 2.42E-04 0.69(0.56,0.84) 3.26E-02 0.74(0.57,0.97) 1.73E-01 0.69(0.41,1.17) rs1396325 4 172167776 G 1985 A 1.28E-05 0.71(0.6,0.83) 2.42E-04 0.69(0.56,0.84) 3.26E-02 0.74(0.57,0.97) 1.73E-01 0.69(0.41,1.17) rs4692627 4 172165637 T 1985 A 1.28E-05 0.71(0.6,0.83) 2.42E-04 0.69(0.56,0.84) 3.26E-02 0.74(0.57,0.97) 1.73E-01 0.69(0.41,1.17) rs1508507 4 172172780 A 1985 A 1.28E-05 0.71(0.6,0.83) 2.42E-04 0.69(0.56,0.84) 3.28E-02 0.74(0.57,0.97) 1.73E-01 0.69(0.41,1.17) rs25510 4 172175579 A 1985 A 1.28E-05 0.71(0.6,0.83) 2.42E-04 0.69(0.56,0.84) 3.28E-02 0.74(0.57,0.97) 1.73E-01 0.69(0.41,1.17) rs25512 4 172175532 G 1985 A 1.28E-05 0.71(0.6,0.83) 2.42E-04 0.69(0.56,0.84) 3.28E-02 0.74(0.57,0.97) 1.73E-01 0.69(0.41,1.17) rs6849128 4 172176001 A 1985 A 1.28E-05 0.71(0.6,0.83) 2.42E-04 0.69(0.56,0.84) 3.28E-02 0.74(0.57,0.97) 1.73E-01 0.69(0.41,1.17) rs6858075 4 172172043 A 1985 A 1.28E-05 0.71(0.6,0.83) 2.42E-04 0.69(0.56,0.84) 3.28E-02 0.74(0.57,0.97) 1.73E-01 0.69(0.41,1.17) rs8120293 20 21116395 PLK1S1 T 1991 A 1.30E-05 0.69(0.59,0.8) 1.58E-03 0.73(0.6,0.88) 5.05E-02 0.78(0.61,1) 1.58E-03 0.45(0.28,0.74) rs8120377 20 21116361 PLK1S1 T 1991 A 1.30E-05 0.69(0.59,0.8) 1.58E-03 0.73(0.6,0.88) 5.05E-02 0.78(0.61,1) 1.58E-03 0.45(0.28,0.74) rs765585 20 21119172 PLK1S1 T 1991 A 1.30E-05 0.69(0.59,0.8) 1.58E-03 0.73(0.6,0.88) 5.05E-02 0.78(0.61,1) 1.58E-03 0.45(0.28,0.74) rs393025 1 165211552 A 1745 R 1.32E-05 0.54(0.41,0.71) 3.56E-05 0.47(0.33,0.67) 6.05E-02 0.64(0.41,1.01) rs17187123 4 172206354 LOC100506122 A 1935 A 1.36E-05 0.71(0.61,0.84) 1.95E-04 0.68(0.56,0.83) 3.65E-02 0.75(0.57,0.98) 2.14E-01 0.72(0.43,1.2) rs6047280 20 21091935 PLK1S1 G 1988 A 1.37E-05 0.69(0.59,0.8) 1.47E-03 0.73(0.6,0.88) 6.42E-02 0.79(0.62,1.01) 9.84E-04 0.43(0.26,0.71) rs7973213 12 24067564 SOX5 C 1988 D 1.37E-05 0.59(0.46,0.76) 1.06E-03 0.56(0.4,0.79) 1.20E-03 0.51(0.34,0.76) 9.99E-01 0.98(0.46,2.12) rs12823336 12 24068461 SOX5 C 1989 D 1.38E-05 0.59(0.46,0.76) 1.06E-03 0.57(0.4,0.79) 1.20E-03 0.51(0.34,0.76) 9.99E-01 0.98(0.46,2.12) rs17246878 4 172208800 LOC100506122 T 1935 A 1.39E-05 0.71(0.61,0.84) 2.00E-04 0.68(0.56,0.83) 3.65E-02 0.75(0.57,0.98) 2.14E-01 0.72(0.43,1.2) rs7307316 12 24072675 SOX5 G 1992 D 1.40E-05 0.59(0.46,0.76) 1.07E-03 0.56(0.4,0.79) 1.25E-03 0.51(0.34,0.76) 9.77E-01 0.98(0.45,2.09) rs17403340 12 24069147 SOX5 C 1989 D 1.41E-05 0.6(0.46,0.77) 1.07E-03 0.57(0.4,0.79) 1.22E-03 0.51(0.34,0.76) 9.98E-01 0.99(0.46,2.12) rs2478106 10 13668534 C 1760 D 1.42E-05 1.66(1.33,2.06) 2.42E-03 1.55(1.17,2.06) 1.07E-03 1.8(1.27,2.55) rs17481181 12 24063813 SOX5 G 1983 D 1.43E-05 0.59(0.46,0.76) 1.10E-03 0.56(0.4,0.79) 1.20E-03 0.51(0.34,0.76) 0.98(0.46,2.12) rs4963737 12 24063482 SOX5 C 1983 D 1.43E-05 0.59(0.46,0.76) 1.11E-03 0.56(0.4,0.79) 1.20E-03 0.51(0.34,0.76) 9.99E-01 0.98(0.46,2.12) rs879064 20 21123550 PLK1S1 C 1991 A 1.45E-05 0.69(0.59,0.8) 1.58E-03 0.73(0.6,0.88) 5.05E-02 0.78(0.61,1) 2.11E-03 0.46(0.28,0.75) rs1508296 4 172208949 LOC100506122 C 1976 A 1.49E-05 0.71(0.61,0.83) 2.22E-04 0.69(0.56,0.84) 4.04E-02 0.75(0.58,0.98) 1.72E-01 0.69(0.41,1.17) rs13110268 4 172211262 LOC100506122 G 1976 A 1.50E-05 0.71(0.61,0.83) 2.24E-04 0.69(0.56,0.84) 4.02E-02 0.75(0.58,0.98) 1.73E-01 0.69(0.41,1.17) rs7340816 4 172179585 A 1944 A 1.51E-05 0.71(0.6,0.83) 2.63E-04 0.69(0.56,0.84) 3.60E-02 0.75(0.57,0.98) 1.67E-01 0.69(0.41,1.16) rs9559744 13 109659445 COL4A1 T 1824 R 1.52E-05 0.49(0.35,0.67) 9.29E-05 0.43(0.29,0.66) 3.37E-02 0.56(0.33,0.95) rs2593753 11 45719573 G 1738 D 1.67E-05 0.61(0.49,0.76) 2.55E-03 0.65(0.5,0.86) 1.18E-03 0.56(0.39,0.79) rs10505927 12 24070940 SOX5 A 1976 D 1.67E-05 0.59(0.46,0.77) 1.24E-03 0.56(0.4,0.79) 1.28E-03 0.51(0.34,0.76) 9.95E-01 0.98(0.46,2.12) rs6047273 20 21082799 PLK1S1 T 1991 A 1.73E-05 0.69(0.59,0.8) 2.05E-03 0.73(0.61,0.89) 5.10E-02 0.78(0.61,1) 1.58E-03 0.45(0.28,0.74) rs2155099 11 93961634 PIWIL4 C 1943 A 1.73E-05 0.71(0.61,0.83) 1.96E-03 0.74(0.61,0.89) 1.14E-02 0.73(0.57,0.93) 5.95E-02 0.62(0.38,1.02) rs598893 13 109657744 COL4A1 C 1834 R 1.75E-05 0.49(0.35,0.68) 1.02E-04 0.44(0.29,0.66) 3.52E-02 0.57(0.34,0.95) rs10831246 11 93962343 PIWIL4 C 1943 A 1.77E-05 0.71(0.61,0.83) 1.95E-03 0.74(0.61,0.89) 1.17E-02 0.73(0.57,0.93) 6.02E-02 0.62(0.38,1.02) rs7110167 11 93959885 PIWIL4 C 1943 A 1.77E-05 0.71(0.61,0.83) 2.01E-03 0.74(0.61,0.89) 1.14E-02 0.73(0.57,0.93) 5.95E-02 0.62(0.38,1.02) rs2155100 11 93961046 PIWIL4 T 1943 A 1.77E-05 0.71(0.61,0.83) 1.98E-03 0.74(0.61,0.89) 1.16E-02 0.73(0.57,0.93) 5.99E-02 0.62(0.38,1.02) rs482757 13 109655824 COL4A1 C 1835 R 1.80E-05 0.49(0.35,0.68) 1.05E-04 0.44(0.29,0.66) 3.53E-02 0.57(0.34,0.95) rs677877 13 109655896 