Genetic Variants Associated with Quantitative Glucose Homeostasis

Page 3 of 127 Diabetes

Genetic Variants Associated with Quantitative Glucose Homeostasis Traits Translate to Type 2 Diabetes in Mexican Americans: The GUARDIAN (Genetics Underlying Diabetes in Hispanics) Consortium

Running Title: Glucose Homeostasis in the GUARDIAN Consortium

Nicholette D. Palmer1,2,3,4*, Mark O. Goodarzi5,6*, Carl D. Langefeld4,7*, Nan Wang9,41*, Xiuqing Guo15,16, Kent D. Taylor15,16, Tasha E. Fingerlin11,12, Jill M. Norris11, Thomas A. Buchanan8,13,41, Anny H. Xiang14, Talin Haritunians6, Julie T. Ziegler4,7, Adrienne H. Williams4,7, Darko Stefansovski6, Jinrui Cui6, Adrienne W. Mackay9, Leora F. Henkin4,17, Richard N. Bergman10, Xiaoyi Gao9,28, James Gauderman9,28, Rohit Varma28, Craig L. Hanis21, Nancy J. Cox29, Heather M. Highland21, Jennifer E. Below21, Amy L. Williams19,30,31, Noel P. Burtt19, Carlos A. Aguilar- Salinas32, Alicia Huerta-Chagoya32,33, Clicerio Gonzalez-Villalpando34, Lorena Orozco35, Christopher A. Haiman9, Michael Y. Tsai18, W. Craig Johnson36, Jie Yao15, Laura Rasmussen- Torvik37, James Pankow38, Beverly Snively7, Rebecca D. Jackson39, Simin Liu40, Jerry L. Nadler24, Fouad Kandeel25, Yii-Der I. Chen15,16, Donald W. Bowden1,2,3,26 Stephen S. Rich27, Leslie J. Raffel6, Jerome I. Rotter15,16†, Richard M. Watanabe8,9,41†, Lynne E. Wagenknecht4,17†

*These authors contributed equally to this work †These authors jointly directed this work and are co-corresponding authors

1Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA 2Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA 3Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA 4Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA 5Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 6Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 7Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC 8Department of Physiology and Biophysics, Keck School of Medicine of USC, Los Angeles, CA 9Department of Preventive Medicine, Keck School of Medicine of USC, Los Angeles, CA 10Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, CA 11Departments of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, CO 12Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Denver, Aurora, CO 13Department of Medicine, Keck School of Medicine of USC, Los Angeles, CA 14Research and Evaluation Branch, Kaiser Permanente of Southern California, Pasadena, CA 15Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 16Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 17Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 18Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 19Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 20Department of Genetics, Harvard Medical School, Boston, MA 21Human Genetics Center, School of Public Health, University of Texas Health Science Center, Houston, TX 22Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA 23Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 24Department of Medicine, Eastern Virginia Medical School, Norfolk, VA 25Department of Diabetes, Endocrinology and Metabolism, City of Hope, Duarte, California 26Section on Endocrinology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA 28UIC Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, Chicago, IL 29Department of Human Genetics, University of Chicago, Chicago, IL 30Howard Hughes Medical Institute, Chicago, IL 31Biological Sciences Department, Columbia University, New York, NY 32Endocrinologia y Metabolismo, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico 33Universidad Nacional Autónoma de México, Mexico City, Mexico 34Centro de Estudios en Diabetes Instituto Nacional de Salud Publica, Mexico 35Instituto Nacional de Medicina Genómica 36Collaborative Health Studies Coodinating Center, Department of Biostatistics, University of Washington, Seattle, WA 37Preventive Medicine-Epidemiology, Northwestern University Feinberg School of Medicine, Evanston, IL 38Division of Epidemiology & Community Health, University of Minnesota, Minneapolis, MN 39Ohio State University Medical Center, Columbus, OH

Diabetes Publish Ahead of Print, published online December 18, 2014 Diabetes Page 4 of 127

40Department of Epidemiology, Brown University, Providence, RI 41USC Diabetes and Obesity Research Institute, Keck School of Medicine of USC, Los Angeles, CA

Corresponding Authors:

Jerome I. Rotter Harbor-UCLA Medical Center 1124 W. Carson Street, Bldg., E-5 Torrance, CA 90502 Phone: 310-974-9501 E-mail: [email protected]

Richard M. Watanabe Keck School of Medicine of USC 2250 Alcazar Street, Suite 200 Los Angeles, CA 90033 Phone: 323-442-2053 Fax: 323-442-2349 E-Mail: [email protected]

Lynne E. Wagenknecht Wake Forest School of Medicine 1 Medical Center Blvd. Winston-Salem, NC 27157, USA Phone: 336-716-7652 Fax: 336-716-6427 E-mail: [email protected]

Journal: Diabetes Word Count (max. 4000): 200 (abstract), 4000 (body) References (max 50): 50 Number of Tables and Figures (max. 8): 6

Page 5 of 127 Diabetes

ABSTRACT

Insulin sensitivity, insulin secretion, insulin clearance, and glucose effectiveness exhibit strong genetic components although few studies have examined their genetic architecture or their influence on type 2 diabetes (T2D) risk. We hypothesized that loci affecting variation in these quantitative traits influence T2D. We completed a multi-cohort genome-wide association study to search for loci influencing T2D-related quantitative traits in 4,176 Mexican Americans. Quantitative traits were measured by the frequently-sampled intravenous glucose tolerance test (4 cohorts) or euglycemic clamp (3 cohorts) and random effects models were used to test association between loci and quantitative traits, adjusting for age, gender, and admixture proportions (Discovery). Analysis revealed significant (P<5.00x10-8) association at 11q14.3 (MTNR1B) with acute insulin response. Loci with P<0.0001 among the quantitative traits were examined for translation to T2D risk in 6,463 T2D cases and 9,232 controls of Mexican ancestry (Translation). Non-parametric meta-analysis of the Discovery and Translation cohorts identified significant associations at 6p24 (SLC35B3/TFAP2A) with glucose effectiveness/T2D, 11p15 (KCNQ1) with disposition index/T2D, and 6p22 (CDKAL1) and 11q14 (MTNR1B) with acute insulin response/T2D. These results suggest that T2D and insulin secretion and sensitivity have both shared and distinct genetic factors, potentially delineating genomic components of these quantitative traits that drive risk for T2D.

Diabetes Page 6 of 127

INTRODUCTION

The pathophysiologic basis of type 2 diabetes (T2D) reflects derangements in both insulin sensitivity and beta-cell function(1). Alterations in insulin clearance and glucose effectiveness may also contribute to the development of T2D(2). Genome-wide association studies (GWAS) of T2D have focused almost entirely on clinical presentation of disease and not on these underlying pathophysiologic traits. Expanding the focus to include the genetic basis of insulin sensitivity and beta-cell function has the potential to expand our knowledge of the pathophysiologic pathways underlying T2D. To date, GWAS of T2D and related traits have been conducted primarily in European origin populations(3). However, the prevalence of T2D and related traits vary by ethnicity, suggesting differential genetic architecture will provide important insight into T2D diathesis. GWAS in case/control samples of T2D have had a substantial impact on the current understanding of genetic susceptibility to disease, implicating variants in at least 70 genes/regions that each have relatively small individual effects but are common in the general population(4). Most identified T2D genes appear to mediate their influence through the beta-cell and not through insulin resistance. These data contrast with other evidence and the widely accepted belief that insulin resistance is a major(5; 6) heritable(7-10) component of T2D susceptibility. This suggests that insulin resistance is a part of the necessary milieu, but is insufficient to cause frank T2D in isolation. GWAS of the underlying pathophysiologic traits of insulin sensitivity and beta-cell function have relied almost entirely on surrogate measures such as homeostasis model assessment (HOMA) parameters(11). While these fasting measures do not reflect the dynamic processes of glucose homeostasis, new T2D loci have been identified through GWAS of basic T2D-related traits such as fasting glucose(11; 12). We have recently documented substantial heritability of direct measures of insulin resistance and insulin clearance in Mexican Americans(13), suggesting that genetic factors underlying these traits should be investigated to identify new loci underlying disease susceptibility. In addition, strong genetic correlation was observed between these traits, raising the possibility of shared genetic determinants(13). Only two GWAS(14; 15) of T2D have been conducted in Mexican origin populations, a group whose disease risk is nearly two times greater than that of European origin populations(16). The recent SIGMA (Slim Initiative for Genomic Medicine in the Americas)

Page 7 of 127 Diabetes

T2D Consortium identified a novel risk variant in SLC16A11, which is rare in European and African individuals, suggesting a possible role for triacylglycerol metabolism in T2D(15). Thus, the study of detailed physiologic traits in individuals of Mexican ancestry has the potential to uniquely expand our understanding of T2D. The Genetics Underlying Diabetes in Hispanics (GUARDIAN) Consortium was designed to overcome numerous gaps in the field of T2D genetics. GUARDIAN conducted a GWAS in multiple Mexican-ancestry cohorts with highly detailed glucose homeostasis measures. In the Discovery phase, measures were obtained using gold-standard protocols, i.e., the euglycemic clamp and the frequently sampled intravenous glucose tolerance test (FSIGT). Genomic regions associated with these quantitative traits were carried forward in a Translation phase that evaluated association with the clinical outcome of T2D. Using this approach, GUARDIAN has found novel and known risk variants in a Mexican-ancestry population that specifically translate to T2D. The study identified possible new pathways of disease etiology, and discovered risk variants for glucose homeostasis traits that do not associate with overt T2D, providing unique opportunities to understand physiologic regulation of glucose homeostasis traits within the normal range.

Diabetes Page 8 of 127

RESEARCH DESIGN AND METHODS

Study Populations Discovery Cohorts Seven cohorts were included in the Discovery: five family-based (IRAS-FS(17), BetaGene(18), HTN-IR(10), MACAD(19), NIDDM-Athero(20); n=3,925) and two non-family based studies (IRAS(1), TRIPOD(21); n=411). Cohorts were ascertained on various conditions including diabetes, gestational diabetes, hypertension, or atherosclerosis (Supplementary Text). Cohorts included persons without T2D who self-reported Mexican ancestry. Four studies measured glucose homeostasis traits by FSIGT(22) (IRAS, IRAS-FS, BetaGene, TRIPOD) and three by euglycemic clamp(23) (MACAD, HTN-IR, NIDDM-Athero). The primary traits of

interest were insulin sensitivity (SI from FSIGT or M from clamp, as well as a meta-analysis

combining these, denoted SI+M), metabolic clearance rate of insulin (MCRI), acute insulin response (AIRg), disposition index (DI), and glucose effectiveness (SG). All participants provided written informed consent and institutional review boards at the clinical, laboratory, and coordinating centers approved the study. Phenotyping Glucose homeostasis traits were measured by hyperinsulinemic-euglycemic clamp in three studies using an identical protocol(23). A priming dose of human insulin (Novolin; Clayton, NC) was given followed by infusion for 120 minutes at a constant rate (60mU m-2 min- 1) to establish steady state hyperinsulinemia. Blood was sampled every 5 minutes and the rate of 20% dextrose co-infused was adjusted to maintain plasma glucose concentrations at 95- 100mg/dL. The glucose infusion rate (M, mg m-2 min-1) over the last 30 minutes of steady-state insulin and glucose concentrations reflects glucose uptake by all tissues of the body (primarily insulin-mediated glucose uptake in muscle) and is therefore directly correlated with tissue insulin sensitivity(23). The insulin sensitivity index (mg m-2 min-1 IU-1 mL) was calculated as M/I, where I is the steady-state insulin level. In this study, to distinguish between insulin sensitivity and clearance, we relied on M as an approximation for insulin sensitivity because the calculations of M/I and insulin clearance both use steady-state insulin in the denominator. MCRI (mL m-2 min-1) was calculated as the insulin infusion rate divided by the steady state plasma insulin level of the euglycemic clamp (9; 23). DI, a measure of beta-cell compensation for insulin resistance, was calculated as M/I*delta insulin where delta insulin was calculated as the

Page 9 of 127 Diabetes

difference between insulin at 30 minutes and insulin at baseline from a 2-hr oral glucose tolerance test (OGTT). Glucose homeostasis traits were measured by FSIGT in four studies, with two modifications. An injection of insulin was used (one study, TRIPOD, injected tolbutamide) to ensure adequate plasma insulin levels for computation of insulin resistance across a broad range of glucose tolerance(24). Also, the reduced sampling protocol (which requires 12 rather than 30 plasma samples(25)) was used to facilitate study of large numbers of individuals. A 50% glucose solution (0.3g/kg) and regular human insulin (0.03units/kg) were injected through an intravenous line at 0 and 20 minutes, respectively. Blood was collected at −5, 2, 4, 8, 19, 22, 30, 40, 50, 70,

100, and 180 minutes for plasma glucose and insulin concentrations. SI and SG were calculated

by mathematical modeling using the MINMOD program (version 3.0 [1994](22)). AIRg was calculated as the increase in insulin concentrations at 2–8 minutes above the basal (fasting) insulin level after the bolus glucose injection at 0-1 minute. DI was calculated as the product of

SI and AIRg. MCRI was calculated as the ratio of the insulin dose over the incremental area under the curve of insulin from 20 minutes to infinity(26), using the following equation:

Here, Dose is the amount of insulin injected at 20 minutes. Ins(t) is the plasma insulin concentration in standard units (µU/ml) at each FSIGT sampling point and Ins(0) is the fasting plasma insulin concentration determined prior to the FSIGT glucose injection. Genotyping All samples were genotyped on the Illumina HumanOmniExpress BeadChip and alleles called using GenomeStudio (Illumina, San Diego, CA)(27; 28). Samples with call rates >0.98 and SNPs with call rates >0.99 and MAF>0.001 passed laboratory quality control following usual best practices (e.g., sufficient signal and cluster separation with no replicate errors)(29). Additionally, ~22,000 SNPs were manually reviewed for clustering accuracy. Statistical Analysis Quality Control Samples were removed from analysis if the overall call rate was <0.98, self-reported ethnicity was inconsistent with genetic data (i.e., admixture proportions) relative to other