COL4A1 A 1835 R 1.80E-05 0.49(0.35,0.68) 1.06E-04 0.44(0.29,0.66) 3.53E-02 0.57(0.34,0.95) rs645098 13 109654272 COL4A1 C 1808 R 1.80E-05 0.48(0.34,0.67) 8.98E-05 0.42(0.27,0.65) 4.13E-02 0.56(0.33,0.97) rs10831244 11 93954955 PIWIL4 A 1948 A 1.84E-05 0.71(0.61,0.83) 2.05E-03 0.74(0.61,0.89) 1.14E-02 0.73(0.57,0.93) 5.97E-02 0.62(0.38,1.02) rs538390 13 109653678 COL4A1 G 1806 R 1.84E-05 0.48(0.34,0.67) 9.14E-05 0.42(0.27,0.65) 4.13E-02 0.56(0.33,0.97) rs2786113 1 195570704 CRB1 T 1835 R 1.87E-05 2.09(1.5,2.91) 4.26E-04 2.12(1.4,3.21) 1.08E-02 2.04(1.19,3.52) rs6681441 1 41870908 HIVEP3 G 1937 D 1.90E-05 0.59(0.47,0.74) 3.24E-03 0.64(0.48,0.86) 9.68E-03 0.61(0.43,0.88) 3.43E-02 0.44(0.2,0.94) rs2567957 4 172126198 G 1926 A 1.94E-05 0.73(0.63,0.84) 7.53E-05 0.69(0.57,0.83) 1.97E-01 0.85(0.66,1.08) 4.05E-02 0.61(0.38,0.98) rs2821131 1 195569025 CRB1 T 1822 R 1.99E-05 2.09(1.5,2.91) 4.55E-04 2.12(1.4,3.21) 1.07E-02 2.04(1.19,3.52) rs7153562 14 50301048 NIN C 1816 A 2.02E-05 1.46(1.23,1.74) 6.72E-05 1.58(1.26,1.97) 5.36E-02 1.32(1,1.75) rs12832769 12 124576288 TMEM132B T 1757 R 2.06E-05 2.66(1.74,4.07) 1.60E-02 1.97(1.15,3.38) 7.09E-05 3.97(2.02,7.8) rs11058220 12 124574011 TMEM132B A 1844 R 2.13E-05 2.55(1.7,3.84) 1.32E-02 1.97(1.16,3.32) 1.16E-04 3.58(1.88,6.81) rs10789405 1 41874549 HIVEP3 C 1954 D 2.13E-05 0.59(0.47,0.75) 3.87E-03 0.65(0.49,0.87) 8.29E-03 0.61(0.42,0.88) 3.74E-02 0.44(0.2,0.95) rs6892303 5 11211453 CTNND2 C 1794 R 2.23E-05 0.54(0.41,0.7) 8.38E-03 0.63(0.45,0.88) 2.56E-04 0.43(0.28,0.68) rs13126363 4 172155964 A 1902 A 2.24E-05 0.72(0.61,0.84) 2.38E-04 0.68(0.56,0.84) 4.67E-02 0.76(0.58,0.99) 2.27E-01 0.72(0.42,1.22) rs2023916 5 11214237 CTNND2 C 1778 R 2.24E-05 0.49(0.36,0.68) 1.84E-03 0.52(0.35,0.78) 2.44E-03 0.46(0.28,0.76) rs11210503 1 41873721 HIVEP3 A 1985 D 2.26E-05 0.59(0.47,0.75) 3.94E-03 0.65(0.49,0.87) 8.65E-03 0.61(0.42,0.88) 3.65E-02 0.44(0.2,0.95) rs498619 9 29622345 G 1764 R 2.28E-05 2.74(1.75,4.3) 7.20E-03 2.34(1.27,4.31) 4.25E-04 3.34(1.72,6.51) rs1978156 5 11214625 CTNND2 T 1778 R 2.33E-05 0.49(0.36,0.68) 1.82E-03 0.52(0.35,0.78) 2.62E-03 0.46(0.28,0.76) rs12358982 10 105844319 G 1834 A 2.38E-05 0.67(0.56,0.8) 3.27E-04 0.65(0.51,0.82) 1.77E-02 0.7(0.52,0.94) rs17407659 12 24129277 SOX5 T 1764 D 2.50E-05 0.55(0.41,0.72) 1.40E-03 0.55(0.38,0.79) 4.16E-03 0.54(0.35,0.82) rs1267216 11 93973522 PIWIL4 A 1964 A 2.55E-05 0.72(0.62,0.83) 3.46E-03 0.75(0.62,0.91) 1.01E-02 0.73(0.57,0.92) 4.58E-02 0.6(0.36,0.99) rs569057 18 64224850 A 1966 A 2.57E-05 1.43(1.23,1.67) 8.64E-03 1.31(1.08,1.6) 6.93E-03 1.41(1.1,1.8) 1.23E-02 1.9(1.15,3.12) rs12814129 12 124576151 TMEM132B C 1740 R 2.64E-05 2.73(1.76,4.22) 2.51E-02 1.91(1.1,3.32) 4.15E-05 4.37(2.16,8.81) rs1764786 1 195567119 CRB1 A 1811 R 2.65E-05 2.07(1.48,2.89) 6.02E-04 2.09(1.38,3.18) 1.09E-02 2.04(1.19,3.52) rs13121066 4 172109073 A 1941 A 2.67E-05 0.72(0.62,0.84) 1.97E-04 0.7(0.58,0.84) 1.55E-01 0.83(0.64,1.07) 3.82E-02 0.61(0.38,0.97) rs13128132 4 172115877 A 1941 A 2.67E-05 0.72(0.62,0.84) 1.97E-04 0.7(0.58,0.84) 1.55E-01 0.83(0.64,1.07) 3.82E-02 0.61(0.38,0.97) rs1560560 4 172117155 C 1945 A 2.67E-05 0.72(0.62,0.84) 1.96E-04 0.7(0.58,0.84) 1.56E-01 0.83(0.64,1.07) 3.82E-02 0.61(0.38,0.97) rs6715141 2 188331398 C 1836 A 2.70E-05 0.66(0.55,0.79) 8.55E-03 0.73(0.58,0.92) 3.49E-04 0.57(0.42,0.78) rs6572695 14 50302085 NIN C 1823 A 2.70E-05 1.45(1.22,1.73) 1.26E-04 1.55(1.24,1.93) 4.41E-02 1.34(1.01,1.78) rs1615444 1 195565938 CRB1 C 1807 R 2.72E-05 2.07(1.48,2.89) 6.28E-04 2.09(1.38,3.17) 1.08E-02 2.05(1.19,3.52) rs580067 1 195564996 CRB1 T 1804 R 2.77E-05 2.07(1.48,2.88) 6.54E-04 2.08(1.37,3.16) 1.06E-02 2.05(1.19,3.52) rs512195 18 64226458 T 1956 A 2.82E-05 1.43(1.23,1.67) 9.45E-03 1.31(1.07,1.59) 6.94E-03 1.41(1.1,1.8) 1.24E-02 1.9(1.15,3.12) rs10460550 2 53641781 C 1762 A 2.86E-05 0.64(0.52,0.78) 7.66E-03 0.71(0.55,0.91) 5.22E-04 0.56(0.41,0.78) rs550098 1 195564031 CRB1 A 1803 R 2.87E-05 2.07(1.48,2.88) 6.61E-04 2.08(1.37,3.16) 1.08E-02 2.05(1.19,3.52) rs7566120 2 53649671 A 1789 A 2.92E-05 0.67(0.57,0.8) 7.46E-03 0.73(0.58,0.91) 5.37E-04 0.61(0.47,0.81) rs2349872 2 188308550 G 1848 D 3.06E-05 0.62(0.51,0.77) 5.45E-03 0.68(0.52,0.89) 8.58E-04 0.56(0.4,0.79) rs10137294 14 50331422 NIN C 1760 A 3.08E-05 1.59(1.28,1.97) 3.17E-04 1.67(1.27,2.21) 2.26E-02 1.49(1.06,2.09) rs6748449 2 188328927 T 1838 A 3.13E-05 0.66(0.55,0.79) 8.75E-03 0.73(0.58,0.92) 4.15E-04 0.58(0.43,0.78) rs718349 2 53644591 T 1752 A 3.33E-05 0.67(0.56,0.8) 9.42E-03 0.73(0.58,0.92) 4.09E-04 0.6(0.45,0.79) rs13032640 2 188326395 G 1843 D 3.33E-05 0.63(0.51,0.77) 6.01E-03 0.68(0.52,0.89) 8.34E-04 0.56(0.4,0.78) rs2567959 4 172122862 A 1987 A 3.40E-05 0.74(0.64,0.85) 1.11E-04 0.69(0.58,0.83) 2.05E-01 0.85(0.66,1.08) 6.11E-02 0.64(0.4,1.02) rs970431 4 172118367 C 1987 A 3.40E-05 0.74(0.64,0.85) 1.11E-04 0.69(0.58,0.83) 2.05E-01 0.85(0.66,1.08) 6.11E-02 0.64(0.4,1.02) rs2567965 4 172119896 T 1987 A 3.42E-05 0.74(0.64,0.85) 1.11E-04 0.69(0.58,0.83) 2.06E-01 0.85(0.66,1.08) 6.11E-02 0.64(0.4,1.02) rs970432 4 172118096 C 1987 A 3.42E-05 0.74(0.64,0.85) 1.11E-04 0.69(0.58,0.83) 2.06E-01 0.85(0.66,1.08) 6.11E-02 0.64(0.4,1.02) rs970430 4 172118447 C 1987 A 3.42E-05 0.74(0.64,0.85) 1.11E-04 0.69(0.58,0.83) 2.06E-01 0.85(0.66,1.08) 6.11E-02 0.64(0.4,1.02) rs2719791 20 8215739 PLCB1 T 1819 R 3.43E-05 2.35(1.61,3.43) 1.06E-02 1.84(1.16,2.91) 3.34E-04 3.23(1.71,6.11) rs4667192 2 188325223 T 1843 D 3.43E-05 0.63(0.51,0.77) 6.12E-03 0.68(0.52,0.89) 8.45E-04 0.56(0.4,0.78) rs2860282 8 70772643 SLCO5A1 C 1850 D 3.45E-05 1.98(1.45,2.71) 1.44E-03 1.93(1.29,2.88) 5.73E-03 2.05(1.24,3.4) rs2933054 8 70779354 SLCO5A1 G 1850 D 3.45E-05 1.98(1.45,2.71) 1.44E-03 1.93(1.29,2.87) 5.74E-03 2.05(1.24,3.4) rs2959579 8 70779187 SLCO5A1 A 1850 D 3.45E-05 1.98(1.45,2.71) 1.44E-03 1.93(1.29,2.87) 5.74E-03 2.05(1.24,3.4) rs1223314 4 172116697 A 1947 A 3.47E-05 0.73(0.63,0.85) 1.12E-04 0.69(0.58,0.83) 2.18E-01 0.85(0.66,1.09) 6.27E-02 0.64(0.4,1.02) rs1402145 2 188309956 C 1845 A 3.49E-05 0.66(0.55,0.8) 8.55E-03 0.73(0.58,0.92) 5.00E-04 0.58(0.43,0.79) rs13122956 4 172109229 T 1933 A 3.50E-05 0.74(0.63,0.85) 1.11E-04 0.69(0.58,0.83) 2.18E-01 0.85(0.66,1.09) 6.27E-02 0.64(0.4,1.02) rs6856523 4 172106310 C 1945 A 3.52E-05 0.73(0.63,0.85) 1.13E-04 0.69(0.58,0.83) 2.18E-01 0.85(0.66,1.09) 6.27E-02 0.64(0.4,1.02) rs13250976 8 73942706 KCNB2 A 1996 D 3.52E-05 1.58(1.28,1.95) 6.30E-03 1.45(1.12,1.89) 4.72E-03 1.64(1.17,2.29) 9.02E-02 1.83(0.91,3.67) rs6831331 4 172106220 T 1945 A 3.52E-05 0.73(0.63,0.85) 1.13E-04 0.69(0.58,0.83) 2.18E-01 0.85(0.66,1.09) 6.27E-02 0.64(0.4,1.02) rs559131 18 64228794 T 1978 A 3.54E-05 1.43(1.22,1.66) 1.02E-02 1.3(1.07,1.59) 7.98E-03 1.4(1.1,1.8) 1.23E-02 1.9(1.15,3.12) rs930466 9 118565661 ASTN2 T 1847 R 3.57E-05 1.96(1.41,2.71) 1.94E-05 2.46(1.63,3.71) 1.81E-01 1.45(0.86,2.45) rs17186473 4 172126040 T 1988 A 3.60E-05 0.74(0.64,0.85) 1.11E-04 0.69(0.58,0.83) 2.13E-01 0.85(0.67,1.09) 6.12E-02 0.64(0.4,1.02) rs1402144 2 188315648 A 1849 D 3.64E-05 0.63(0.51,0.77) 6.33E-03 0.69(0.52,0.89) 8.58E-04 0.56(0.4,0.79) rs11591291 10 105819482 COL17A1 A 1824 A 3.71E-05 0.68(0.56,0.81) 4.76E-04 0.66(0.52,0.83) 1.94E-02 0.7(0.53,0.94) rs1546445 4 172158105 A 1968 A 3.74E-05 0.73(0.63,0.85) 1.55E-04 0.7(0.58,0.84) 1.97E-01 0.85(0.66,1.08) 4.94E-02 0.62(0.39,1) rs10759854 9 118562266 ASTN2 C 1836 R 3.76E-05 1.95(1.41,2.69) 1.93E-05 2.45(1.63,3.69) 1.91E-01 1.44(0.85,2.43) rs2274107 10 105828693 COL17A1 A 1835 A 3.77E-05 0.68(0.56,0.81) 5.32E-04 0.66(0.52,0.83) 1.78E-02 0.7(0.52,0.94) rs2056117 4 12619190 T 1892 A 3.79E-05 0.74(0.63,0.86) 3.55E-05 0.66(0.54,0.8) 2.07E-01 0.84(0.64,1.09) 3.24E-01 0.79(0.49,1.26) rs13145748 4 179340295 A 1948 D 3.84E-05 0.63(0.5,0.78) 6.74E-04 0.61(0.46,0.81) 4.65E-02 0.68(0.47,0.99) 1.27E-01 0.57(0.28,1.16) rs1520477 2 188319285 C 1846 A 3.94E-05 0.66(0.55,0.8) 9.52E-03 0.73(0.58,0.92) 4.93E-04 0.58(0.43,0.79) rs8097533 18 64215820 G 1981 A 3.94E-05 1.42(1.22,1.65) 1.22E-02 1.29(1.06,1.57) 7.25E-03 1.4(1.1,1.78) 1.23E-02 1.9(1.15,3.13) rs9288147 2 188317982 G 1836 D 4.00E-05 0.62(0.5,0.77) 1.14E-02 0.7(0.53,0.92) 3.78E-04 0.53(0.38,0.75) rs1368005 4 172102070 T 1879 A 4.10E-05 0.73(0.62,0.85) 3.56E-04 0.69(0.57,0.85) 5.24E-02 0.76(0.58,1) 2.74E-01 0.74(0.44,1.25) rs1508508 4 172172919 C 1971 A 4.18E-05 0.74(0.64,0.85) 1.71E-04 0.7(0.58,0.84) 1.91E-01 0.84(0.66,1.08) 5.73E-02 0.63(0.4,1.01) rs2219449 4 179341091 G 1952 D 4.30E-05 0.63(0.5,0.79) 5.87E-04 0.6(0.46,0.8) 5.76E-02 0.69(0.48,1) 1.28E-01 0.58(0.28,1.16) rs7241738 18 64236778 T 1978 A 4.35E-05 1.42(1.22,1.66) 1.21E-02 1.3(1.06,1.58) 8.01E-03 1.4(1.1,1.8) 1.23E-02 1.9(1.15,3.12) rs13110811 4 172220343 T 1773 A 4.35E-05 0.71(0.61,0.84) 3.26E-04 0.69(0.57,0.84) 3.15E-02 0.74(0.56,0.97) rs2933060 8 70770795 SLCO5A1 A 1849 D 4.40E-05 1.97(1.44,2.7) 1.82E-03 1.91(1.28,2.85) 5.74E-03 2.05(1.24,3.39) rs10969287 9 29604435 G 1851 R 4.44E-05 3.12(1.86,5.25) 1.18E-02 2.46(1.24,4.88) 4.09E-04 4.26(1.92,9.48) rs10885193 10 113219570 T 1939 A 4.45E-05 1.36(1.17,1.59) 3.64E-04 1.42(1.17,1.72) 8.60E-02 1.25(0.97,1.59) 1.17E-01 1.48(0.91,2.42) rs17485232 12 24106293 SOX5 C 1974 D 4.47E-05 0.6(0.47,0.78) 1.88E-03 0.57(0.41,0.81) 3.44E-03 0.53(0.35,0.81) 8.33E-01 0.91(0.42,1.98) rs4963565 12 24105525 SOX5 G 1975 D 4.51E-05 0.6(0.47,0.78) 1.87E-03 