Diabetes Page 10 of 127

members of the cohort (i.e., a genetic outlier), self-reported gender was inconsistent with genotype data, the sample exhibited excess or insufficient heterozygosity relative to cohort expectations, or the genotype data was inconsistent with the genotype data from existing SNP data (i.e., fingerprinting). The primary inferential SNPs did not exhibit differential missingness by trait, had a SNP call rate >95% and were consistent with Hardy-Weinberg Expectation proportions. For family-based studies, pedigree structures were confirmed using standard procedures (e.g. KING, http://people.virginia.edu/~wc9c/KING/index.html). Each SNP was examined for Mendelian inconsistencies using PedCheck (http://watson.hgen.pitt.edu/register/docs/pedcheck.html) and inconsistencies were converted to missing. A maximum of 693,128 SNPs were meta-analyzed among the Discovery cohorts. Population Stratification Population substructure was estimated using ADMIXTURE (http://www.genetics.ucla.edu/software/admixture/) v1.21 at each study site based on SNPs that passed quality control (n=117,347 LD-pruned SNPs). Data from the HapMap Project (CEU, CHB/JPT, YRI, and MEX; n=591) were utilized as reference populations. Depending on the cohort, up to k=5 subpopulations were identified based on low cross-validation error. In all tests for association, admixture proportions were included as covariates in the linear or variance component models such that the covariates were not collinear and tests of association did not exhibit evidence of inflation. Association Variance component models as implemented in GWAF(30) or SOLAR(31) were used to test for association in family cohorts and linear regression models as implemented in QSNPGWA (www.phs.wakehealth.edu) in non-family cohorts. All models included age, gender, study site (in multi-center recruitment studies), and admixture proportions. Conditional analyses were performed for significant loci with multiple uncorrelated variants by including the most significant variant as an additional covariate. If necessary, winsorization or transformation was applied to best approximate the distributional assumptions of conditional normality (conditional on the covariates) and homogeneity of variance. For traits warranting transformation, the same transformation was computed across all cohorts and included natural logarithm of the trait plus a constant (SI), natural logarithm (MCRI derived from FSIGT), and square root (M, AIRg, and DI);

MCRI derived from clamp and SG were not transformed. The primary inference was derived

Page 11 of 127 Diabetes

from the additive genetic model. However, we also tested for a lack of fit to additivity using the orthogonal contrast. If that lack of fit was significant (P<0.05), we report the “best” p-value as the minimum of the three genetic models. It can be shown that this approach has an inflation factor of 1.3. For robust estimation purposes, the additive and recessive genetic models were not computed if there were not at least 10 and 20 individuals homozygous for the minor allele, respectively. In addition to single variant association tests, a genetic risk score was computed, i.e. risk allele load was determined by the number of previously reported T2D risk alleles (Supplementary Table 2) carried by each individual, and analyzed for association with the

primary traits of interest (SI+M MCRI, and AIRg). Subsequently, an enrichment analysis was performed among these variants to determine if an excess of nominally significant values were observed. A non-parametric meta-analysis was computed to combine the evidence of association across cohorts as implemented in METAL (http://www.sph.umich.edu/csg/abecasis/metal/). For each genetic model and T2D-related quantitative trait, a weighted, fixed effects meta-analysis was computed weighting by cohort sample size and not by the standard error of the parameter estimate because the traits were not identical and studies had different designs and ascertainment criteria. Power for the association analysis in the Discovery cohorts accounting for the familial correlations, with stimulation-based estimations resulting in an effective sample size of 92%, was estimated to be 80% to detect SNP-quantitative trait associations that explain 1% and 0.56% of the variance at α=5x10-8 and α=1x10-4, respectively. Translation Evaluation of T2D-related quantitative traits is a potentially powerful approach to identify genetic variants contributing to defects in specific underlying pathways leading to T2D; however, the true impact can be gauged only through direct validation in a population with clinically defined disease. Translation Cohorts Six cohorts were included in the Translation effort: LALES, MESA Family, MESA, Starr County, WHI, and SIGMA (Supplementary Text). All cohorts were of self-reported Mexican origin and provided either look-ups of the index SNPs or a pre-selected proxy. SNP Selection for Translation

Diabetes Page 12 of 127

Results from the Discovery GWAS were reviewed to generate the list of SNPs to be

examined for translation to T2D. For each of seven traits (SI+M, SI, M, MCRI, AIRg, DI, and -4 SG), SNPs associated in the GWAS (P<1.00x10 ) or with both primary traits (SI+M and MCRI; P<0.05) were included. After removal of correlated SNPs (r2>0.90 within a 500kb window in the largest set of unrelated samples; n=553 from BetaGene and TRIPOD), this yielded a total of 594 SNPs for translation to T2D. Meta-analysis of Discovery and Translation Results Discovery and Translation cohort genotype data were aligned to the positive strand for compatibility. After alignment, the same non-parametric meta-analysis approach was used to combine the association statistics. Lower values for the quantitative traits were hypothesized to be associated with T2D risk(2; 32). Supplementary Figure 1 estimates the power of the Translation cohort to detect various odds ratios for T2D over a range of minor allele frequencies. Functional Database Validation Queries of the Encyclopedia of DNA Elements (ENCODE) data were carried out using both the UCSC genome browser (http://genome.ucsc.edu) and RegulomeDB (http://regulome.stanford.edu/). The positions of associated loci were overlaid with DNase I hypersensitivity hotspots from ENCODE that identified regions of chromatin accessibility and transcription factor motifs in 125 diverse cell lines and tissues. We utilized the browsers set up by the Genotype-Tissue Expression (GTEx) project to determine whether any of our association signals represented expression quantitative trait loci (eQTL), i.e. SNPs associated with mRNA transcript levels(33).

Page 13 of 127 Diabetes

RESULTS

The Discovery sample included 4,176 Mexican Americans without T2D (Table 1 and Supplementary Table 1). Characteristics of the sample have been previously reviewed(13). The Translation sample was comprised of 6,463 T2D cases and 9,232 controls (Supplementary Text). Figure 1 displays associations with T2D-related quantitative traits in the Discovery cohorts with signals that were significant at P<2.00x10-6 listed in Table 2 (Supplementary Table 2 lists nominally significant hits). Results were broadly similar with inclusion of BMI as a covariate (Supplementary Table 3). The top signal (P=5.23x10-12) was association of rs10830963 in

MTNR1B (melatonin receptor 1B gene) with AIRg; this SNP was also associated with DI but not

with SI (Figure 2). Associations with insulin sensitivity (SI, M, or SI+M), MCRI, and SG did not reach genome-wide significance levels. One signal for M (rs11683087) was located near IRS1, a locus previously identified for T2D and deemed to act via insulin resistance based on association with HOMA-IR(34). These variants were not highly correlated (r2=0.04) and the previously described variant (rs2943641) failed to show evidence of association with M (P=0.63) or reduce the level of significance at rs11683087 upon conditional analysis (P=1.29x10-6; Supplementary Table 4). Within the Discovery cohorts, we evaluated the association of previously reported T2D- susceptibility variants (n=90; Supplementary Table 5) with seven T2D-related quantitative traits. Using the reported variant (n=76) or a HapMap MEX proxy (n=14; r2>0.80), the most -8 profound effects were observed with decreased AIRg for 17 of the SNPs evaluated (P=2.3x10 - 0.021). The most significant association was at the MTNR1B locus (rs1387153)(35).

Comparatively, SI+M (n=9; P=0.0019-0.041) and MCRI (n=5; P=0.0053-0.050) had markedly -8 fewer nominal associations. Similarly, the cumulative genetic risk score (P=1.11x10 ) and

enrichment analysis (P<0.00001) were significantly associated with AIRg. Notably, we also

observed an enrichment for previously reported T2D SNPs with insulin sensitivity (SI+M; P=3.6x10-4) although the significance was attenuated in comparison. Meta-analysis of the Discovery and Translation cohorts identified multiple SNPs that met or approached genome-wide significance (Table 3, Supplementary Figure 3; Supplementary Table 6 for all results) and included novel and established T2D loci. Results were broadly similar with the additional inclusion of BMI as a covariate (Supplementary Table 7). The most

Diabetes Page 14 of 127

significant association observed was at rs2237897 (P=1.24x10-21) in KCNQ1 (potassium voltage- gated channel, KQT-like subfamily, member 1 gene). This variant was associated with DI in the Discovery cohort (P=7.04x10-6) and after conditional analysis for previously associated T2D variants (rs2237892, P=1.57x10-4; rs231362, P=1.06x10-5; Supplementary Table 8). Three

established T2D genes, motivated by their association with AIRg, remained associated in the meta-analysis: rs10830963 within MTNR1B (P=5.86x10-9); rs2206734 within CDKAL1 (CDK5 regulatory subunit associated protein 1-like 1 gene; P=1.11x10-8); and rs7018745 near CDKN2A/B (cyclin-dependent kinase inhibitor 2A and 2B gene cluster; P=7.3x10-8) which is a strong genetic susceptibility locus for cardiovascular disease (36) and linked to T2D (37). Four novel associations were observed that reached or approached genome-wide

significance. At 6p24, rs2064197 was associated with SG and the meta-analysis with T2D reached genome-wide significance (P=2.56x10-8). Other novel associations included rs322394 -7 -7 (M/T2D, P=1.12x10 ) at 5q35; rs7219451 at 17q21 (SI+M/T2D, P=3.97x10 ); and rs4266763 (DI/T2D, P=4.34x10-7) in SNAPC4 (small nuclear RNA activating complex, polypeptide 4 gene).

Page 15 of 127 Diabetes

DISCUSSION GUARDIAN conducted a GWAS in seven Mexican-American cohorts of insulin sensitivity, insulin secretion, insulin clearance, and glucose effectiveness directly quantified by the euglycemic clamp and the FSIGT. We posited that the measurements of insulin sensitivity and clearance obtained by detailed physiologic phenotyping procedures are closer to the gene products and would yield increased statistical power to detect SNPs influencing trait variation. Establishing these loci in the Mexican-American population will inform diabetes risk in an ethnicity that experiences a disproportionately high diabetes burden(16) and may explain risk in other ethnicities either directly or through a deeper understanding of the relevant biological pathways. The most significant association observed (rs10830963, P=5.23x10-12; Table 2) which translated to T2D (P=5.86x10-9; Table 3) was at MTNR1B, which was initially identified as a locus for fasting glucose(35). Two modestly correlated variants in MTNR1B, rs10830963 and 2 -12 -9 rs1387153 (r =0.68), were associated with AIRg (P=5.23x10 and 2.21x10 , respectively). These variants were also, but less significantly, associated with fasting glucose in the Discovery cohorts (P=3.92x10-8 and 2.09x10-5, respectively). As suggested by ENCODE, rs10830963 resides in a FOX2A transcription factor binding site and has a lower RegulomeDB Score (3a versus 5, respectively) which corroborates the stronger evidence of association observed at rs10830963. MTNR1B is expressed in both rodent and human islets and co-localizes with insulin. Gene expression increases with each copy of the rs10830963 risk allele in human islets from non-diabetic individuals. Consistent with this observation, MTNR1B gene expression levels are higher in human islets from patients with T2D compared to those from individuals without diabetes. MTNR1B is hypothesized to inhibit glucose-stimulated insulin secretion through binding of its ligand, melatonin, and decreasing cAMP levels(38), consistent with the direction of effect observed in our study. Among novel variants that translated to disease risk was rs2064197 (P=2.56x10-8), which -6 was also associated with SG in the Discovery cohorts (P=7.23x10 ) and located intergenically on 6p24.3 between the SLC35B3 (solute carrier family 35, member B3) and TFAP2A (transcription

factor AP-2 alpha). SG is the ability of glucose to enhance its own disappearance and suppress its

production at fasting insulin levels(39; 40). The role of SG in the regulation of glucose tolerance

is often ignored, but may be physiologically significant(40; 41). SG varies by both physiologic

Diabetes Page 16 of 127

and pathologic state(42) and has been shown to be predictive of conversion to T2D(43). Notably, this variant resides distally (1.7Mb) to the recently implicated T2D susceptibility locus, RREB1

(ras responsive element binding protein 1), which was not associated with SG in our analysis (Supplementary Table 4G). Other variants more nominally associated with this phenotype and translation to T2D included rs1260326, a missense variant located in GCKR (glucokinase regulator gene). This association is supported biologically, as the ATP-dependent phosphorylation of glucose, which is catalyzed by glucokinase, is the first and rate-limiting step in liver glucose metabolism(44). Since this step of glucose metabolism is independent of dynamic insulin response, it is thought that a large portion of SG results from the ability of the liver to take up glucose via the glucokinase pathway, independent of insulin. It is widely accepted that replication of GWAS results in independent samples is critical. However, we are unaware of additional Mexican-ancestry cohorts with highly detailed glucose homeostasis phenotypes available in which to directly replicate our findings. Given that these phenotypes predict the subsequent occurrence of T2D, we have taken a unique approach by translating our findings to the directly relevant clinical phenotype, T2D. This approach provides support that these loci are involved in deterioration from impaired glucose homeostasis to T2D. Not surprisingly, we observed that only some of the quantitative trait loci identified via our Discovery sample -- as loci associated with regulation of glucose homeostasis -- were associated with T2D. While likely not attributable to power (we had 80% power to detect modest effect sizes (OR=1.10-1.15) among common variants (MAF>0.15) at stringent significance levels (P=5.00x10-8; Supplementary Figure 1)), this observation likely reflects the pleiotropic nature of quantitative intermediate phenotypes of glucose homeostasis and the common observation that not all individuals with impaired glucose tolerance transition to overt T2D. Alternatively, a lack of association with T2D could reflect association of higher values for the quantitative traits with T2D which conflicts with our underlying hypothesis. While requiring further verification, these loci are still of substantial interest and have the potential to aid in understanding specific physiologic pathways that may ultimately lead to disease or phenotypic variation within the normal range. GWAS for T2D have identified over 70 susceptibility loci; association studies with quantitative traits have identified disturbed insulin secretion as the most frequent observation. The inability to identify insulin resistance loci may be partially explained by the high frequency

Page 17 of 127 Diabetes

of insulin resistance in non-diabetic controls(45). Furthermore, cohorts included in GWAS for T2D generally do not have detailed measures of insulin resistance. Fasting insulin and the closely-related homeostasis model assessment of insulin resistance have been most commonly used to represent insulin resistance in large-scale genetic studies(11). These traits only partially reflect insulin resistance(46), and therefore may be inadequate for gene discovery. Other than a small pilot study(47), the present GWAS is the first to include detailed measures of insulin resistance. A few of the previously reported diabetes loci do appear to act via altered insulin sensitivity (FTO, PPARG, IRS1, KLF14, ADAMTS9, GCKR, RBMS1/ITGB6) (48), suggesting the likely presence of other as yet undiscovered loci. The discovery of additional such traits was a major goal of GUARDIAN. However, consistent with prior GWAS, we did not identify any insulin sensitivity loci at genome-wide significance levels. While none of the more modestly significant insulin sensitivity loci translated to T2D, rs7219451 and rs322394, nearly reached genome-wide significance. It is possible that environmental or lifestyle factors have a relatively greater effect on insulin sensitivity than genetic factors. We do not believe that differences in phenotyping of this trait (euglycemic clamp or FSIGT) hampered our ability to discover insulin sensitivity loci, given that these methods produce highly correlated measures(49). Failure to meet genome-wide significance does not necessarily indicate that the detected variants are not of importance; such variants have been found to be enriched in enhancer elements in relevant tissues(50). Whether this is the case for the variants described herein will require further experimentation. To gain insight on the functional potential of our association signals, we queried ENCODE and GTEx databases. The linked SNAPC4 SNPs rs3812570 and rs4266763 (r2=0.85), associated with DI/T2D in the Translational meta-analysis, had RegulomeDB scores of 1f and 1b, respectively, indicating a high likelihood of functionality based on eQTL evidence, residence in transcription factor binding sites, and DNAse hypersensitivity sites. These SNPs are associated in multiple tissues not only with mRNA levels of SNAPC4, but also the nearby genes INPP5E and CARD9. INPP5E codes for an inositol polyphosphate-5-phosphatase that has been implicated in Golgi-vesicular trafficking(51), alterations in which might affect beta-cell insulin granule formation. Of interest, another variant with a putatively functional RegulomeDB score, rs10870202 (score 1f, associated with

AIRg/T2D in Table 3) is also an eQTL for INPP5E as well as DNLZ, a gene adjacent to CARD9

Diabetes Page 18 of 127

and SNAPC4, suggesting this region on chromosome 9 may be key to insulin secretion.