0.57(0.4,0.81) 3.50E-03 0.53(0.35,0.81) 8.32E-01 0.91(0.42,1.98) rs12810574 12 24105932 SOX5 T 1975 D 4.52E-05 0.6(0.47,0.78) 1.88E-03 0.57(0.41,0.81) 3.49E-03 0.53(0.35,0.81) 8.30E-01 0.91(0.42,1.98) rs4963564 12 24105317 SOX5 T 1975 D 4.56E-05 0.6(0.47,0.78) 1.88E-03 0.57(0.41,0.81) 3.49E-03 0.53(0.35,0.81) 8.38E-01 0.91(0.42,1.98) rs1878241 10 113217538 T 1899 A 4.59E-05 1.38(1.18,1.61) 4.70E-04 1.42(1.17,1.72) 9.82E-02 1.24(0.97,1.59) 6.38E-02 1.6(0.98,2.62) rs1764623 1 195554931 CRB1 G 1851 R 4.64E-05 1.99(1.44,2.74) 1.51E-03 1.96(1.3,2.95) 7.58E-03 2.03(1.21,3.39) rs10759855 9 118568299 ASTN2 A 1846 R 4.64E-05 1.94(1.4,2.68) 2.06E-05 2.46(1.63,3.72) 2.08E-01 1.42(0.84,2.39) rs1878244 10 113216808 G 1902 A 4.66E-05 1.38(1.18,1.6) 4.69E-04 1.42(1.17,1.72) 9.97E-02 1.24(0.97,1.59) 6.33E-02 1.6(0.98,2.62) rs13264816 8 73940417 KCNB2 T 1971 D 4.68E-05 1.57(1.27,1.94) 5.57E-03 1.46(1.12,1.91) 7.46E-03 1.61(1.14,2.27) 9.54E-02 1.82(0.91,3.65) rs7816119 8 73942565 KCNB2 G 1968 D 4.69E-05 1.57(1.27,1.94) 8.19E-03 1.45(1.11,1.89) 4.77E-03 1.63(1.17,2.29) 9.15E-02 1.83(0.91,3.67) rs11058222 12 124574307 TMEM132B G 1784 R 4.76E-05 2.52(1.65,3.83) 2.85E-02 1.88(1.08,3.27) 9.70E-05 3.64(1.91,6.94) rs943374 1 41828781 HIVEP3 A 1973 A 4.78E-05 0.73(0.63,0.85) 3.22E-04 0.7(0.58,0.85) 1.52E-01 0.83(0.65,1.06) 4.42E-02 0.59(0.36,0.98) rs11675507 2 188303243 A 1836 D 4.81E-05 0.63(0.51,0.78) 7.64E-03 0.69(0.53,0.9) 9.35E-04 0.56(0.4,0.79) rs482526 1 195535386 CRB1 A 1852 R 5.07E-05 1.98(1.44,2.73) 1.65E-03 1.95(1.29,2.93) 7.58E-03 2.03(1.21,3.39) rs664767 1 195546918 CRB1 A 1852 R 5.07E-05 1.98(1.44,2.73) 1.65E-03 1.95(1.29,2.93) 7.58E-03 2.03(1.21,3.39) rs17324385 8 131888626 ADCY8 C 1823 A 5.15E-05 0.7(0.59,0.82) 2.03E-03 0.71(0.57,0.88) 6.09E-03 0.68(0.51,0.89) rs7966098 12 94962773 G 1966 A 5.25E-05 1.33(1.15,1.54) 3.61E-04 1.41(1.17,1.7) 4.43E-02 1.28(1.01,1.63) 4.35E-01 1.22(0.75,1.98) rs6137286 20 21127752 PLK1S1 T 1987 A 5.36E-05 0.7(0.61,0.82) 4.43E-03 0.75(0.62,0.91) 6.93E-02 0.79(0.62,1.01) 1.51E-03 0.45(0.28,0.74) rs7080157 10 6552566 PRKCQ A 1779 D 5.56E-05 1.61(1.28,2.01) 1.57E-03 1.58(1.2,2.1) 8.79E-03 1.64(1.14,2.36) rs930465 9 118565286 ASTN2 T 1846 R 5.61E-05 1.92(1.39,2.65) 2.63E-05 2.42(1.61,3.64) 2.08E-01 1.42(0.84,2.39) rs1010444 18 64208012 C 2000 A 5.70E-05 1.41(1.21,1.64) 1.72E-02 1.28(1.05,1.56) 6.80E-03 1.4(1.1,1.78) 1.22E-02 1.9(1.15,3.12) rs17202895 6 1388800 C 1888 D 5.71E-05 1.57(1.27,1.93) 3.99E-03 1.49(1.14,1.96) 2.19E-02 1.49(1.06,2.09) 4.67E-02 1.97(1.01,3.82) rs10132785 14 50291422 NIN C 1805 A 5.73E-05 1.53(1.24,1.9) 4.37E-05 1.76(1.35,2.3) 1.60E-01 1.28(0.92,1.8) rs1415214 1 195549808 CRB1 C 1832 R 5.92E-05 1.97(1.43,2.72) 1.25E-03 1.99(1.32,3) 1.21E-02 1.95(1.17,3.27) rs2835358 21 36739523 A 1788 D 5.98E-05 0.63(0.51,0.78) 3.56E-03 0.65(0.49,0.87) 3.74E-03 0.6(0.42,0.84) rs1502251 4 27135045 G 1819 R 6.10E-05 2.81(1.68,4.68) 5.85E-05 3.82(2,7.3) 1.46E-01 1.87(0.82,4.28) rs10762795 10 80075943 A 1956 D 6.15E-05 0.58(0.45,0.75) 4.67E-02 0.7(0.49,0.98) 1.12E-04 0.43(0.28,0.66) 3.29E-01 0.66(0.3,1.49) rs10472030 5 57347315 T 1761 R 6.24E-05 2.17(1.5,3.14) 1.51E-03 2.15(1.35,3.43) 1.05E-02 2.2(1.21,4) rs1815826 11 93946933 PIWIL4 T 1940 A 6.27E-05 0.73(0.63,0.85) 5.15E-03 0.76(0.63,0.92) 1.02E-02 0.72(0.57,0.92) 1.13E-01 0.66(0.4,1.1) rs1476801 18 64212708 T 1984 A 6.29E-05 1.41(1.21,1.64) 1.74E-02 1.28(1.05,1.55) 7.58E-03 1.4(1.1,1.78) 1.23E-02 1.9(1.15,3.13) rs441577 6 90648944 C 1819 D 6.32E-05 0.53(0.41,0.7) 3.97E-02 0.69(0.49,0.97) 4.35E-03 0.51(0.32,0.81) 3.20E-03 0.29(0.12,0.66) rs7971150 12 94958877 A 1989 A 6.46E-05 1.36(1.18,1.58) 2.45E-03 1.34(1.11,1.62) 3.85E-02 1.29(1.02,1.64) 4.76E-02 1.6(1.01,2.55) rs2913774 5 177672235 COL23A1 C 1789 A 6.48E-05 1.52(1.25,1.85) 7.55E-03 1.42(1.1,1.84) 1.48E-03 1.66(1.22,2.25) rs8095325 18 64211971 C 1994 A 6.49E-05 1.41(1.21,1.64) 1.79E-02 1.28(1.05,1.55) 7.54E-03 1.4(1.1,1.78) 1.23E-02 1.9(1.15,3.13) rs16879459 4 27137622 G 1821 R 6.60E-05 2.8(1.68,4.67) 6.15E-05 3.81(1.99,7.29) 1.48E-01 1.87(0.82,4.25) rs9974322 21 36740175 G 1820 D 6.61E-05 0.63(0.51,0.79) 3.56E-03 0.66(0.5,0.87) 4.12E-03 0.6(0.42,0.85) rs9971100 10 105816409 COL17A1 C 1823 A 6.63E-05 0.68(0.57,0.82) 8.44E-04 0.67(0.53,0.84) 2.03E-02 0.71(0.53,0.94) rs7519983 1 41855956 HIVEP3 G 1957 D 6.75E-05 0.61(0.48,0.77) 5.25E-03 0.64(0.47,0.87) 9.93E-03 0.6(0.41,0.88) 1.28E-01 0.53(0.24,1.19) rs6817733 4 172177077 T 1895 A 6.75E-05 0.73(0.62,0.85) 3.75E-04 0.69(0.57,0.85) 1.11E-01 0.8(0.61,1.05) 1.47E-01 0.68(0.4,1.14) rs6137292 20 21143803 PLK1S1 A 1970 A 6.78E-05 0.7(0.6,0.82) 6.45E-03 0.76(0.63,0.92) 6.93E-02 0.79(0.62,1.01) 8.97E-04 0.43(0.26,0.71) rs1338657 6 102956029 T 1818 R 6.82E-05 0.56(0.42,0.73) 7.84E-03 0.62(0.44,0.88) 1.48E-03 0.49(0.32,0.76) rs9953072 18 64211988 C 1995 A 6.85E-05 1.41(1.21,1.64) 1.86E-02 1.27(1.05,1.55) 7.54E-03 1.4(1.1,1.78) 1.23E-02 1.9(1.15,3.13) rs10890151 1 41874430 HIVEP3 C 1882 D 6.92E-05 0.6(0.47,0.76) 6.80E-03 0.66(0.49,0.89) 1.50E-02 0.62(0.42,0.91) 4.00E-02 0.43(0.19,0.96) rs1022337 2 183615031 T 1786 A 6.94E-05 1.45(1.2,1.74) 7.03E-05 1.61(1.28,2.04) 1.40E-01 1.26(0.94,1.69) rs1993402 4 27139792 C 1819 R 7.00E-05 2.79(1.67,4.65) 6.80E-05 3.79(1.98,7.26) 1.46E-01 1.87(0.82,4.25) rs2933069 8 70765480 SLCO5A1 C 1842 D 7.04E-05 1.96(1.42,2.69) 2.89E-03 1.88(1.25,2.83) 5.72E-03 2.06(1.24,3.42) rs2933068 8 70765498 SLCO5A1 G 1842 D 7.07E-05 1.95(1.42,2.69) 2.90E-03 1.88(1.25,2.83) 5.72E-03 2.06(1.24,3.42) rs10939164 4 27142444 G 1819 R 7.23E-05 2.78(1.67,4.64) 7.09E-05 3.78(1.97,7.25) 1.46E-01 1.87(0.82,4.23) TTLL11,MIR548D rs10985423 9 123663014 1,MIR548AA1 A 1795 R 7.23E-05 0.47(0.33,0.68) 1.08E-03 0.45(0.28,0.72) 1.72E-02 0.5(0.29,0.88) rs11210501 1 41864221 HIVEP3 T 1964 A 7.28E-05 0.74(0.64,0.86) 1.06E-03 0.73(0.61,0.88) 6.40E-02 0.8(0.63,1.01) 9.37E-02 0.65(0.39,1.07) rs944981 9 118909914 ASTN2 G 1922 D 7.34E-05 0.59(0.46,0.77) 1.17E-03 0.58(0.41,0.8) 4.19E-02 0.63(0.41,0.98) 1.82E-01 0.56(0.25,1.3) rs10513066 5 11129061 CTNND2 C 1837 A 7.40E-05 0.71(0.6,0.84) 3.53E-03 0.73(0.6,0.9) 4.77E-03 0.68(0.53,0.89) rs809220 20 21362037 C 1973 D 7.41E-05 0.63(0.51,0.77) 1.68E-02 0.72(0.55,0.94) 7.94E-03 0.62(0.44,0.88) 1.53E-02 0.43(0.22,0.85) rs2380563 8 70767626 SLCO5A1 T 1845 D 7.43E-05 1.95(1.42,2.67) 3.03E-03 1.87(1.24,2.81) 5.77E-03 2.05(1.24,3.39) rs2887104 12 94959574 A 1977 A 7.57E-05 1.36(1.18,1.57) 2.92E-03 1.34(1.11,1.62) 3.77E-02 1.29(1.02,1.64) 4.82E-02 1.6(1.01,2.54) rs11210498 1 41850545 HIVEP3 T 1961 D 7.58E-05 0.61(0.48,0.77) 5.87E-03 0.65(0.48,0.88) 9.93E-03 0.6(0.41,0.88) 1.27E-01 0.53(0.24,1.19) rs3895387 9 139693629 EHMT1 T 1941 D 7.65E-05 0.64(0.51,0.81) 9.76E-04 0.6(0.44,0.81) 2.67E-02 0.65(0.44,0.95) 4.51E-01 0.75(0.37,1.54) rs11624766 14 50284680 NIN C 1817 A 7.68E-05 1.5(1.22,1.85) 2.04E-05 1.78(1.37,2.31) 2.87E-01 1.21(0.87,1.69) rs4692059 4 25681849 T 1936 A 7.79E-05 0.72(0.63,0.84) 2.02E-02 0.79(0.66,0.96) 5.43E-03 0.71(0.55,0.9) 2.20E-02 0.59(0.38,0.92) rs2205960 1 171458098 T 1770 R 7.82E-05 2.41(1.59,3.64) 1.17E-02 1.98(1.18,3.32) 1.02E-03 3.08(1.58,5.99) rs1984207 1 237792870 G 1971 D 7.85E-05 0.66(0.52,0.83) 2.12E-05 0.54(0.41,0.72) 4.05E-01 0.84(0.58,1.22) 3.18E-01 0.67(0.31,1.45) rs12406060 1 237787081 C 1979 D 7.87E-05 0.66(0.53,0.83) 2.00E-05 0.54(0.41,0.72) 4.08E-01 0.85(0.59,1.22) 3.24E-01 0.67(0.31,1.45) rs292263 6 90606211 CASP8AP2 C 1954 D 7.89E-05 0.55(0.42,0.71) 3.39E-02 0.68(0.48,0.96) 4.04E-03 0.51(0.33,0.8) 9.36E-03 0.34(0.15,0.76) rs2933061 8 70769644 SLCO5A1 A 1848 D 7.91E-05 1.94(1.41,2.66) 3.21E-03 1.86(1.24,2.79) 5.74E-03 2.05(1.24,3.39) rs1018967 5 11159572 CTNND2 A 1764 A 7.91E-05 0.71(0.6,0.84) 3.46E-03 0.73(0.59,0.9) 5.29E-03 0.68(0.52,0.89) TTLL11,MIR548A rs4836869 9 123679741 A1,MIR548D1 G 1841 R 7.99E-05 0.47(0.33,0.68) 1.19E-03 0.45(0.28,0.73) 1.73E-02 0.5(0.29,0.88) TTLL11,MIR548D rs10121618 9 123679608 1,MIR548AA1 C 1841 R 8.01E-05 0.47(0.33,0.68) 1.21E-03 0.45(0.28,0.73) 1.73E-02 0.5(0.29,0.88) rs7316268 12 31358297 FAM60A C 1760 A 8.06E-05 1.5(1.23,1.82) 1.23E-03 1.51(1.18,1.93) 1.70E-02 1.48(1.08,2.04) rs3748438 20 21144089 PLK1S1 G 1972 A 8.09E-05 0.71(0.61,0.82) 6.57E-03 0.76(0.63,0.92) 6.95E-02 0.79(0.62,1.01) 1.50E-03 0.45(0.28,0.74) rs12591953 15 69787332 THSD4 A 1756 R 8.16E-05 1.85(1.38,2.49) 1.16E-02 1.68(1.13,2.5) 1.10E-03 2.09(1.35,3.24) rs7485624 12 20508680 PDE3A G 1833 D 8.18E-05 0.63(0.51,0.79) 9.12E-03 0.69(0.52,0.91) 1.47E-03 0.57(0.4,0.8) rs6819553 4 172177986 T 1900 A 8.30E-05 0.73(0.62,0.86) 3.46E-04 0.69(0.57,0.85) 1.13E-01 0.8(0.61,1.05) 2.10E-01 0.71(0.42,1.2) rs1863005 7 134704002 CNOT4 A 1994 D 8.31E-05 1.66(1.31,2.11) 2.34E-03 1.63(1.2,2.22) 6.35E-02 1.44(0.99,2.11) 2.97E-02 2.37(1.09,5.12) rs1321919 9 118287396 ASTN2 A 1922 D 8.43E-05 0.61(0.47,0.78) 9.96E-04 0.59(0.43,0.8) 7.79E-02 0.7(0.47,1.03) 1.03E-01 0.5(0.22,1.14) TTLL11,MIR548A rs7863807 9 123665707 A1,MIR548D1 G 1833 R 8.47E-05 0.48(0.33,0.68) 1.26E-03 0.46(0.28,0.73) 1.75E-02 0.5(0.29,0.88) rs13077992 3 68669012 FAM19A1 A 1848 D 8.50E-05 1.54(1.25,1.9) 3.22E-03 1.5(1.15,1.96) 6.26E-03 1.6(1.15,2.23) rs10912694 1 169502847 FMO1 G 1761 D 8.60E-05 0.65(0.53,0.8) 9.56E-04 0.64(0.49,0.83) 2.37E-02 0.67(0.48,0.94) rs13253030 8 73976133 KCNB2 T 1848 D 8.70E-05 1.56(1.26,1.93) 6.01E-03 1.46(1.12,1.91) 2.86E-03 1.69(1.2,2.38) rs2526401 