Additionally, SNP rs1978648 was associated with SI (RegulomeDB score 2b) and resides in a DNAase hypersensitive region harboring multiple transcription factor binding sites in HepG2 cells. In summary, GUARDIAN has performed the first GWAS to explore the genetic architecture of T2D-related quantitative phenotypes in a large Mexican-American cohort. As defects in the maintenance of glucose homeostasis are postulated to contribute to the development of T2D, a direct translation of our findings was performed to identify possible new disease pathways and test whether these variants explain T2D risk. Consistent with the literature, our results suggest a strong contribution for variants that affect insulin secretion pathways as assessed by AIRg and DI, e.g. CDKAL1, MTNR1B and KCNQ1. Although novel signals of association with insulin sensitivity traits were observed, they did not translate with statistical significance to the clinically relevant phenotype of T2D. Notably, a novel association with glucose effectiveness was observed, adding further to the complex pathophysiology underlying T2D.

Page 19 of 127 Diabetes

AUTHOR CONTRIBUTIONS

N.D.P., M.O.G., C.D.L., N.W., R.M.W., L.E.W. wrote the manuscript.

T.A.B., L.F.H., D.W.B., S.S.R., L.J.R., J.I.R., R.M.W., L.E.W. designed, managed and coordinated the project.

T.E.F., J.M.N., D.S., R.N.B., J.L.N., F.K. conducted phenotyping.

T.H. and K.D.T. carried out genotyping in GUARDIAN.

N.W., X.G., A.H.X., J.C., A.W.M., Y-D.I.C. carried out initial data analysis in GUARDIAN.

X.G., J.G., R.V. coordinated and carried out data analysis in LALES.

C.L.H., N.J.C., H.M.H., J.E.B. coordinated and carried out data analysis in Starr County Health Studies.

A.L.W., N.P.B., C.A.A-S., A.H-C., C.G-V., L.O., C.A.H. coordinated and carried out data analysis in the SIGMA T2D Consortium.

M.Y.T., W.C.J., J.Y., L.R-T., J.P. coordinated and carried out data analysis in the MESA and MESA Family Studies.

B.S., R.D.J., S.L. coordinated and carried out data analysis in WHI.

J.T.Z., A.H.W., C.D.L., N.W., R.M.W. carried out meta-analysis of the data.

All authors have read and approved the manuscript.

Drs. Jerome I. Rotter, Richard M. Watanabe, and Lynne E. Wagenknecht are the guarantors of this work and, as such, had full access to all the data in the study and take full responsibility for the integrity of the data and the accuracy of the analysis.

Diabetes Page 20 of 127

ACKNOWLEDGEMENTS This research was supported by the GUARDIAN Study DK085175 from the The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and from the following grants: HL047887 (IRAS), HL047889 (IRAS), HL047890 (IRAS), HL47902 (IRAS), HL060944 (IRASFS), HL061019 (IRASFS), HL060919 (IRASFS), DK061628 (BetaGene), American Diabetes Association Distinguished Clinical Scientist Award (BetaGene), HL088457 (MACAD), HL0697974 (HTN-IR), HL055798 (NIDDM-Atherosclerosis), and DK079888 (work related to insulin clearance in HTN-IR, MACAD and NIDDM-Atherosclerosis). Research support for the Translation cohorts was provided by U10EY011753 (LALES), R01EY022651 (LALES), P30EY001792 (LALES), an unrestricted Departmental Grant from the Research to Prevent Blindness, New York, NY 10022 (LALES), DK073541 (Starr County Health Studies), DK085501 (Starr County Health Studies), DK020595 (Starr County Health Studies), HL102830 (Starr County Health Studies), and Consejo Nacional de Ciencia y Tecnología grants 138826, 128877, CONACyT- SALUD 2009-01- 115250, Mexico City (SIGMA Type 2 Diabetes Consortium; UNAM/INCMNSZ Diabetes Study). The Multi-Ethnic Study of Atherosclerosis (MESA) was supported by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC- 95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01- HC-95168, N01-HC-95169 and by grants UL1-TR-000040 and UL1-RR-025005 from NCRR . Funding for MESA Family was provided by grants R01-HL-071051, R01-HL-071205, R01-HL- 071250, R01-HL-071251, R01-HL-071252, R01-HL-071258, R01-HL-071259, and UL1-RR- 025005. Funding for MESA SHARe genotyping was provided by NHLBI Contract N02-HL-6- 4278. The provision of genotyping data was supported in part by UL1TR000124 (CTSI), and DK063491 (DRC).Computing resources were provided, in part, by the Wake Forest School of Medicine Center for Public Health Genomics. The authors thank the other investigators, the staff, and the participants of the studies for their valuable contributions.

Page 21 of 127 Diabetes

REFERENCES

1. Lorenzo C, Wagenknecht LE, D'Agostino RB, Jr., Rewers MJ, Karter AJ, Haffner SM: Insulin resistance, beta-cell dysfunction, and conversion to type 2 diabetes in a multiethnic population: the Insulin Resistance Atherosclerosis Study. Diabetes Care 33:67-72, 2010 2. Lee CC, Haffner SM, Wagenknecht LE, Lorenzo C, Norris JM, Bergman RN, Stefanovski D, Anderson AM, Rotter JI, Goodarzi MO, Hanley AJ: Insulin clearance and the incidence of type 2 diabetes in Hispanics and African Americans: the IRAS Family Study. Diabetes Care 36:901-907, 2013 3. Voight BF, Scott LJ, Steinthorsdottir V, Morris AP, Dina C, Welch RP, Zeggini E, Huth C, Aulchenko YS, Thorleifsson G, McCulloch LJ, Ferreira T, Grallert H, Amin N, Wu G, Willer CJ, Raychaudhuri S, McCarroll SA, Langenberg C, Hofmann OM, Dupuis J, Qi L, Segre AV, van Hoek M, Navarro P, Ardlie K, Balkau B, Benediktsson R, Bennett AJ, Blagieva R, Boerwinkle E, Bonnycastle LL, Bengtsson Bostrom K, Bravenboer B, Bumpstead S, Burtt NP, Charpentier G, Chines PS, Cornelis M, Couper DJ, Crawford G, Doney AS, Elliott KS, Elliott AL, Erdos MR, Fox CS, Franklin CS, Ganser M, Gieger C, Grarup N, Green T, Griffin S, Groves CJ, Guiducci C, Hadjadj S, Hassanali N, Herder C, Isomaa B, Jackson AU, Johnson PR, Jorgensen T, Kao WH, Klopp N, Kong A, Kraft P, Kuusisto J, Lauritzen T, Li M, Lieverse A, Lindgren CM, Lyssenko V, Marre M, Meitinger T, Midthjell K, Morken MA, Narisu N, Nilsson P, Owen KR, Payne F, Perry JR, Petersen AK, Platou C, Proenca C, Prokopenko I, Rathmann W, Rayner NW, Robertson NR, Rocheleau G, Roden M, Sampson MJ, Saxena R, Shields BM, Shrader P, Sigurdsson G, Sparso T, Strassburger K, Stringham HM, Sun Q, Swift AJ, Thorand B, Tichet J, Tuomi T, van Dam RM, van Haeften TW, van Herpt T, van Vliet-Ostaptchouk JV, Walters GB, Weedon MN, Wijmenga C, Witteman J, Bergman RN, Cauchi S, Collins FS, Gloyn AL, Gyllensten U, Hansen T, Hide WA, Hitman GA, Hofman A, Hunter DJ, Hveem K, Laakso M, Mohlke KL, Morris AD, Palmer CN, Pramstaller PP, Rudan I, Sijbrands E, Stein LD, Tuomilehto J, Uitterlinden A, Walker M, Wareham NJ, Watanabe RM, Abecasis GR, Boehm BO, Campbell H, Daly MJ, Hattersley AT, Hu FB, Meigs JB, Pankow JS, Pedersen O, Wichmann HE, Barroso I, Florez JC, Frayling TM, Groop L, Sladek R, Thorsteinsdottir U, Wilson JF, Illig T, Froguel P, van Duijn CM, Stefansson K, Altshuler D, Boehnke M, McCarthy MI: Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet 42:579-589, 2010 4. McCarthy MI: Genomics, type 2 diabetes, and obesity. N Engl J Med 363:2339-2350, 2010 5. DeFronzo RA: Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 37:667-687, 1988 6. Haffner SM, D'Agostino R, Saad MF, Rewers M, Mykkanen L, Selby J, Howard G, Savage PJ, Hamman RF, Wagenknecht LE, Bergman RN: Increased insulin resistance and insulin secretion in nondiabetic African-Americans and Hispanics compared with non-Hispanic whites. The Insulin Resistance Atherosclerosis Study. Diabetes 45:742-748, 1996 7. Rich SS, Bowden DW, Haffner SM, Norris JM, Saad MF, Mitchell BD, Rotter JI, Langefeld CD, Wagenknecht LE, Bergman RN: Identification of quantitative trait loci for glucose homeostasis: the Insulin Resistance Atherosclerosis Study (IRAS) Family Study. Diabetes 53:1866-1875, 2004 8. Watanabe RM, Valle T, Hauser ER, Ghosh S, Eriksson J, Kohtamaki K, Ehnholm C, Tuomilehto J, Collins FS, Bergman RN, Boehnke M: Familiality of quantitative metabolic traits in Finnish families with non-insulin-dependent diabetes mellitus. Finland-United States

Diabetes Page 22 of 127

Investigation of NIDDM Genetics (FUSION) Study investigators. Hum Hered 49:159-168, 1999 9. Goodarzi MO, Taylor KD, Guo X, Quinones MJ, Cui J, Li X, Hang T, Yang H, Holmes E, Hsueh WA, Olefsky J, Rotter JI: Variation in the gene for muscle-specific AMP deaminase is associated with insulin clearance, a highly heritable trait. Diabetes 54:1222-1227, 2005 10. Xiang AH, Azen SP, Raffel LJ, Tan S, Cheng LS, Diaz J, Toscano E, Henderson PC, Hodis HN, Hsueh WA, Rotter JI, Buchanan TA: Evidence for joint genetic control of insulin sensitivity and systolic blood pressure in hispanic families with a hypertensive proband. Circulation 103:78-83, 2001 11. Dupuis J, Langenberg C, Prokopenko I, Saxena R, Soranzo N, Jackson AU, Wheeler E, Glazer NL, Bouatia-Naji N, Gloyn AL, Lindgren CM, Magi R, Morris AP, Randall J, Johnson T, Elliott P, Rybin D, Thorleifsson G, Steinthorsdottir V, Henneman P, Grallert H, Dehghan A, Hottenga JJ, Franklin CS, Navarro P, Song K, Goel A, Perry JR, Egan JM, Lajunen T, Grarup N, Sparso T, Doney A, Voight BF, Stringham HM, Li M, Kanoni S, Shrader P, Cavalcanti-Proenca C, Kumari M, Qi L, Timpson NJ, Gieger C, Zabena C, Rocheleau G, Ingelsson E, An P, O'Connell J, Luan J, Elliott A, McCarroll SA, Payne F, Roccasecca RM, Pattou F, Sethupathy P, Ardlie K, Ariyurek Y, Balkau B, Barter P, Beilby JP, Ben-Shlomo Y, Benediktsson R, Bennett AJ, Bergmann S, Bochud M, Boerwinkle E, Bonnefond A, Bonnycastle LL, Borch-Johnsen K, Bottcher Y, Brunner E, Bumpstead SJ, Charpentier G, Chen YD, Chines P, Clarke R, Coin LJ, Cooper MN, Cornelis M, Crawford G, Crisponi L, Day IN, de Geus EJ, Delplanque J, Dina C, Erdos MR, Fedson AC, Fischer- Rosinsky A, Forouhi NG, Fox CS, Frants R, Franzosi MG, Galan P, Goodarzi MO, Graessler J, Groves CJ, Grundy S, Gwilliam R, Gyllensten U, Hadjadj S, Hallmans G, Hammond N, Han X, Hartikainen AL, Hassanali N, Hayward C, Heath SC, Hercberg S, Herder C, Hicks AA, Hillman DR, Hingorani AD, Hofman A, Hui J, Hung J, Isomaa B, Johnson PR, Jorgensen T, Jula A, Kaakinen M, Kaprio J, Kesaniemi YA, Kivimaki M, Knight B, Koskinen S, Kovacs P, Kyvik KO, Lathrop GM, Lawlor DA, Le Bacquer O, Lecoeur C, Li Y, Lyssenko V, Mahley R, Mangino M, Manning AK, Martinez-Larrad MT, McAteer JB, McCulloch LJ, McPherson R, Meisinger C, Melzer D, Meyre D, Mitchell BD, Morken MA, Mukherjee S, Naitza S, Narisu N, Neville MJ, Oostra BA, Orru M, Pakyz R, Palmer CN, Paolisso G, Pattaro C, Pearson D, Peden JF, Pedersen NL, Perola M, Pfeiffer AF, Pichler I, Polasek O, Posthuma D, Potter SC, Pouta A, Province MA, Psaty BM, Rathmann W, Rayner NW, Rice K, Ripatti S, Rivadeneira F, Roden M, Rolandsson O, Sandbaek A, Sandhu M, Sanna S, Sayer AA, Scheet P, Scott LJ, Seedorf U, Sharp SJ, Shields B, Sigurethsson G, Sijbrands EJ, Silveira A, Simpson L, Singleton A, Smith NL, Sovio U, Swift A, Syddall H, Syvanen AC, Tanaka T, Thorand B, Tichet J, Tonjes A, Tuomi T, Uitterlinden AG, van Dijk KW, van Hoek M, Varma D, Visvikis-Siest S, Vitart V, Vogelzangs N, Waeber G, Wagner PJ, Walley A, Walters GB, Ward KL, Watkins H, Weedon MN, Wild SH, Willemsen G, Witteman JC, Yarnell JW, Zeggini E, Zelenika D, Zethelius B, Zhai G, Zhao JH, Zillikens MC, Borecki IB, Loos RJ, Meneton P, Magnusson PK, Nathan DM, Williams GH, Hattersley AT, Silander K, Salomaa V, Smith GD, Bornstein SR, Schwarz P, Spranger J, Karpe F, Shuldiner AR, Cooper C, Dedoussis GV, Serrano-Rios M, Morris AD, Lind L, Palmer LJ, Hu FB, Franks PW, Ebrahim S, Marmot M, Kao WH, Pankow JS, Sampson MJ, Kuusisto J, Laakso M, Hansen T, Pedersen O, Pramstaller PP, Wichmann HE, Illig T, Rudan I, Wright AF, Stumvoll M, Campbell H, Wilson JF, Bergman RN, Buchanan TA, Collins FS, Mohlke KL, Tuomilehto J, Valle TT, Altshuler D, Rotter JI, Siscovick DS, Penninx BW, Boomsma