7 25054861 C 1808 A 8.74E-05 0.73(0.63,0.85) 8.13E-04 0.72(0.59,0.87) 2.77E-02 0.76(0.6,0.97) rs6047404 20 21300236 XRN2 A 2000 A 8.77E-05 0.69(0.59,0.81) 9.38E-03 0.76(0.62,0.93) 5.81E-02 0.78(0.6,1) 1.04E-03 0.42(0.25,0.71) rs4815041 20 21301409 XRN2 A 2000 A 8.79E-05 0.69(0.59,0.81) 9.38E-03 0.76(0.62,0.93) 5.81E-02 0.78(0.6,1) 1.04E-03 0.42(0.25,0.71) rs17363834 1 41849194 HIVEP3 C 1960 D 8.81E-05 0.61(0.48,0.78) 6.76E-03 0.65(0.48,0.88) 9.96E-03 0.6(0.41,0.88) 1.26E-01 0.53(0.24,1.19) rs2526404 7 25056222 G 1810 A 8.82E-05 0.74(0.63,0.86) 8.24E-04 0.72(0.59,0.87) 2.76E-02 0.76(0.6,0.97) rs4497932 20 21290378 XRN2 T 2000 A 8.84E-05 0.69(0.59,0.81) 9.43E-03 0.76(0.62,0.93) 5.81E-02 0.78(0.6,1) 1.04E-03 0.42(0.25,0.71) rs6047407 20 21303846 XRN2 A 1999 A 8.87E-05 0.69(0.59,0.81) 9.49E-03 0.76(0.62,0.93) 5.80E-02 0.78(0.6,1) 1.05E-03 0.42(0.25,0.71) rs3812274 7 134711869 CNOT4 C 1994 D 8.98E-05 1.65(1.3,2.09) 2.47E-03 1.62(1.19,2.21) 6.34E-02 1.44(0.99,2.1) 3.13E-02 2.32(1.08,4.98) rs6892747 5 177648059 COL23A1 T 1820 D 8.98E-05 1.59(1.27,1.99) 1.93E-03 1.58(1.19,2.1) 1.20E-02 1.6(1.11,2.31) rs9322644 6 102855022 C 1814 R 9.23E-05 0.57(0.43,0.74) 5.54E-03 0.61(0.43,0.86) 3.52E-03 0.52(0.33,0.8) rs6047414 20 21308528 XRN2 A 1999 A 9.23E-05 0.69(0.59,0.81) 9.65E-03 0.76(0.62,0.93) 5.82E-02 0.77(0.6,1) 1.10E-03 0.43(0.26,0.71) rs13259257 8 73973407 KCNB2 T 1847 D 9.33E-05 1.56(1.26,1.93) 6.46E-03 1.46(1.12,1.91) 2.82E-03 1.69(1.2,2.39) rs7839758 8 73973908 KCNB2 G 1847 D 9.37E-05 1.56(1.26,1.92) 6.46E-03 1.46(1.12,1.91) 2.83E-03 1.69(1.2,2.39) rs13255723 8 73976395 KCNB2 C 1849 D 9.42E-05 1.56(1.26,1.92) 6.46E-03 1.46(1.12,1.91) 2.87E-03 1.69(1.2,2.38) rs1288692 3 71487960 FOXP1 T 1748 R 9.50E-05 2.19(1.49,3.24) 1.23E-03 2.24(1.38,3.62) 2.02E-02 2.14(1.14,4.04) rs9320924 6 123665894 TRDN T 1800 A 9.57E-05 0.67(0.54,0.81) 1.09E-03 0.66(0.52,0.84) 2.33E-02 0.67(0.48,0.94) rs1982036 6 123664286 TRDN G 1800 A 9.59E-05 0.67(0.54,0.81) 1.09E-03 0.66(0.52,0.84) 2.33E-02 0.67(0.48,0.94) rs9283099 6 123669820 TRDN T 1800 A 9.61E-05 0.67(0.54,0.81) 1.09E-03 0.66(0.52,0.84) 2.33E-02 0.67(0.48,0.94) rs9320926 6 123669987 TRDN C 1801 A 9.62E-05 0.67(0.55,0.81) 1.09E-03 0.66(0.52,0.84) 2.34E-02 0.68(0.48,0.94) rs1982035 6 123662950 TRDN C 1800 A 9.66E-05 0.67(0.54,0.81) 1.10E-03 0.66(0.52,0.84) 2.33E-02 0.67(0.48,0.94) TTLL11,MIR548A rs7860920 9 123673643 A1,MIR548D1 T 1852 R 9.66E-05 0.48(0.34,0.69) 1.46E-03 0.46(0.29,0.74) 1.73E-02 0.5(0.29,0.88) rs1555946 20 21319371 A 1995 A 9.67E-05 0.7(0.59,0.82) 9.65E-03 0.76(0.62,0.93) 5.72E-02 0.77(0.6,1) 1.21E-03 0.43(0.26,0.71) rs1955926 14 49769618 A 1948 A 9.71E-05 1.39(1.19,1.61) 6.45E-04 1.4(1.16,1.7) 3.42E-01 1.14(0.89,1.46) 3.66E-03 2.05(1.26,3.32) TTLL11,MIR548A rs4390017 9 123673532 A1,MIR548D1 C 1852 R 9.71E-05 0.48(0.34,0.69) 1.47E-03 0.46(0.29,0.74) 1.73E-02 0.5(0.29,0.88) TTLL11,MIR548A rs4370602 9 123672917 A1,MIR548D1 G 1852 R 9.74E-05 0.48(0.34,0.69) 1.47E-03 0.46(0.29,0.74) 1.73E-02 0.5(0.29,0.88) rs10883966 10 105859905 G 1770 A 9.78E-05 0.69(0.57,0.83) 1.65E-03 0.69(0.55,0.87) 1.55E-02 0.69(0.52,0.93) rs7343261 20 21246731 XRN2 T 2000 A 9.79E-05 0.7(0.59,0.82) 9.35E-03 0.76(0.62,0.93) 6.44E-02 0.78(0.6,1.01) 1.04E-03 0.42(0.25,0.71) rs7345973 20 21246732 XRN2 G 2000 A 9.79E-05 0.7(0.59,0.82) 9.35E-03 0.76(0.62,0.93) 6.44E-02 0.78(0.6,1.01) 1.04E-03 0.42(0.25,0.71) TTLL11,MIR548A rs4384052 9 123672556 A1,MIR548D1 C 1852 R 9.79E-05 0.48(0.34,0.69) 1.48E-03 0.46(0.29,0.74) 1.73E-02 0.5(0.29,0.88) rs211978 21 17848756 CXADR A 1995 D 9.83E-05 1.51(1.22,1.86) 2.06E-03 1.53(1.17,2) 2.91E-02 1.47(1.05,2.06) 2.20E-01 1.54(0.78,3.02) TTLL11,MIR548A rs4837907 9 123670419 A1,MIR548D1 C 1852 R 9.84E-05 0.48(0.34,0.69) 1.50E-03 0.46(0.29,0.74) 1.73E-02 0.5(0.29,0.88) rs6047377 20 21249477 XRN2 C 2000 A 9.86E-05 0.7(0.59,0.82) 9.35E-03 0.76(0.62,0.93) 6.49E-02 0.78(0.6,1.01) 1.04E-03 0.42(0.25,0.71) TTLL11,MIR548A rs4240471 9 123668078 A1,MIR548D1 T 1852 R 9.89E-05 0.48(0.34,0.69) 1.50E-03 0.46(0.29,0.74) 1.73E-02 0.5(0.29,0.88) rs10798304 1 169525266 T 1847 D 9.93E-05 0.66(0.53,0.81) 1.17E-03 0.64(0.49,0.84) 2.22E-02 0.67(0.48,0.94) rs12516452 5 55692389 C 1851 A 9.93E-05 1.48(1.22,1.8) 4.08E-04 1.57(1.23,2.01) 5.62E-02 1.36(1,1.87) TTLL11,MIR548A rs9792544 9 123665526 A1,MIR548D1 A 1852 R 9.93E-05 0.48(0.34,0.69) 1.51E-03 0.46(0.29,0.74) 1.73E-02 0.5(0.29,0.88) rs6047396 20 21279541 XRN2 T 1998 A 9.96E-05 0.7(0.59,0.82) 9.35E-03 0.76(0.62,0.93) 6.56E-02 0.78(0.6,1.01) 1.04E-03 0.42(0.25,0.71) rs7105524 11 93966090 PIWIL4 G 1974 A 9.98E-05 0.73(0.63,0.85) 4.33E-03 0.75(0.62,0.91) 2.78E-02 0.76(0.6,0.97) 7.18E-02 0.63(0.38,1.04)

Supplemental Table S5. Clinical characteristics at time of biopsy of the lupus nephritis and control populations from the European Renal cDNA Cell Band (ERCB) included in the renal HG-U133A mRNA analysis.

SLE Characteristic Lupus Control P-value Nephritis N=15 N=32 Gender (number of females:males) 25:7 6:9 Median age, years (min-max) 33.4 (17-72) 55.3 (27-70) <0.0001 World Health Organization classification (number in class II, III, IV, V) 8, 10, 12, 2 N/A American College of Rheumatology Renal disorder (proteinuria), n (%) 32 (100) 0 Immunologic (anti-dsDNA, antibodies), n (%) 20 (90)* N/A Anti-nuclear antibody, n (%) 29 (93)* N/A N/A: not applicable; *Data were not available for some patients.

Supplemental Table S6. Significant enrichment of genes

From the whole human SNPs database (dbSNP Build 131, containing over 26 million SNPs), 10 sets of 22 random SNPs (same number of SNPs than the number of SNPs listed in the Table 4) were generated. For each SNP in each set, we look if the genes located at +/- 500kb were assessed for their regulation in Glomerular and Tubulo-interstitial compartments of LN patients vs controls (see the Table below). The LN SNPs provided in Table 4 of our manuscript show a higher percentage of significance than the transcripts in proximity to the random SNP sets, consistent with higher degree of transcriptional regulation in these loci.

# of chr # of genes in +/- # of genes having % of genes regulated % of genes regulated List # # of SNPs targeted 500 kb (ref. Fig 2) an official gene ID in Glom_LN v LD in Tub_LN v LD Table 4 22 - 26 26 53.8% 76.9% 1 22 16 197 86 18.6% 32.6% 2 22 12 354 174 33.9% 41.4% 3 22 14 308 160 26.3% 34.4% 4 22 14 335 156 26.3% 37.2% 5 22 14 296 142 30.3% 38.0% 6 22 12 281 135 36.3% 35.6% 7 22 12 306 135 23.0% 27.4% 8 22 14 409 205 33.7% 42.0% 9 22 13 354 187 25.1% 33.7% 10 22 13 290 135 34.1% 31.1%

Supplemental Table S7. Enrichment of PDGF pathway for regulated transcripts.

The PDGF signaling pathway was significantly enriched for regulated transcripts, ranking in the software algorithm used (Ingenuity) as number 53 based on the p-value assigned by the algorithm (there were 81 pathways with a p-value<0.05). The enrichment P-value is based on the following parameters: 1) the number of genes that participate in that process, and 2) the total number of genes that are known to be associated with that process in the selected reference set (Affymetrix Human HG133A chip). From the LN regulated genes (961) used as input (corresponding to the genes with a q-value<0.05 and a fold-change ≥1.5 and ≤0.7 for the up-regulated and down-regulated genes respectively), there were 81 pathways giving a p-value<0.05. PDGFRA was ranked as pathway #53 with a p- value of 0.013 and a ratio of 0.152 (12 of 79 molecules). The pathway having the smallest p-value does not necessarily reflect the pathway with the highest number of genes regulated in this pathway. Indeed the ratios of regulated genes to genes in pathway were 0.053 and 0.556 respectively, corresponding to a p-value of 0.024 and 3.8x10-4, respectively. Below is the list of the pathways significantly regulated in human LN glomeruli compared to controls.

Ingenuity Canonical Pathways p-value Ratio Ingenuity Canonical Pathways p-value Ratio 1 Cytotoxic T Lymphocyte-mediated Apoptosis of Target Cells 1.0E-07 0.198 42 Macropinocytosis Signaling 7.8E-03 0.158 2 Role of Pattern Recognition Receptors in Recognition of Bacteria and Viruses 4.9E-07 0.230 43 One Carbon Pool by Folate 8.1E-03 0.139 3 B Cell Development 4.9E-06 0.297 44 Crosstalk between Dendritic Cells and Natural Killer Cells 8.3E-03 0.144 4 Allograft Rejection Signaling 6.6E-06 0.143 45 Communication between Innate and Adaptive Immune Cells 8.9E-03 0.110 5 Calcium-induced T Lymphocyte Apoptosis 1.1E-05 0.214 46 ILK Signaling 9.5E-03 0.119 6 CTLA4 Signaling in Cytotoxic T Lymphocytes 1.6E-05 0.194 47 Chemokine Signaling 1.0E-02 0.162 7 Cdc42 Signaling 1.9E-05 0.138 48 Toll-like Receptor Signaling 1.1E-02 0.164 8 Phospholipase C Signaling 2.0E-05 0.135 49 Role of Tissue Factor in Cancer 1.1E-02 0.140 9 Complement System 2.3E-05 0.314 50 Thyroid Cancer Signaling 1.2E-02 0.174 10 Antigen Presentation Pathway 3.2E-05 0.256 51 Fc Epsilon RI Signaling 1.2E-02 0.135 11 Hepatic Fibrosis / Hepatic Stellate Cell Activation 5.0E-05 0.177 52 VDR/RXR Activation 1.2E-02 0.160 12 Nur77 Signaling in T Lymphocytes 5.1E-05 0.206 53 PDGF Signaling 1.3E-02 0.152 13 Role of NFAT in Regulation of the Immune Response 6.6E-05 0.140 54 Altered T Cell and B Cell Signaling in Rheumatoid Arthritis 1.4E-02 0.130 14 Autoimmune Thyroid Disease Signaling 8.3E-05 0.180 55 Prolactin Signaling 1.4E-02 0.150 15 OX40 Signaling Pathway 8.5E-05 0.144 56 FcγRIIB Signaling in B Lymphocytes 1.6E-02 0.136 16 CCR5 Signaling in Macrophages 1.3E-04 0.160 57 Polyamine Regulation in Colon Cancer 1.7E-02 0.172 17 Systemic Lupus Erythematosus Signaling 1.6E-04 0.133 58 Glioma Signaling 1.8E-02 0.125 18 Interferon Signaling 1.9E-04 0.278 59 p70S6K Signaling 1.9E-02 0.123 19 Graft-versus-Host Disease Signaling 1.9E-04 0.220 60 Corticotropin Releasing Hormone Signaling 2.2E-02 0.112 20 Leukocyte Extravasation Signaling 2.2E-04 0.146 61 iCOS-iCOSL Signaling in T Helper Cells 2.2E-02 0.115 21 PKCθ Signaling in T Lymphocytes 2.5E-04 0.141 62 fMLP Signaling in Neutrophils 2.2E-02 0.117 22 Natural Killer Cell Signaling 2.8E-04 0.173 63 NF-κB Signaling 2.3E-02 0.114 23 CD28 Signaling in T Helper Cells 3.3E-04 0.152 64 Starch and Sucrose Metabolism 2.4E-02 0.053 24 Dendritic Cell Maturation 3.8E-04 0.128 65 G Beta Gamma Signaling 2.6E-02 0.111 25 Pathogenesis of Multiple Sclerosis 3.8E-04 0.556 66 Renin-Angiotensin Signaling 2.6E-02 0.121 26 Coagulation System 4.2E-04 0.263 67 Activation of IRF by Cytosolic Pattern Recognition Receptors 2.6E-02 0.139 27 Fcγ Receptor-mediated Phagocytosis in Macrophages and Monocytes 9.8E-04 0.167 68 B Cell Receptor Signaling 2.8E-02 0.115 28 Endothelin-1 Signaling 1.1E-03 0.131 69 IL-4 Signaling 3.2E-02 0.137 29 Intrinsic Prothrombin Activation Pathway 1.2E-03 0.235 70 Tight Junction Signaling 3.4E-02 0.110 30 T Helper Cell Differentiation 1.3E-03 0.181 71 Ceramide Signaling 3.5E-02 0.126 31 IL-8 Signaling 1.8E-03 0.130 72 Aldosterone Signaling in Epithelial Cells 3.7E-02 0.100 32 Tumoricidal Function of Hepatic Natural Killer Cells 2.7E-03 0.292 73 C21-Steroid Hormone Metabolism 3.9E-02 0.059 33 Growth Hormone Signaling 2.8E-03 0.173 74 Role of Macrophages, Fibroblasts and Endothelial Cells in Rheumatoid Arthritis 4.2E-02 0.090 34 PI3K Signaling in B Lymphocytes 3.0E-03 0.133 75 LPS/IL-1 Mediated Inhibition of RXR Function 4.5E-02 0.096 35 Eicosanoid Signaling 3.2E-03 0.145 76 Glycine, Serine and Threonine Metabolism 4.6E-02 0.062 36 Acute Phase Response Signaling 3.5E-03 0.135 77 IL-10 Signaling 4.6E-02 0.128 37 Production of Nitric Oxide and Reactive Oxygen Species in Macrophages 4.0E-03 0.118 78 Erythropoietin Signaling 4.6E-02 0.128 38 Type I Diabetes Mellitus Signaling 4.0E-03 0.140 79 Cell Cycle Regulation by BTG Family Proteins 4.7E-02 0.167 39 Thrombopoietin Signaling 4.5E-03 0.175 80 Virus Entry via Endocytic Pathways 4.9E-02 0.120 40 Primary Immunodeficiency Signaling 4.9E-03 0.143 81 Apoptosis Signaling 4.9E-02 0.125 41 TREM1 Signaling 6.5E-03 0.152 Online Methods