Page 23 of 127 Diabetes

DI, Deloukas P, Spector TD, Frayling TM, Ferrucci L, Kong A, Thorsteinsdottir U, Stefansson K, van Duijn CM, Aulchenko YS, Cao A, Scuteri A, Schlessinger D, Uda M, Ruokonen A, Jarvelin MR, Waterworth DM, Vollenweider P, Peltonen L, Mooser V, Abecasis GR, Wareham NJ, Sladek R, Froguel P, Watanabe RM, Meigs JB, Groop L, Boehnke M, McCarthy MI, Florez JC, Barroso I: New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 42:105-116, 2010 12. Manning AK, Hivert MF, Scott RA, Grimsby JL, Bouatia-Naji N, Chen H, Rybin D, Liu CT, Bielak LF, Prokopenko I, Amin N, Barnes D, Cadby G, Hottenga JJ, Ingelsson E, Jackson AU, Johnson T, Kanoni S, Ladenvall C, Lagou V, Lahti J, Lecoeur C, Liu Y, Martinez- Larrad MT, Montasser ME, Navarro P, Perry JR, Rasmussen-Torvik LJ, Salo P, Sattar N, Shungin D, Strawbridge RJ, Tanaka T, van Duijn CM, An P, de Andrade M, Andrews JS, Aspelund T, Atalay M, Aulchenko Y, Balkau B, Bandinelli S, Beckmann JS, Beilby JP, Bellis C, Bergman RN, Blangero J, Boban M, Boehnke M, Boerwinkle E, Bonnycastle LL, Boomsma DI, Borecki IB, Bottcher Y, Bouchard C, Brunner E, Budimir D, Campbell H, Carlson O, Chines PS, Clarke R, Collins FS, Corbaton-Anchuelo A, Couper D, de Faire U, Dedoussis GV, Deloukas P, Dimitriou M, Egan JM, Eiriksdottir G, Erdos MR, Eriksson JG, Eury E, Ferrucci L, Ford I, Forouhi NG, Fox CS, Franzosi MG, Franks PW, Frayling TM, Froguel P, Galan P, de Geus E, Gigante B, Glazer NL, Goel A, Groop L, Gudnason V, Hallmans G, Hamsten A, Hansson O, Harris TB, Hayward C, Heath S, Hercberg S, Hicks AA, Hingorani A, Hofman A, Hui J, Hung J, Jarvelin MR, Jhun MA, Johnson PC, Jukema JW, Jula A, Kao WH, Kaprio J, Kardia SL, Keinanen-Kiukaanniemi S, Kivimaki M, Kolcic I, Kovacs P, Kumari M, Kuusisto J, Kyvik KO, Laakso M, Lakka T, Lannfelt L, Lathrop GM, Launer LJ, Leander K, Li G, Lind L, Lindstrom J, Lobbens S, Loos RJ, Luan J, Lyssenko V, Magi R, Magnusson PK, Marmot M, Meneton P, Mohlke KL, Mooser V, Morken MA, Miljkovic I, Narisu N, O'Connell J, Ong KK, Oostra BA, Palmer LJ, Palotie A, Pankow JS, Peden JF, Pedersen NL, Pehlic M, Peltonen L, Penninx B, Pericic M, Perola M, Perusse L, Peyser PA, Polasek O, Pramstaller PP, Province MA, Raikkonen K, Rauramaa R, Rehnberg E, Rice K, Rotter JI, Rudan I, Ruokonen A, Saaristo T, Sabater-Lleal M, Salomaa V, Savage DB, Saxena R, Schwarz P, Seedorf U, Sennblad B, Serrano-Rios M, Shuldiner AR, Sijbrands EJ, Siscovick DS, Smit JH, Small KS, Smith NL, Smith AV, Stancakova A, Stirrups K, Stumvoll M, Sun YV, Swift AJ, Tonjes A, Tuomilehto J, Trompet S, Uitterlinden AG, Uusitupa M, Vikstrom M, Vitart V, Vohl MC, Voight BF, Vollenweider P, Waeber G, Waterworth DM, Watkins H, Wheeler E, Widen E, Wild SH, Willems SM, Willemsen G, Wilson JF, Witteman JC, Wright AF, Yaghootkar H, Zelenika D, Zemunik T, Zgaga L, Wareham NJ, McCarthy MI, Barroso I, Watanabe RM, Florez JC, Dupuis J, Meigs JB, Langenberg C: A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance. Nat Genet 44:659-669, 2012 13. Goodarzi MO, Langefeld CD, Xiang AH, Chen YD, Guo X, Hanley AJ, Raffel LJ, Kandeel F, Nadler JL, Buchanan TA, Norris JM, Fingerlin TE, Lorenzo C, Rewers MJ, Haffner SM, Bowden DW, Rich SS, Bergman RN, Rotter JI, Watanabe RM, Wagenknecht LE: Insulin sensitivity and insulin clearance are heritable and have strong genetic correlation in Mexican Americans. Obesity (Silver Spring) 22:1157-1164, 2014 14. Below JE, Gamazon ER, Morrison JV, Konkashbaev A, Pluzhnikov A, McKeigue PM, Parra EJ, Elbein SC, Hallman DM, Nicolae DL, Bell GI, Cruz M, Cox NJ, Hanis CL: Genome- wide association and meta-analysis in populations from Starr County, Texas, and Mexico

Diabetes Page 24 of 127

City identify type 2 diabetes susceptibility loci and enrichment for expression quantitative trait loci in top signals. Diabetologia 54:2047-2055, 2011 15. Williams AL, Jacobs SB, Moreno-Macias H, Huerta-Chagoya A, Churchhouse C, Marquez- Luna C, Garcia-Ortiz H, Jose Gomez-Vazquez M, Burtt NP, Aguilar-Salinas CA, Gonzalez- Villalpando C, Florez JC, Orozco L, Haiman CA, Tusie-Luna T, Altshuler D, Ripke S, Manning AK, Neale B, Reich D, Stram DO, Fernandez-Lopez JC, Romero-Hidalgo S, Patterson N, Aguilar-Delfin I, Martinez-Hernandez A, Centeno-Cruz F, Mendoza-Caamal E, Revilla-Monsalve C, Islas-Andrade S, Cordova E, Rodriguez-Arellano E, Soberon X, Gonzalez-Villalpando ME, Henderson BE, Monroe K, Wilkens L, Kolonel LN, Le Marchand L, Riba L, Ordonez-Sanchez ML, Rodriguez-Guillen R, Cruz-Bautista I, Rodriguez-Torres M, Munoz-Hernandez LL, Saenz T, Gomez D, Alvirde U, Onofrio RC, Brodeur WM, Gage D, Murphy J, Franklin J, Mahan S, Ardlie K, Crenshaw AT, Winckler W, Prufer K, Shunkov MV, Sawyer S, Stenzel U, Kelso J, Lek M, Sankararaman S, Macarthur DG, Derevianko AP, Paabo S, Gopal S, Grammatikos JA, Smith IC, Bullock KH, Deik AA, Souza AL, Pierce KA, Clish CB, Fennell T, Farjoun Y, Genomics Platform B, Gabriel S, Gross MD, Pereira MA, Seielstad M, Koh WP, Tai ES, Flannick J, Fontanillas P, Morris A, Teslovich TM, Atzmon G, Blangero J, Bowden DW, Chambers J, Shin Cho Y, Duggirala R, Glaser B, Hanis C, Kooner J, Laakso M, Lee JY, Ying Teo Y, Wilson JG, Puppala S, Farook VS, Thameem F, Abboud HE, Defronzo RA, Jenkinson CP, Lehman DM, Curran JE, Cortes ML: Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico. Nature, 2013 16. Cowie CC, Rust KF, Ford ES, Eberhardt MS, Byrd-Holt DD, Li C, Williams DE, Gregg EW, Bainbridge KE, Saydah SH, Geiss LS: Full accounting of diabetes and pre-diabetes in the U.S. population in 1988-1994 and 2005-2006. Diabetes Care 32:287-294, 2009 17. Henkin L, Bergman RN, Bowden DW, Ellsworth DL, Haffner SM, Langefeld CD, Mitchell BD, Norris JM, Rewers M, Saad MF, Stamm E, Wagenknecht LE, Rich SS: Genetic epidemiology of insulin resistance and visceral adiposity. The IRAS Family Study design and methods. Ann Epidemiol 13:211-217, 2003 18. Watanabe RM, Allayee H, Xiang AH, Trigo E, Hartiala J, Lawrence JM, Buchanan TA: Transcription factor 7-like 2 (TCF7L2) is associated with gestational diabetes mellitus and interacts with adiposity to alter insulin secretion in Mexican Americans. Diabetes 56:1481- 1485, 2007 19. Goodarzi MO, Guo X, Taylor KD, Quinones MJ, Samayoa C, Yang H, Saad MF, Palotie A, Krauss RM, Hsueh WA, Rotter JI: Determination and use of haplotypes: ethnic comparison and association of the lipoprotein lipase gene and coronary artery disease in Mexican- Americans. Genet Med 5:322-327, 2003 20. Wang Y-P, Kandeel F, Taylor KD, Hernandez D, Saad MF, Nadler JL, Raffel LJ: Insulin and blood pressure are linked to the LDL receptor-related protein locus on chromosome 12q (Abstract). Diabetes 49(Supp 1):A204, 2000 21. Buchanan TA, Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J, Ochoa C, Tan S, Berkowitz K, Hodis HN, Azen SP: Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. Diabetes 51:2796-2803, 2002 22. Pacini G, Bergman RN: MINMOD: a computer program to calculate insulin sensitivity and pancreatic responsivity from the frequently sampled intravenous glucose tolerance test. Comput Methods Programs Biomed 23:113-122, 1986

Page 25 of 127 Diabetes

23. DeFronzo RA, Tobin JD, Andres R: Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237:E214-223, 1979 24. Welch S, Gebhart SS, Bergman RN, Phillips LS: Minimal model analysis of intravenous glucose tolerance test-derived insulin sensitivity in diabetic subjects. J Clin Endocrinol Metab 71:1508-1518, 1990 25. Steil GM, Volund A, Kahn SE, Bergman RN: Reduced sample number for calculation of insulin sensitivity and glucose effectiveness from the minimal model. Suitability for use in population studies. Diabetes 42:250-256, 1993 26. Polonsky KS, Pugh W, Jaspan JB, Cohen DM, Karrison T, Tager HS, Rubenstein AH: C- peptide and insulin secretion. Relationship between peripheral concentrations of C-peptide and insulin and their secretion rates in the dog. J Clin Invest 74:1821-1829, 1984 27. Shen R, Fan JB, Campbell D, Chang W, Chen J, Doucet D, Yeakley J, Bibikova M, Wickham Garcia E, McBride C, Steemers F, Garcia F, Kermani BG, Gunderson K, Oliphant A: High-throughput SNP genotyping on universal bead arrays. Mutat Res 573:70-82, 2005 28. Gunderson KL, Steemers FJ, Ren H, Ng P, Zhou L, Tsan C, Chang W, Bullis D, Musmacker J, King C, Lebruska LL, Barker D, Oliphant A, Kuhn KM, Shen R: Whole-genome genotyping. Methods Enzymol 410:359-376, 2006 29. Grove ML, Yu B, Cochran BJ, Haritunians T, Bis JC, Taylor KD, Hansen M, Borecki IB, Cupples LA, Fornage M, Gudnason V, Harris TB, Kathiresan S, Kraaij R, Launer LJ, Levy D, Liu Y, Mosley T, Peloso GM, Psaty BM, Rich SS, Rivadeneira F, Siscovick DS, Smith AV, Uitterlinden A, van Duijn CM, Wilson JG, O'Donnell CJ, Rotter JI, Boerwinkle E: Best practices and joint calling of the HumanExome BeadChip: the CHARGE Consortium. PLoS One 8:e68095, 2013 30. Chen MH, Yang Q: GWAF: an R package for genome-wide association analyses with family data. Bioinformatics 26:580-581, 2010 31. Almasy L, Blangero J: Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet 62:1198-1211, 1998 32. Hanley AJ, Wagenknecht LE, Norris JM, Bryer-Ash M, Chen YI, Anderson AM, Bergman R, Haffner SM: Insulin resistance, beta cell dysfunction and visceral adiposity as predictors of incident diabetes: the Insulin Resistance Atherosclerosis Study (IRAS) Family study. Diabetologia 52:2079-2086, 2009 33. The Genotype-Tissue Expression (GTEx) project. Nat Genet 45:580-585, 2013 34. Rung J, Cauchi S, Albrechtsen A, Shen L, Rocheleau G, Cavalcanti-Proenca C, Bacot F, Balkau B, Belisle A, Borch-Johnsen K, Charpentier G, Dina C, Durand E, Elliott P, Hadjadj S, Jarvelin MR, Laitinen J, Lauritzen T, Marre M, Mazur A, Meyre D, Montpetit A, Pisinger C, Posner B, Poulsen P, Pouta A, Prentki M, Ribel-Madsen R, Ruokonen A, Sandbaek A, Serre D, Tichet J, Vaxillaire M, Wojtaszewski JF, Vaag A, Hansen T, Polychronakos C, Pedersen O, Froguel P, Sladek R: Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia. Nat Genet 41:1110-1115, 2009 35. Prokopenko I, Langenberg C, Florez JC, Saxena R, Soranzo N, Thorleifsson G, Loos RJ, Manning AK, Jackson AU, Aulchenko Y, Potter SC, Erdos MR, Sanna S, Hottenga JJ, Wheeler E, Kaakinen M, Lyssenko V, Chen WM, Ahmadi K, Beckmann JS, Bergman RN, Bochud M, Bonnycastle LL, Buchanan TA, Cao A, Cervino A, Coin L, Collins FS, Crisponi L, de Geus EJ, Dehghan A, Deloukas P, Doney AS, Elliott P, Freimer N, Gateva V, Herder C, Hofman A, Hughes TE, Hunt S, Illig T, Inouye M, Isomaa B, Johnson T, Kong A, Krestyaninova M, Kuusisto J, Laakso M, Lim N, Lindblad U, Lindgren CM, McCann OT,

Diabetes Page 26 of 127

Mohlke KL, Morris AD, Naitza S, Orru M, Palmer CN, Pouta A, Randall J, Rathmann W, Saramies J, Scheet P, Scott LJ, Scuteri A, Sharp S, Sijbrands E, Smit JH, Song K, Steinthorsdottir V, Stringham HM, Tuomi T, Tuomilehto J, Uitterlinden AG, Voight BF, Waterworth D, Wichmann HE, Willemsen G, Witteman JC, Yuan X, Zhao JH, Zeggini E, Schlessinger D, Sandhu M, Boomsma DI, Uda M, Spector TD, Penninx BW, Altshuler D, Vollenweider P, Jarvelin MR, Lakatta E, Waeber G, Fox CS, Peltonen L, Groop LC, Mooser V, Cupples LA, Thorsteinsdottir U, Boehnke M, Barroso I, Van Duijn C, Dupuis J, Watanabe RM, Stefansson K, McCarthy MI, Wareham NJ, Meigs JB, Abecasis GR: Variants in MTNR1B influence fasting glucose levels. Nat Genet 41:77-81, 2009 36. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447:661-678, 2007 37. Saxena R, Voight BF, Lyssenko V, Burtt NP, de Bakker PI, Chen H, Roix JJ, Kathiresan S, Hirschhorn JN, Daly MJ, Hughes TE, Groop L, Altshuler D, Almgren P, Florez JC, Meyer J, Ardlie K, Bengtsson Bostrom K, Isomaa B, Lettre G, Lindblad U, Lyon HN, Melander O, Newton-Cheh C, Nilsson P, Orho-Melander M, Rastam L, Speliotes EK, Taskinen MR, Tuomi T, Guiducci C, Berglund A, Carlson J, Gianniny L, Hackett R, Hall L, Holmkvist J, Laurila E, Sjogren M, Sterner M, Surti A, Svensson M, Tewhey R, Blumenstiel B, Parkin M, Defelice M, Barry R, Brodeur W, Camarata J, Chia N, Fava M, Gibbons J, Handsaker B, Healy C, Nguyen K, Gates C, Sougnez C, Gage D, Nizzari M, Gabriel SB, Chirn GW, Ma Q, Parikh H, Richardson D, Ricke D, Purcell S: Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316:1331-1336, 2007 38. Lyssenko V, Nagorny CL, Erdos MR, Wierup N, Jonsson A, Spegel P, Bugliani M, Saxena R, Fex M, Pulizzi N, Isomaa B, Tuomi T, Nilsson P, Kuusisto J, Tuomilehto J, Boehnke M, Altshuler D, Sundler F, Eriksson JG, Jackson AU, Laakso M, Marchetti P, Watanabe RM, Mulder H, Groop L: Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion. Nat Genet 41:82-88, 2009 39. Bergman RN, Ider YZ, Bowden CR, Cobelli C: Quantitative estimation of insulin sensitivity. Am J Physiol 236:E667-677, 1979 40. Ader M, Pacini G, Yang YJ, Bergman RN: Importance of glucose per se to intravenous glucose tolerance. Comparison of the minimal-model prediction with direct measurements. Diabetes 34:1092-1103, 1985 41. Bergman RN: Lilly lecture 1989. Toward physiological understanding of glucose tolerance. Minimal-model approach. Diabetes 38:1512-1527, 1989 42. Best JD, Kahn SE, Ader M, Watanabe RM, Ni TC, Bergman RN: Role of glucose effectiveness in the determination of glucose tolerance. Diabetes Care 19:1018-1030, 1996 43. Lorenzo C, Wagenknecht LE, Rewers MJ, Karter AJ, Bergman RN, Hanley AJ, Haffner SM: Disposition index, glucose effectiveness, and conversion to type 2 diabetes: the Insulin Resistance Atherosclerosis Study (IRAS). Diabetes Care 33:2098-2103, 2010 44. Mueckler M, Thorens B: The SLC2 (GLUT) family of membrane transporters. Mol Aspects Med 34:121-138, 2013 45. Watanabe RM: The genetics of insulin resistance: Where's Waldo? Curr Diab Rep 10:476- 484, 2010 46. Goodarzi MO, Cui J, Chen YD, Hsueh WA, Guo X, Rotter JI: Fasting insulin reflects heterogeneous physiologic processes: role of insulin clearance. Am J Physiol Endocrinol Metab 301:E402-408, 2011

Page 27 of 127 Diabetes

47. Saxena R, Hivert MF, Langenberg C, Tanaka T, Pankow JS, Vollenweider P, Lyssenko V, Bouatia-Naji N, Dupuis J, Jackson AU, Kao WH, Li M, Glazer NL, Manning AK, Luan J, Stringham HM, Prokopenko I, Johnson T, Grarup N, Boesgaard TW, Lecoeur C, Shrader P, O'Connell J, Ingelsson E, Couper DJ, Rice K, Song K, Andreasen CH, Dina C, Kottgen A, Le Bacquer O, Pattou F, Taneera J, Steinthorsdottir V, Rybin D, Ardlie K, Sampson M, Qi L, van Hoek M, Weedon MN, Aulchenko YS, Voight BF, Grallert H, Balkau B, Bergman RN, Bielinski SJ, Bonnefond A, Bonnycastle LL, Borch-Johnsen K, Bottcher Y, Brunner E, Buchanan TA, Bumpstead SJ, Cavalcanti-Proenca C, Charpentier G, Chen YD, Chines PS, Collins FS, Cornelis M, G JC, Delplanque J, Doney A, Egan JM, Erdos MR, Firmann M, Forouhi NG, Fox CS, Goodarzi MO, Graessler J, Hingorani A, Isomaa B, Jorgensen T, Kivimaki M, Kovacs P, Krohn K, Kumari M, Lauritzen T, Levy-Marchal C, Mayor V, McAteer JB, Meyre D, Mitchell BD, Mohlke KL, Morken MA, Narisu N, Palmer CN, Pakyz R, Pascoe L, Payne F, Pearson D, Rathmann W, Sandbaek A, Sayer AA, Scott LJ, Sharp SJ, Sijbrands E, Singleton A, Siscovick DS, Smith NL, Sparso T, Swift AJ, Syddall H, Thorleifsson G, Tonjes A, Tuomi T, Tuomilehto J, Valle TT, Waeber G, Walley A, Waterworth DM, Zeggini E, Zhao JH, Illig T, Wichmann HE, Wilson JF, van Duijn C, Hu FB, Morris AD, Frayling TM, Hattersley AT, Thorsteinsdottir U, Stefansson K, Nilsson P, Syvanen AC, Shuldiner AR, Walker M, Bornstein SR, Schwarz P, Williams GH, Nathan DM, Kuusisto J, Laakso M, Cooper C, Marmot M, Ferrucci L, Mooser V, Stumvoll M, Loos RJ, Altshuler D, Psaty BM, Rotter JI, Boerwinkle E, Hansen T, Pedersen O, Florez JC, McCarthy MI, Boehnke M, Barroso I, Sladek R, Froguel P, Meigs JB, Groop L, Wareham NJ, Watanabe RM: Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge. Nat Genet 42:142-148, 2010 48. Grarup N, Sparso T, Hansen T: Physiologic characterization of type 2 diabetes-related loci. Curr Diab Rep 10:485-497, 2010 49. Bergman RN, Prager R, Volund A, Olefsky JM: Equivalence of the insulin sensitivity index in man derived by the minimal model method and the euglycemic glucose clamp. J Clin Invest 79:790-800, 1987 50. Ernst J, Kheradpour P, Mikkelsen TS, Shoresh N, Ward LD, Epstein CB, Zhang X, Wang L, Issner R, Coyne M, Ku M, Durham T, Kellis M, Bernstein BE: Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 473:43-49, 2011 51. Kong AM, Speed CJ, O'Malley CJ, Layton MJ, Meehan T, Loveland KL, Cheema S, Ooms LM, Mitchell CA: Cloning and characterization of a 72-kDa inositol-polyphosphate 5- phosphatase localized to the Golgi network. J Biol Chem 275:24052-24064, 2000

Diabetes Page 28 of 127

Table 1. Clinical characteristics of the Discovery cohorts.

FSIGT Cohorts Clamp Cohorts

BetaGene TRIPOD IRAS IRAS Family HTN-IR MACAD NIDDM-Athero

Sample Size 1202 125 187 1034 694 752 182

Age (yr) 34.6±7.9 34.8±6.3 58.8±8.3 40.6±13.7 37.4±14.2 34.5±8.8 31.8±9.69

Women (%) 72.1 100.0 58.3 59.0 59.4 56.7 58.2

BMI (kg/m2) 29.5±6.1 30.6±5.4 28.9±5.1 28.3±5.7 28.8±5.5 28.9±5.1 28.6±6.3

-1 AIRg (µU ml min) 569±480 488±450 673±702 760±649 NA NA NA

-1 SG (min ) 0.0178±0.0067 0.0157±0.0041 0.0208±0.0088 0.0202±0.0091 NA NA NA

MCRI (L/min) 10.1±5.7 NA* 4.2±2.0 5.5±2.4 NA NA NA

MCRI (ml m-2 min-1) NA NA NA NA 458.2±111.8 471.8±116.3 416.2±140.3

-4 -1 -1 SI (x10 min µU ml) 3.03±1.63 2.57±1.79 1.33±1.24 2.14±1.86 NA NA NA

M (mol m-2 min-1) NA NA NA NA 1273±547 1364±646 1255±533

DI 1409±946 1004±724 1245±1184 1202±1236 NA NA NA

DI (mol m-2 min-1) NA NA NA NA NA† 136.8±100.2 93.23±54.4

Values are expressed as the mean and standard deviation unless otherwise indicated. *MCRI is not available for TRIPOD due to the use of tolbutamide in the FSIGT. †DI is not available for HTN-IR due to the lack of 30-minute insulin values from oral glucose tolerance testing. Abbreviations: NA, not available.

Page 29 of 127 Diabetes

Table 2. Top Discovery hits from the GUARDIAN Consortium ordered by trait.

SNP Chr Position* Gene Name Alleles† RAF‡ Trait Beta P-value rs2302063 19 3150418 GNA15 A/C 0.336 MCRI -0.29 7.31E-08

rs1602084 4 128843480 MFSD8 G/A 0.041 SI+M 8.97 5.20E-07

rs896232 2 2732877 MYT1L / TSSC1 T/C 0.291 SI+M -5.28 1.26E-06

rs6719442 2 2722295 MYT1L / TSSC1 A/G 0.184 SI+M -5.03 1.53E-06 § rs1978648 2 43371542 HAAO / ZFP36L2 / THADA T/C 0.324 SI 0.20 5.31E-07

rs896598 15 74036629 C15orf59 A/G 0.116 SI 0.37 5.83E-07

rs4887140 15 74046663 C15orf59 / TBC1D21 G/T 0.139 SI 0.31 6.91E-08

rs196701 6 80147187 HMGN3 / LCA5 C/T 0.132 SI -0.35 1.37E-06 rs10492494 13 74920186 KLF12 / LINC00347 A/C 0.240 M -22.02 5.04E-07 rs11683087 2 227586606 LOC646736 / IRS1|| G/A 0.412 M 20.54 7.42E-07 ¶ rs10830963 11 92708710 MTNR1B G/C 0.220 AIRg -2.76 5.23E-12 # rs1387153 11 92673828 FAT3 / MTNR1B T/C 0.220 AIRg -2.55 2.21E-09 ** rs2206734 6 20694884 CDKAL1 T/C 0.198 AIRg -2.05 1.02E-06 †† rs3847554 11 92668826 FAT3 / MTNR1B A/G 0.341 AIRg -1.64 1.08E-06 ‡‡ rs9368222 6 20686996 CDKAL1 A/C 0.264 AIRg -1.46 1.28E-06 rs6803803 3 180116563 PEX5L / TTC14 C/T 0.003 AIRg 17.53 1.64E-06 rs10830963 11 92708710 MTNR1B¶ G/C 0.230 DI -3.40 1.03E-11 rs1387153 11 92673828 FAT3 / MTNR1B# T/C 0.220 DI -3.20 1.32E-09 rs2149423 13 36772381 CCDC169-SOHLH2; SOHLH2 G/A 0.315 DI 2.18 3.67E-07 rs3812570 9 139275204 SNAPC4 A/C 0.461 DI -1.87 1.72E-06

rs523079 3 187615862 BCL6 / LPP T/C 0.069 SG 0.25 1.53E-07 §§ rs780093 2 27742603 GCKR T/C 0.341 SG 0.14 1.12E-06

rs788338 19 50778543 MYH14 C/T 0.287 SG -0.17 1.66E-06 Independent signals (r2<0.80) with evidence of association (P<2.00E-06) with the nearest annotated RefSeq gene(s) listed. *Build hg19, †Reference Allele/Other Allele, ‡Reference Allele Frequency, §Previously identified T2D locus (THADA rs7578597; r2=0.0079, ||Previously identified T2D locus (IRS1 rs2943641; r2=0.04), ¶Previously identified T2D locus (MTNR1B rs1387153; r2=0.69), #Previously identified T2D locus (MTNR1B rs1387153), **Previously identified T2D locus (CDKAL1 rs7754840; r2=0.42), ††Previously identified T2D locus (MTNR1B rs1387153; r2=0.54), ‡‡Previously identified T2D locus (CDKAL1 rs7754840; r2=0.72), §§Previously identified T2D locus (GCKR rs780094; r2=0.98)

Diabetes Page 30 of 127

Table 3. Top regions from GWAS of T2D-related quantitative traits with translation to T2D in Mexican-origin cohorts ordered by trait from the Discovery stage.