This study reports the results of a meta-analysis for LN based on three GWAS of women of European descent with SLE. The three GWAS used include: (1) Set I: samples genotyped using the Illumina HumanHap550v1 as described by Hom et al.; 1 2) Set II: samples genotyped

using the Illumina HumanHap300 as described by Harley et al.; 2 and 3) Set III: samples

genotyped using the Affymetrix 5.0 as described by Graham et al. 3 The primary inference of

this study is based on a female-only case-case (i.e., LN cases versus SLE cases without LN)

analysis to minimize the potential influence of SLE susceptibility variants in our tests of

association with LN. The classification of SLE and LN in all three GWAS samples was based

on the American College of Rheumatology (ACR) criteria, including proteinuria and/or cellular

casts in the urine. 4; 5

The individual SLE GWAS designs attempted to maximize the number of SLE multiplex

cases (i.e., SLE cases with family members with confirmed SLE) but only one case was selected

per pedigree (93/1163 in Set I; 591/720 in Set II; and 122/282 in Set III). Details of the

individual calling algorithms, call rates and study-specific quality control were previously

reported.1-3 Briefly, each sample was tested for cryptic relatedness (duplicates and first-degree relatives) via the proportion of alleles shared identical by descent, autosomal heterozygosity, gender inconsistencies and departures from Hardy-Weinberg Equilibrium expectations. Four hundred highly polymorphic SNPs common to both the Illumina and Affymetrix chips were used to identify duplicate or first-degree relatives across Sets I, II and III. In total across these three studies, 282 duplicates and 71 first-degree relatives were identified. The data from female samples with the most complete LN data and then the highest call rate was used in the meta- analysis. Thus, the difference in the number of SLE individuals in the previously published GWAS (1163 in Set I; 720 in Set II; and 282 in Set III) and the numbers in Table 1 reflect the

removal of males, related individuals (first degree relatives and identical individuals) and

individuals who did not have information on LN status (presence/absence).

Admixture, SNP statistical quality control and association testing.

To account for potential population substructure, principal component (PC) analyses

were computed using SNPs that passed quality control and were not in genomic regions with

extended linkage disequilibrium (LD). 6 For Set I, a PC analysis was computed using all SNPs

that remained after removal of markers in regions with extensive LD on chromosomes 5 (44-51.5

Mb), 6 (25-33.5 Mb), 8 (8-12 Mb), 11 (45-57 Mb), and 17 (40-43 Mb). An independent PC

analysis was computed on the combined Set II and Set III samples using 38,092 SNPs common

to the two genotyping platforms (i.e., Infinium HumanHap 300 and Affymetrix 5.0), again after

removing the regions of extended LD. All tests of association were computed using a logistic

regression model and adjusted for five PCs in the Set I samples and four PCs in the Set II and Set

III scans.

It is well established that polymorphisms in the extended HLA region are strongly

associated with SLE. In an effort to increase the statistical power of the tests of association, the

analyses were repeated adjusting for rs9271366 and rs2187668, two SNPs that are reported to tag

HLA-DR2 and HLA-DR3, respectively. 7 These two HLA serotypes are the most strongly associated with SLE. 8-10 These two SNPs and the PCs were added as covariates to the logistic

regression model and the results were combined as described in the meta-analysis. Separate

models were computed for dominant, additive and recessive genetic models.

Imputation

Within each GWAS set, autosomal SNPs that passed quality control filters and exhibited

a minor allele frequency greater than 0.01 were used to impute the ~2.5 million SNPs in

HapMap2 (Build 35) using IMPUTE. 11 The reference set for imputation was the CEU (i.e.,

United States samples of northern and western European origin available via the HapMap).

Standard post imputation quality control was completed for each SNP, yielding an imputation set

of 1,621,689 SNPs in 2000 individuals. Within each GWAS set, logistic regression models

included the above stated PCs and accounted for the imputation uncertainty using the software

SNPTEST. 11 For each SNP, dominant, additive and recessive genetic models were computed.

To increase the robustness of the tests of association, the additive and recessive genetic models

required at least 10 and 30 individuals homozygous for the minor allele, respectively.

Meta-Analysis

The evidence of association from each of the three GWAS sets was combined using the weighted inverse normal method as implemented in METAL 12 and weighted by sample size.

Assuming appropriate numbers of homozygotes for the model, meta-analysis p-values were

calculated for additive, dominant and recessive models and the minimum p-value was chosen

from the three. A test for heterogeneity of the odds ratios across the three studies was also computed using METAL. It is important to recognize that because of the small number of samples in Set III that are independent of the Set I and Set II scans, a higher proportion of the

SNPs from Set III failed to meet the additive and recessive model count criteria for homozygotes for the minor allele.

Renal biopsies for mRNA analysis

Renal biopsies from 15 healthy pre-transplant living donor controls and 32 patients with

LN were collected from an international multi-center repository (European Renal cDNA Bank).

13 All healthy controls had normal kidney function as determined by estimated MDRD-GFR

between 80 and 120 ml/min/m2. The glomerular and tubulointerstitial compartments of kidney biopsies were microdissected and processed as previously described, 13 including the RNA

isolation and reverse transcription. 14; 15

Human microarray data processing and analysis

The glomerular and tubulointerstitial compartments were analyzed using Affymetrix

Human Genome U133A Genechips (Affymetrix, Inc, Santa Clara, CA) at the University of

Michigan Microarray Core Facility following the manufacturer’s instructions. 15 The CEL files

were normalized in GenePattern pipeline (www.GenePattern.org) using the RMA (Robust

MultiChip Average) method and the Human Entrez Gene custom annotation version 10

(http://brainarray.mbni.med.umich.edu/Brainarray/default.asp). Of the 12,029 gene IDs

(corresponding to the 22,283 Affymetrix probe sets), 11,285 and 11,429 genes were expressed

above the Poly-A Affymetrix control expression baseline (negative controls) in the glomeruli and

tubulointerstitium, respectively, and used for further analyses. Normalized data files were

uploaded onto the Gene Omnibus website (http://www.ncbi.nlm.nih.gov/geo/) under the

reference GSE32591.

mRNA expression levels generated from the biopsies of the LN cases and from healthy

controls (no lupus, no nephritis) were compared using unpaired t-tests and Significance Analysis

of Microarrays (SAM) implemented in the MultiExperiment Viewer (MeV) application in the SAM software. 16; 17 Genes regulated between the two groups with a q-value (False Discovery

Rate) less than 0.05 were considered significant and used for further transcriptional analyses.

A transcriptional network from all the genes significantly differentially regulated as

defined by our filter criteria was generated using Genomatix Pathway System software (GePS,

www.genomatix.de). GePS allows visualization of dependencies among genes in pathways,

networks and processes derived from literature based knowledge and genome-wide sequence analysis. As PDGFRA was found to be the locus most significantly associated with LN, we queried the software to show the shortest path network from PDGFRA. We applied a function- word filter, meaning that to be displayed in the transcriptional network, two genes have to be co- cited in the same sentence with a function word (e.g. gene A activates gene B). Pearson correlations were used to determine the regulated transcripts significantly correlating with

PDGFRA mRNA expression in LN (p-value<0.05).

Reference List

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