Discovery Cohorts Translation Cohorts Discovery and Translation Marker Chr Position* Gene Trait RA† RAF‡ Beta P-value OR (95% CI)§ P-value Meta-Analysis P-value rs7219451 17 38957002 KRT28 / KRT10 SI +M C 0.380 -6.80 3.92E-06 1.08 (1.00-1.16) 1.06E-02 3.97E-07 rs6815953 4 183109012 TENM3 SI +M T 0.431 4.10 3.14E-05 0.92 (0.86-0.99) 1.25E-02 2.47E-06 rs7581057 2 115958079 DPP10 SI +M G 0.056 -5.47 1.74E-04 1.29 (1.10-1.50) 6.67E-03 4.82E-06 rs322394 5 172157768 NEURL1B / DUSP1 M C 0.360 -15.83 3.38E-05 1.17 (1.09-1.26) 7.87E-04 1.12E-07 rs17060946 9 77808519 OSTF1 / PCSK5 M G 0.068 37.86 2.56E-06 0.87 (0.75-1.01) 6.89E-02 3.99E-06 rs13252932 8 25198091 DOCK5 M T 0.049 47.71 5.17E-06 0.89 (0.75-1.04) 6.61E-02 6.11E-06 || rs10830963 11 92708710 MTNR1B AIRg G 0.220 -2.76 5.23E-12 1.08 (1.00-1.18) 1.83E-01 5.86E-09 ¶ rs2206734 6 20694884 CDKAL1 AIRg T 0.194 -2.05 1.02E-06 1.19 (1.09-1.30) 1.41E-03 1.11E-08 # rs7018475 9 22137685 CDKN2B-AS1 / DMRTA1 AIRg G 0.323 -1.64 4.90E-06 1.09 (1.02-1.17) 2.34E-03 7.31E-08 ** rs1387153 11 92673828 MTNR1B AIRg T 0.220 -2.55 2.21E-09 1.07 (0.98-1.16) 1.97E-01 2.72E-07 rs2129969 11 45586169 PRDN11 / CHST1 AIRg G 0.477 1.14 2.10E-05 0.91 (0.85-0.98) 2.38E-02 4.10E-06 rs2053797 2 46370892 PRKCE AIRg A 0.162 1.89 5.02E-05 0.91 (0.83-1.00) 1.42E-02 4.21E-06 rs9553849 13 27082326 CDK8 / WASF3 AIRg A 0.199 1.57 6.70E-05 0.86 (0.79-0.94) 1.29E-02 4.70E-06 rs10870202 9 139257411 DNLZ AIRg T 0.430 -1.04 5.37E-05 1.12 (1.05-1.20) 2.08E-02 7.10E-06 rs10898909 11 72952496 P2RY2 AIRg A 0.404 1.41 4.03E-06 0.94 (0.86-1.02) 9.27E-02 8.64E-06 rs2237897 11 2858546 KCNQ1†† DI A 0.251 1.75 7.04E-06 0.73 (0.68-0.79) 1.89E-19 1.24E-21 rs4266763 9 139289825 SNAPC4 DI A 0.489 -2.00 3.46E-06 1.10 (1.03-1.18) 1.23E-02 4.34E-07 rs2064197 6 8998811 SLC35B3 / TFAP2A SG G 0.164 -0.19 7.23E-06 1.18 (1.08-1.30) 7.01E-04 2.56E-08 rs2291004 19 37997952 ZNF793 SG A 0.153 0.16 3.82E-05 0.89 (0.82-0.97) 9.88E-03 2.18E-06 ‡‡ rs1260326 2 27730940 GCKR SG T 0.335 0.13 4.04E-06 0.96 (0.89-1.03) 5.58E-02 3.99E-06 SNPs with evidence of association with the nearest annotated RefSeq gene(s) listed. *Build hg19, †Reference Allele, ‡Reference Allele Frequency, §Odds Ratio (OR) and 95% Confidence Interval (95% CI), ||Previously identified T2D locus (MTNR1B rs1387153, r2=0.69), ¶Previously identified T2D locus (CDKAL1 rs7754840, r2=0.42), #Previously identified T2D locus (CDKN2B rs7018475), **Previously identified T2D locus (MTNR1B rs1387153), ††Previously identified T2D locus (KCNQ1 rs2237892, r2=0.90; and KCNQ1 rs231362, r2=0.038), ‡‡Previously identified T2D locus (GCKR rs780094, r2=0.91)

Page 31 of 127 Diabetes

FIGURE LEGENDS

Figure 1. Genome-wide Manhattan plots for the GUARDIAN Discovery meta-analysis. a)

Metabolic Clearance Rate of Insulin (MCRI), b) Insulin Sensitivity (SI+M), c) SI, d) M, e) Acute Insulin Response (AIRg), f) Disposition Index (DI), g) Glucose Effectiveness (SG).

Figure 2. Regional plot of the MTNR1B locus in the GUARDIAN Discovery cohorts meta-

analysis. a) Disposition Index (DI) b) Acute Insulin Response (AIRg), and c) Insulin Sensitivity (SI). Genotyped SNPs passing quality control measures across all Discovery cohorts are plotted with their Discovery meta-analysis p-values (as -log10 values) as a function of genomic position (hg19). In each panel, the index variant is represented by a purple diamond. Color of additional variants indicates correlation with the index SNP (red, r2≥0.80; orange, 0.60≤r2<0.80; green, 0.40≤r2<0.60; blue, 0.20≤r2<0.40; white, r2<0.20; gray no r2 value available) based on pairwise r2 values from HapMap. Estimated recombination rates (taken from HapMap) are plotted to reflect the local LD structure. Gene annotations were taken from the University of California Santa Cruz genome browser.

Figure 3. Regional plots of loci attaining genome-wide significance (P<5.00x10-8) in the combined Discovery and Translation meta-analysis. a) KCNQ1 rs2237897 with DI/T2D, b)

MTNR1B rs10830963 with AIRg/T2D, c) CDKAL1 rs2206734 and AIRg/T2D d) 6p24.3 rs2064197 and SG/T2D. Genotyped SNPs passing quality control measures across all Discovery cohorts are plotted with their Discovery meta-analysis p-values (as -log10 values) as a function of genomic position (hg19). In each panel, the index variant from the Discovery cohort is represented by a purple circle and the Discovery and Translation meta-analysis is represented by a purple square. Color of additional variants indicates correlation with the index SNP (red, r2≥0.80; orange, 0.60≤r2<0.80; green, 0.40≤r2<0.60; blue, 0.20≤r2<0.40; white, r2<0.20; gray no r2 value available) based on pairwise r2 values from HapMap. Estimated recombination rates (taken from HapMap) are plotted to reflect the local LD structure. Gene annotations were taken from the University of California Santa Cruz genome browser.

Diabetes Page 32 of 127

Figure 1. a. MCRI GNA15

S +M I

MFSD8 MYT1L/TSSC1

S I HAAO/ZFP36L2/THADA C15orf59 HMGN3/LCA5

Page 33 of 127 Diabetes

d. M

LOC646736/IRS1 KLF12/LINC00347

AIRg MTNR1B

CDKAL1 PEX5L/TTC14

f. DI MTNR1B

SNAPC4 SOHLH2/CCDC169

Diabetes Page 34 of 127

BCL6/LPP GCKR MYH14

Page 35 of 127 Diabetes

Figure 2.

a. DI b. AIRg c. SI

Diabetes Page 36 of 127

Figure 3. a. b.

DI/T2D AIRg/T2D

c. d.

S /T2D AIRg/T2D G

Page 37 of 127 Diabetes

SUPPLEMENTARY MATERIALS

Page Supplementary Text …………………………………………………………………………………. 2 Discovery Cohort Descriptions ……………………………………………………………………. 2 Translational Cohort Descriptions …………………………………………………………………. 6 Clinical characteristics of the Translation cohorts ………………………………………………… 7 References …………………………………………………………………………………………. 8

Supplementary Table 1. Pearson’s correlation matrix for T2D-related quantitative traits in the Discovery cohorts. A) Euglycemic clamp cohorts including MACAD, HTN-IR, NIDDM-Athero and B) FSIGT cohorts including IRAS, IRAS Family, BetaGene, TRIPOD. …………………………...... 10

Supplementary Table 2. Top Discovery hits (P<1.00x10‐4) from the GUARDIAN Consortium. SNPs with evidence of association are tabulated by trait (a. MCRI, b. SI+M, c. SI, d. M, e. AIRg, f. DI, g. SG) in order of genomic position. ...…………………………………………………………...... 11

Supplementary Table 3. Top Discovery hits from the GUARDIAN Consortium ordered by trait. … 41

Supplementary Table 4. Top Discovery hits from the GUARDIAN Consortium ordered by trait with conditional analyses performed at loci with multiple signals of association or in close proximity to previously identified T2D loci. ……………………………………………………………………... 42

Supplementary Table 5. Association with reported type 2 diabetes (T2D) susceptibility loci (a. MCRI, b. SI+M, c. SI, d. M, e. AIRg, f. DI, and g. SG) in GUARDIAN Hispanic Americans (nmax=3,787). Index SNPs reaching genome‐wide significance (P<5.0E‐08) for association with T2D were selected from the NHGRI GWAS catalog. ……………………………………………………… 43

Supplementary Table 6. All SNPs from GWAS of T2D-related quantitative traits with Translation to T2D in Mexican-origin cohorts ordered by trait from the Discovery stage. ……………………….. 65

Supplementary Table 7. Top regions from GWAS of T2D-related quantitative traits with translation to T2D in Mexican-origin. ………………………………………………………………… 86

Supplementary Figure 1. Power to detect association with T2D (n=6,463 T2D cases and 9,232 controls) with an α of 5.00x10-8 at minor allele frequencies (MAF) ranging from 0.05-0.45. ……….. 89

Supplementary Figure 2. Regional plots of loci with evidence of association (P<2.00x10-6) in the Discovery meta-analysis. A) GNA15 rs2302063 with MCRI/T2D, B) MFSD8 rs1602084 with SI+M/T2D, C) MYT1L/TSSC1 rs896232 with SI+M/T2D, D) HAAO/SFP36L2/THADA rs1978648 with SI/T2D, E) C15orf59 rs4887140 with SI/T2D, F) HMGN3/LCA5 rs196701 with SI/T2D, G) KLF12/LINC00347 rs10492494 with M/T2D, H) LOC646736/IRS1 rs11683087 with M/T2D, I) MTNR1B rs10830963 with AIRg/T2D, J) CDKAL1 rs2206734 with AIRg/T2D, K) PEX5L/TTC14 rs6803803 with AIRg/T2D, L) SOHLH2 rs2149423 with DI/T2D, M) SNAPC4 rs3812570 with DI/T2D, N) BCL6/LPP rs523079 with SG/T2D, O) GCKR rs780093 with SG/T2D, and P) MYH14 rs788338 with SG/T2D. ……………………………………………………...... 91

1 Diabetes Page 38 of 127

SUPPLEMENTARY TEXT

Discovery Cohort Descriptions

BetaGene. BetaGene was a family study designed to identify genetic determinants of beta-cell function (1). BetaGene recruited non-diabetic women with a history of gestational diabetes mellitus (GDM), their adult family members, and women without history of GDM. GUARDIAN includes 1217 of these individuals in 390 pedigrees, 238 families of probands with previous GDM and 152 families of probands with normal pregnancies. Recruitment occurred in the Los Angeles area. Insulin sensitivity was obtained by FSIGT. Other phenotypes include OGTT and total body fat by DXA scan.

TRIPOD. The Troglitazone in the Prevention of Diabetes (TRIPOD) study was designed to address the impact of troglitazone treatment on -cell function and glucose levels in women with prior GDM (2). TRIPOD recruited non-diabetic women with history of GDM in the Los Angeles area; family members were not recruited. GUARDIAN includes baseline (pre-intervention) data from 217 of these individuals. Insulin sensitivity was obtained by tolbutamide-modified FSIGT. Other phenotypes include OGTT and carotid intima-media thickness by B-mode ultrasonography.

IRAS. The Insulin Resistance Atherosclerosis Study (IRAS) was an epidemiologic cohort study designed to examine the relationship between insulin resistance and carotid atherosclerosis across a range of glucose tolerance (3). Individuals of self-reported Mexican-American ethnicity were recruited in San Antonio, TX and San Luis Valley, CO. Recruitment was balanced across age and glucose tolerance status. GUARDIAN includes 194 individuals from the IRAS. Insulin sensitivity was obtained by FSIGT. Other phenotypes include OGTT and carotid intima-media thickness by B-mode ultrasonography.

IRAS Family Study. The Insulin Resistance Atherosclerosis Study (IRAS) Family Study was a family study designed to examine the genetic and epidemiologic basis of glucose homeostasis traits and abdominal adiposity; details of the IRAS Family Study are described elsewhere (4).

2 Page 39 of 127 Diabetes

Briefly, self-reported Mexican pedigrees were recruited in San Antonio, TX and San Luis Valley, CO. Probands with large families were recruited from the initial non-family-based IRAS Study (3), which was modestly enriched for impaired glucose tolerance and T2D. GUARDIAN includes 1040 individuals in 88 pedigrees from the IRAS Family Study. Insulin sensitivity was obtained by FSIGT. Other phenotypes include abdominal fat areas measured by computed tomography scan and total body fat by dual X-ray absorptiometry (DXA) scan.

HTN-IR. The Hypertension-Insulin Resistance Family Study (HTN-IR) was designed as a family study to examine the genetic basis of hypertension and insulin resistance (5). Family members of probands with documented hypertension were recruited in the Los Angeles area. GUARDIAN includes 708 of these individuals from 156 families. Insulin sensitivity was obtained by euglycemic clamp. Other phenotypes include OGTT, carotid intima-media thickness by B-mode ultrasonography, and salt sensitivity.

MACAD. The Mexican-American Coronary Artery Disease (MACAD) Study was designed as a family study to examine the genetic basis of coronary artery disease and insulin resistance (6). Family members of probands with documented coronary artery disease were recruited from the Los Angeles area. GUARDIAN includes 772 of these individuals from 208 families. Insulin sensitivity was obtained by euglycemic clamp. Other phenotypes include OGTT, carotid intima- media thickness by B-mode ultrasonography, total body fat by DXA scan, and post-heparin lipase activity assessment.

NIDDM-Athero. The NIDDM-Atherosclerosis Study was designed as a family study to examine the genetic basis of subclinical atherosclerosis and diabetes (7). Family members of probands with T2D were recruited in the Los Angeles area. GUARDIAN includes 188 of these individuals from 93 families. Insulin sensitivity was obtained by euglycemic clamp. Other phenotypes include OGTT and carotid intima-media thickness by B-mode ultrasonography.

3 Diabetes Page 40 of 127

Translation Cohort Descriptions

MESA. The Multi-Ethnic Study of Atherosclerosis (MESA) was initiated in 2000 to investigate the prevalence, correlates, and progression of subclinical cardiovascular disease (CVD) in a population-based sample of 6,814 men and women aged 45-84 years (8). Participant who were free of clinically apparent CVD were recruited from portions of 6 US communities: Baltimore City and Baltimore County, Maryland; Chicago, Illinois; Forsyth County, North Carolina; Los Angeles County, California; Northern Manhattan and the Bronx, New York; and St. Paul, Minnesota. Each field site recruited from locally available sources, which included lists of residents, lists of dwellings, and telephone exchanges. Twenty-two percent (1494) of the cohort is Hispanic; this analysis was limited to Hispanic participants who were classified as ‘Mexican’ via principal component analysis (all Caribbean Hispanics were excluded in this study). The PCA classified ‘Mexicans’ were mainly self-identified as Mexican, South America, or Central- American. Diabetes was defined as fasting glucose >126 mg/dL or use of hypoglycemic medication at baseline.

MESA Family. The MESA Family Study is an ancillary study to MESA. This study recruited family members specifically for genetic analysis. Participants in the MESA Family Study include 2,128 individuals from 528 families. Similarly, this analysis considers only those families classified as ‘Mexican’ via principal component analysis. Diabetes was defined as fasting glucose ≥126 mg/dL or use of insulin or hypoglycemic medication.

LALES. The Los Angeles Latino Eye Study (LALES) is a population-based study of 6357 Latinos, living in six census tracts in the city of La Puente, Los Angeles County, California (9). All subjects were 40 years of age and older. Written, informed consent was obtained from all participants. The data obtained from LALES have been used to document the prevalence, incidence, and impact of visual impairment in Latinos. GWAS data from 1,768 samples was used for in silico translation.

Starr County. The Starr County study participants were selected from genetic and epidemiological resources developed in the Mexican-American population in Starr County, TX (10). Diabetes was defined using the 1997 ADA criteria. Of 931 successfully genotyped case samples, 837 unrelated individuals were used for in silico translation. A representative type 2

4 Page 41 of 127 Diabetes

diabetes control sample was selected from a systematic survey of the primary population centers of Starr County conducted from 2002 to 2006.

WHI. The Women’s Health Initiative (WHI) consisted of multiple components including an observational study and clinical trial cohorts of postmenopausal women in the US (11). All participating institutions obtained Institutional Review Board approval. WHI SHARe included a total sample of 3,642 self-identified Mexican or Hispanic origin subjects from WHI, who had consented to genetic research. Type 2 diabetes was defined by self-report as ever being treated for diabetes (insulin shots or oral hypoglycemic medication) when participants were not pregnant. Medical histories were obtained at baseline and updates on disease status were obtained through self-administered questionnaires or contact with clinical staff every 6 months for the randomized clinical trial or annually for the observational study participants. Prevalent type 2 diabetes was identified from self-report in the baseline medical history. Incident type 2 diabetes was identified as first-time use of hypoglycemic medication after baseline. Both prevalent and incident cases were used for in silico translation.

SIGMA. The Slim Initiative in Genomic Medicine for the Americas (SIGMA) Type 2 Diabetes Consortium was conducted to characterize the genetic basis of type 2 diabetes in Mexican and other Latin American populations (12). Four cohorts contributed to the SIGMA GWAS. Diabetes in Mexico Study: A prospective cohort residing in Mexico City, Mexico, including 690 cases (defined as either a previous T2D diagnosis or fasting glucose levels above 125 mg/dL; individuals with fasting glycemia between 100-125 mg/dL were excluded) and 472 controls who were unrelated healthy subjects older than 45 years and with fasting glucose levels below 100 mg/dL. Mexico City Diabetes Study: A prospective cohort residing in Mexico City, Mexico, including 287 cases (defined using the ADA criteria, fasting glucose 126 mg/dL or more or 2 hr post 75 gr of glucose load 200 or more; in addition, a participant diagnosed as diabetic by a physician and under pharmacologic therapy for diabetes was considered as diabetic regardless the blood glucose levels) and 613 participants without diabetes ever as diagnosed by ADA criteria. UNAM/INCMNSZ Diabetes Study: A prospective cohort residing in Mexico City, Mexico, including 815 cases (defined in accordance with ADA criteria, fasting plasma glucose values ≥126 mg/dL, current treatment with a hypoglycemic agent, or casual glucose values ≥200 mg/dL) and 1,138 control subjects who were recruited from a cohort of adults aged 45 years or

5 Diabetes Page 42 of 127

older among government employees, blue collar workers and subjects seeking for attention in medical units for any condition besides those considered as exclusion criteria. Normoglycemic status was defined as having a fasting plasma glucose concentration < 100 mg/dl and no previous history of hyperglycemia, gestational diabetes or use of metformin. Multiethnic Cohort: A case- control study conducted in Los Angeles, California, USA, including 2056 cases defined as (a) a self-report of diabetes on the baseline questionnaire, 2nd questionnaire or 3rd questionnaire; and (b) self-report of taking medication for T2D at the time of blood draw; and (c) no diagnosis of T1D in the absence of a T2D diagnosis from the OSHPD (California Residents). Controls (n=2,143) were defined as: (a) no self-report of diabetes; (b) no use of medications for T2D at the time of blood draw; and (c) no diabetes diagnosis (type 1 or 2) from the OSHPD, Hawaii Medical Service Association (HMSA) or Kaiser Permanente Hawaii (KPH) registries.

6 Page 43 of 127 Diabetes

Clinical characteristics of the Translation cohorts.

Gender Age BMI Sample Size (% female) (range) (range) Genotyping Platform Case Control Case Control Case Control Case Control 57 37 31.7 29.6 Affy 6.0 Starr County, TX 805 340 60 70 (25-87) (26-77) (15.4-60.8) (18.4-55.3) Imputed to 1000G 62 60 34 29.4 Affy 6.0 MESA Family 81 304 62 56 (45-85) (41-90) (22.3-56.3) (17.3-50.1) Imputed to 1000G 64 61 31.6 29.2 Affy 6.0 MESA 221 886 47 52 (45-84) (44-84) (19.6-49.8) (17.6-52.5) Imputed to 1000G 60 60 31.5 28.3 Affy 6.0 WHI 614 2869 100 100 (50-78) (50-79) (18.4-55.3) (17.2-60.9) 58 60 32.4 29.2 Illumina OmniExpress LALES 894 467 57 50 (40-88) (40-92) (17.7–58.5) (14.6-52.1) 58 58 29.5 27.5 Illumina 2.5M SIGMA 3848* 4366* 57 57 (19-89) (34-94) (15.0-67.8) (11.0-57.4) Imputed to 1000G *47% of cases and 51% of controls from Mexico City, Mexico.

7 Diabetes Page 44 of 127

REFERENCES

1. Watanabe RM, Allayee H, Xiang AH, Trigo E, Hartiala J, Lawrence JM, Buchanan TA: Transcription factor 7-like 2 (TCF7L2) is associated with gestational diabetes mellitus and interacts with adiposity to alter insulin secretion in Mexican Americans. Diabetes 56:1481- 1485, 2007 2. Buchanan TA, Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J, Ochoa C, Tan S, Berkowitz K, Hodis HN, Azen SP: Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. Diabetes 51:2796-2803, 2002 3. Wagenknecht LE, Mayer EJ, Rewers M, Haffner S, Selby J, Borok GM, Henkin L, Howard G, Savage PJ, Saad MF, Bergman RN, Hamman R: The insulin resistance atherosclerosis study (IRAS) objectives, design, and recruitment results. Ann Epidemiol 5:464-472, 1995 4. Henkin L, Bergman RN, Bowden DW, Ellsworth DL, Haffner SM, Langefeld CD, Mitchell BD, Norris JM, Rewers M, Saad MF, Stamm E, Wagenknecht LE, Rich SS: Genetic epidemiology of insulin resistance and visceral adiposity. The IRAS Family Study design and methods. Ann Epidemiol 13:211-217, 2003 5. Xiang AH, Azen SP, Raffel LJ, Tan S, Cheng LS, Diaz J, Toscano E, Henderson PC, Hodis HN, Hsueh WA, Rotter JI, Buchanan TA: Evidence for joint genetic control of insulin sensitivity and systolic blood pressure in hispanic families with a hypertensive proband. Circulation 103:78-83, 2001 6. Goodarzi MO, Guo X, Taylor KD, Quinones MJ, Samayoa C, Yang H, Saad MF, Palotie A, Krauss RM, Hsueh WA, Rotter JI: Determination and use of haplotypes: ethnic comparison and association of the lipoprotein lipase gene and coronary artery disease in Mexican- Americans. Genet Med 5:322-327, 2003 7. Wang Y-P, Kandeel F, Taylor KD, Hernandez D, Saad MF, Nadler JL, Raffel LJ: Insulin and blood pressure are linked to the LDL receptor-related protein locus on chromosome 12q (Abstract). Diabetes 49(Supp 1):A204, 2000 8. Bild DE, Bluemke DA, Burke GL, Detrano R, Diez Roux AV, Folsom AR, Greenland P, Jacob DR, Jr., Kronmal R, Liu K, Nelson JC, O'Leary D, Saad MF, Shea S, Szklo M, Tracy RP: Multi-ethnic study of atherosclerosis: objectives and design. Am J Epidemiol 156:871- 881, 2002 9. Varma R, Paz SH, Azen SP, Klein R, Globe D, Torres M, Shufelt C, Preston-Martin S: The Los Angeles Latino Eye Study: design, methods, and baseline data. Ophthalmology 111:1121-1131, 2004 10. Below JE, Gamazon ER, Morrison JV, Konkashbaev A, Pluzhnikov A, McKeigue PM, Parra EJ, Elbein SC, Hallman DM, Nicolae DL, Bell GI, Cruz M, Cox NJ, Hanis CL: Genome- wide association and meta-analysis in populations from Starr County, Texas, and Mexico City identify type 2 diabetes susceptibility loci and enrichment for expression quantitative trait loci in top signals. Diabetologia 54:2047-2055, 2011 11. Design of the Women's Health Initiative clinical trial and observational study. The Women's Health Initiative Study Group. Control Clin Trials 19:61-109, 1998 12. Williams AL, Jacobs SB, Moreno-Macias H, Huerta-Chagoya A, Churchhouse C, Marquez- Luna C, Garcia-Ortiz H, Jose Gomez-Vazquez M, Burtt NP, Aguilar-Salinas CA, Gonzalez- Villalpando C, Florez JC, Orozco L, Haiman CA, Tusie-Luna T, Altshuler D, Ripke S, Manning AK, Neale B, Reich D, Stram DO, Fernandez-Lopez JC, Romero-Hidalgo S,

8 Page 45 of 127 Diabetes

Patterson N, Aguilar-Delfin I, Martinez-Hernandez A, Centeno-Cruz F, Mendoza-Caamal E, Revilla-Monsalve C, Islas-Andrade S, Cordova E, Rodriguez-Arellano E, Soberon X, Gonzalez-Villalpando ME, Henderson BE, Monroe K, Wilkens L, Kolonel LN, Le Marchand L, Riba L, Ordonez-Sanchez ML, Rodriguez-Guillen R, Cruz-Bautista I, Rodriguez-Torres M, Munoz-Hernandez LL, Saenz T, Gomez D, Alvirde U, Onofrio RC, Brodeur WM, Gage D, Murphy J, Franklin J, Mahan S, Ardlie K, Crenshaw AT, Winckler W, Prufer K, Shunkov MV, Sawyer S, Stenzel U, Kelso J, Lek M, Sankararaman S, Macarthur DG, Derevianko AP, Paabo S, Gopal S, Grammatikos JA, Smith IC, Bullock KH, Deik AA, Souza AL, Pierce KA, Clish CB, Fennell T, Farjoun Y, Genomics Platform B, Gabriel S, Gross MD, Pereira MA, Seielstad M, Koh WP, Tai ES, Flannick J, Fontanillas P, Morris A, Teslovich TM, Atzmon G, Blangero J, Bowden DW, Chambers J, Shin Cho Y, Duggirala R, Glaser B, Hanis C, Kooner J, Laakso M, Lee JY, Ying Teo Y, Wilson JG, Puppala S, Farook VS, Thameem F, Abboud HE, Defronzo RA, Jenkinson CP, Lehman DM, Curran JE, Cortes ML: Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico. Nature, 2013

9 Diabetes Page 46 of 127

A) MCRI M DI MCRI 0.172 0.14 M 0.423 DI

B) SI Sg AIRg DI MCRI SI 0.29436 -0.3181 0.421 0.6555 Sg 0.2193 0.5312 0.02974 AIRg 0.4597 -0.32868 DI 0.17068 MCRI

10 Page 47 of 127 Diabetes

Supplementary Table 2. Top Discovery hits (P<1.00x10‐4) from the GUARDIAN Consortium. SNPs with evidence of association are tabulated by

trait (a. MCRI, b. SI+M, c. SI, d. M, e. AIRg, f. DI, g. SG) in order of genomic position. For each SNP, position from Build hg19 is listed with the nearest annotated RefSeq gene.

11 Diabetes Page 48 of 127

a. MCRI (nmax=3,787)

Direction of Association Ref (BetaGene, HTN, Allele IRAS, IRASFS, Marker Chr Position Gene ref/nonref Freq β±SE Best model MACAD, NIDDM) Best p‐value rs4350219 1 19858807 T/C 0.244 0.24 ± 0.07 dom ++++++ 7.45E‐05 rs11247954 1 26741285 LIN28A A/G 0.179 0.26 ± 0.08 dom +++++‐ 9.76E‐05 rs2278979 1 26877708 RPS6KA1 A/G 0.405 0.31 ± 0.07 dom ++++++ 3.16E‐05 rs3790645 1 26884864 RPS6KA1 A/G 0.421 0.34 ± 0.07 dom ++++++ 6.07E‐06 rs1064196 1 26887592 RPS6KA1 C/T 0.424 0.34 ± 0.07 dom ++++++ 9.75E‐06 rs282177 1 26899125 RPS6KA1 T/C 0.451 0.34 ± 0.08 dom ++‐++? 3.30E‐05 rs6697598 1 241105515 RGS7 C/T 0.042 ‐0.60 ± 0.15 dom ‐‐‐‐‐? 1.88E‐05 rs6718111 2 8201262 LINC00299 C/T 0.487 ‐0.19 ± 0.05 add ‐‐‐‐‐‐ 9.33E‐05 rs1044280 2 8871342 KIDINS220 A/C 0.287 0.19 ± 0.07 dom ++++++ 6.97E‐05 rs7572039 2 31061392 T/G 0.078 0.36 ± 0.10 dom ++++++ 2.74E‐05 rs6745880 2 171105318 MYO3B G/A 0.138 ‐0.30 ± 0.09 dom ‐‐+‐‐‐ 7.34E‐05 rs13024014 2 173530946 T/C 0.023 ‐0.62 ± 0.19 dom ‐+‐‐‐? 9.17E‐05 rs11688831 2 199299078 A/G 0.384 ‐0.14 ± 0.05 add ‐‐‐‐‐‐ 7.08E‐05 rs6741187 2 222065721 T/C 0.010 2.15 ± 0.72 dom +?++?? 8.62E‐05 rs9847647 3 19813225 G/A 0.024 0.58 ± 0.18 dom +++++? 8.50E‐05 rs13321674 3 51704721 C/T 0.009 ‐1.57 ± 0.38 dom ‐?‐‐‐? 7.70E‐05 rs6444236 3 187225416 G/A 0.195 0.22 ± 0.07 dom ++++++ 8.73E‐05 rs16835397 4 4268642 T/C 0.018 ‐0.71 ± 0.21 dom ‐‐‐‐‐? 1.85E‐05 rs2124794 4 62290634 LPHN3 A/G 0.437 ‐0.15 ± 0.05 add ‐‐+‐‐‐ 5.27E‐05 rs6821028 4 62293449 LPHN3 A/C 0.376 ‐0.13 ± 0.05 add ‐‐‐‐‐‐ 1.03E‐04 rs6822279 4 99745705 C/A 0.406 ‐0.21 ± 0.06 add ‐?‐‐‐‐ 2.33E‐05 rs7728957 5 64505977 ADAMTS6 G/T 0.075 0.30 ± 0.10 dom +++++‐ 9.73E‐05 rs7726659 5 74478078 ANKRD31 G/A 0.015 ‐0.90 ± 0.25 dom ‐‐‐‐‐? 4.58E‐05 rs4957640 5 111601600 EPB41L4A C/T 0.048 ‐0.41 ± 0.14 dom ‐‐‐‐‐? 5.85E‐05 rs523848 6 15830025 A/G 0.467 0.20 ± 0.05 add ++++++ 3.48E‐05 rs220933 6 15845797 C/T 0.421 ‐0.19 ± 0.05 add ‐‐‐‐‐+ 9.83E‐05

12 Page 49 of 127 Diabetes

rs3749855 6 17283321 RBM24 G/T 0.057 ‐0.52 ± 0.12 dom ‐‐‐‐‐? 5.04E‐06 rs6938736 6 22441270 C/T 0.469 0.22 ± 0.05 add +++++? 7.64E‐05 rs13219760 6 110761189 SLC22A16 G/A 0.111 0.35 ± 0.09 dom +++++‐ 3.15E‐06 rs723685 6 110763875 SLC22A16 G/A 0.114 0.33 ± 0.09 dom +++++‐ 8.04E‐06 rs17166951 7 13302054 A/C 0.06 0.42 ± 0.12 dom +‐+++? 8.25E‐05 rs4629751 7 16825580 G/T 0.284 0.26 ± 0.07 dom ++++++ 9.58E‐05 rs10251809 7 32044030 PDE1C T/C 0.180 ‐0.25 ± 0.08 dom ‐‐‐‐‐‐ 4.28E‐05 rs1597137 8 464083 C8orf42 C/T 0.365 0.18 ± 0.05 add ++++++ 7.91E‐05 rs11136431 8 1791433 ARHGEF10 T/C 0.383 0.14 ± 0.05 add ++++++ 6.90E‐05 rs6651438 8 1794023 ARHGEF10 C/T 0.377 0.20 ± 0.06 add ++++?+ 9.10E‐05 rs13258014 8 4165460 CSMD1 T/C 0.392 0.26 ± 0.07 add +?+++? 7.99E‐05 rs4434590 8 100860657 VPS13B T/C 0.161 ‐0.29 ± 0.08 dom ‐‐‐‐‐‐ 8.09E‐05 rs6468694 8 100865836 VPS13B A/G 0.125 ‐0.34 ± 0.08 dom ‐‐‐‐‐‐ 2.13E‐05 rs4409375 8 100889987 A/C 0.143 ‐0.33 ± 0.08 dom ‐‐‐‐‐‐ 3.64E‐05 rs13253073 8 100897383 COX6C A/C 0.129 ‐0.35 ± 0.08 dom ‐‐‐‐‐‐ 5.89E‐06 rs12544943 8 100903890 COX6C G/A 0.129 ‐0.34 ± 0.08 dom ‐‐‐‐‐‐ 6.90E‐06 rs7851513 9 9842176 PTPRD A/C 0.129 0.38 ± 0.09 dom ++++++ 2.72E‐05 rs7025024 9 25816219 G/A 0.342 ‐0.18 ± 0.05 add ‐‐‐‐‐‐ 8.33E‐05 rs6602203 10 17596121 T/C 0.403 ‐0.32 ± 0.07 dom ‐‐‐‐‐‐ 4.80E‐06 rs10825203 10 55798117 PCDH15 A/C 0.268 0.23 ± 0.07 dom ++++++ 5.80E‐05 rs1911409 10 55806316 PCDH15 G/A 0.243 0.23 ± 0.07 dom ++++++ 5.05E‐05 rs716594 10 112006311 MXI1 A/G 0.019 ‐0.65 ± 0.21 dom ‐‐‐‐‐? 3.84E‐05 rs11016332 10 130363802 G/A 0.008 2.07 ± 0.49 dom +?++?? 4.72E‐05 rs7944706 11 10331311 A/G 0.285 0.31 ± 0.07 dom ++++++ 4.70E‐05 rs2449501 11 20044696 NAV2 G/A 0.198 ‐0.22 ± 0.07 dom ‐‐+‐‐‐ 1.27E‐05 rs16918932 11 29309078 G/T 0.003 3.45 ± 0.84 dom +??+?? 4.38E‐05 rs10400279 11 36270057 G/A 0.058 ‐0.31 ± 0.12 dom ‐‐‐‐‐? 8.87E‐05 rs7124 11 57174559 PRG2 A/G 0.003 8.24 ± 1.81 dom ??+??? 8.33E‐06 rs1784499 11 73359236 PLEKHB1 T/C 0.018 0.97 ± 0.22 dom +++++? 5.50E‐06 rs2510094 11 102981300 DYNC2H1 C/T 0.044 0.45 ± 0.14 dom +++++? 5.69E‐05 rs1334870 13 54838415 A/C 0.309 ‐0.26 ± 0.07 dom ‐‐‐‐‐+ 8.31E‐05 rs9565115 13 75269569 G/A 0.364 ‐0.22 ± 0.07 dom ‐‐‐‐‐? 9.23E‐05 rs9530368 13 75270057 C/A 0.358 ‐0.22 ± 0.07 dom ‐‐‐‐‐? 6.37E‐05

13 Diabetes Page 50 of 127

rs6576136 14 28737460 C/T 0.381 0.18 ± 0.06 add +++++? 9.18E‐05 rs2210313 14 40835874 G/A 0.085 0.32 ± 0.10 dom +++++? 1.01E‐04 rs2031271 14 42344822 LRFN5 C/A 0.158 0.23 ± 0.08 dom ++++++ 3.73E‐05 rs8003026 14 72482760 RGS6 G/T 0.003 3.07 ± 0.75 dom +?++?? 4.04E‐05 rs10147864 14 97919601 C/T 0.005 3.27 ± 0.86 dom +??+?? 6.21E‐05 rs637568 15 29692391 FAM189A1 G/A 0.027 ‐0.46 ± 0.17 dom ‐‐‐‐‐? 8.96E‐05 rs11853158 15 56364902 A/G 0.320 ‐0.18 ± 0.06 add ‐‐‐‐‐+ 6.96E‐05 rs2718934 15 56557418 G/A 0.466 ‐0.17 ± 0.05 add ‐‐+‐‐+ 2.50E‐05 rs8032549 15 56572176 G/A 0.328 ‐0.18 ± 0.05 add ‐‐‐‐‐+ 7.52E‐05 rs11857306 15 56746003 MNS1 C/A 0.341 ‐0.19 ± 0.05 add ‐‐‐‐‐+ 7.27E‐05 rs12441883 15 58456850 ALDH1A2 A/G 0.370 0.23 ± 0.07 dom +++++‐ 3.60E‐05 rs7172809 15 77819676 A/G 0.484 0.18 ± 0.05 add +++++? 9.20E‐06 rs2701405 15 87539918 AGBL1 A/C 0.486 ‐0.23 ± 0.06 add ‐‐‐‐?‐ 2.15E‐05 rs781856 17 3950224 ZZEF1 A/G 0.014 0.94 ± 0.25 dom +++++? 7.06E‐06 rs4790177 17 4067900 ANKFY1 T/C 0.012 0.95 ± 0.28 dom +++++? 4.21E‐05 rs2325989 17 4199320 UBE2G1 G/A 0.015 1.10 ± 0.26 dom ++++‐? 5.63E‐05 rs1986507 17 10082301 GAS7 A/G 0.152 ‐0.26 ± 0.08 dom ‐‐+‐‐‐ 9.92E‐05 rs4791426 17 10752513 A/G 0.098 ‐0.16 ± 0.09 dom ‐‐‐‐‐‐ 6.50E‐05 rs2274892 17 16852027 TNFRSF13B G/T 0.372 ‐0.16 ± 0.05 add ‐‐‐‐‐+ 7.67E‐05 rs16530 17 37357034 RPL19 T/C 0.099 ‐0.34 ± 0.09 dom ‐‐‐‐‐‐ 6.22E‐05 rs9912528 17 77387550 RBFOX3 C/T 0.150 0.27 ± 0.08 dom ++++++ 1.65E‐05 rs2339345 18 49957255 DCC A/C 0.343 ‐0.25 ± 0.06 add ‐‐‐‐‐? 7.80E‐06 rs11872993 18 71104519 T/C 0.006 ‐1.74 ± 0.49 dom ‐?‐+‐? 8.65E‐05 rs2276210 18 74587458 ZNF236 A/G 0.015 ‐0.89 ± 0.24 dom ‐‐‐‐‐? 9.92E‐05 rs3786947 19 3114229 GNA11 A/G 0.222 ‐0.28 ± 0.07 dom ‐‐‐‐‐+ 1.21E‐05 rs2302063 19 3150418 GNA15 A/C 0.336 ‐0.29 ± 0.07 dom ‐‐‐‐‐‐ 7.31E‐08 rs7247790 19 5311412 PTPRS G/T 0.185 ‐0.28 ± 0.08 dom ‐‐‐‐‐‐ 6.88E‐05

14 Page 51 of 127 Diabetes

b. SI+M (nmax=4,153)

Direction of Association (BetaGene, HTN, IRAS, IRASFS, Ref MACAD, Allele Best NIDDM, Best p‐ Marker Chr Position Gene ref/nonref Freq β±SE SI β±SE M model TRIPOD) value rs10492966 1 8598005 RERE T/C 0.258 0.10 ± 0.08 18.42 ± 5.67 dom +++++‐+ 1.01E‐04 rs3766466 1 54505437 TMEM59 A/C 0.047 ‐0.21 ± 0.16 ‐25.2 ± 9.4 dom ‐‐+‐‐0‐ 7.39E‐05 rs6685355 1 79458347 ELTD1 C/A 0.326 ‐0.13 ± 0.06 ‐18.36 ± 4.25 add +‐‐‐‐‐‐ 6.27E‐05 rs7411591 1 86683345 A/G 0.119 0.26 ± 0.10 13.79 ± 6.51 dom +++++‐+ 6.56E‐05 rs1507290 1 86684713 G/A 0.206 0.23 ± 0.09 11.58 ± 5.6 dom +++++‐+ 6.54E‐05 rs4658244 1 92069188 A/G 0.359 ‐0.06 ± 0.06 ‐13.2 ± 4.07 add ‐‐+‐‐‐‐ 9.64E‐05 rs1256941 1 201392764 TNNI1 A/C 0.128 0.33 ± 0.09 7.02 ± 6.36 dom +++++‐+ 9.52E‐05 rs9427477 1 202032235 T/G 0.345 ‐0.21 ± 0.06 ‐9.95 ± 4.09 add ‐‐‐‐‐‐‐ 1.03E‐04 rs6719442 2 2722295 A/G 0.185 ‐0.29 ± 0.08 ‐11.55 ± 5.87 dom ‐‐‐‐‐+‐ 1.53E‐06 rs896232 2 2732877 T/C 0.282 ‐0.2 ± 0.06 ‐12.27 ± 4.23 add ‐‐‐‐‐‐‐ 1.26E‐06 rs12620694 2 2763051 A/G 0.170 ‐0.38 ± 0.08 ‐12.42 ± 5.82 dom ‐‐‐‐‐+‐ 3.29E‐06 rs13411840 2 29973281 ALK C/A 0.046 ‐0.28 ± 0.16 ‐33.75 ± 8.94 dom ‐‐‐‐‐‐‐ 2.69E‐06 rs4233921 2 37354149 EIF2AK2 A/G 0.301 ‐0.12 ± 0.07 ‐13.79 ± 4.09 add ‐‐+‐‐‐‐ 2.11E‐06 rs1044158 2 85826132 TMEM150A A/G 0.303 ‐0.14 ± 0.08 ‐16.93 ± 5.39 dom ‐‐‐‐‐‐‐ 4.74E‐05 rs6733550 2 85828014 TMEM150A G/T 0.303 ‐0.13 ± 0.08 ‐17.47 ± 5.4 dom ‐‐‐‐‐‐‐ 5.44E‐05 rs207910 2 217018422 XRCC5 G/A 0.150 0.09 ± 0.09 17.1 ± 6.27 dom +++++++ 4.51E‐05 rs7426289 2 218966315 T/C 0.490 0.15 ± 0.06 11.06 ± 3.81 add ++++++‐ 5.47E‐05 rs6723449 2 218997580 CXCR2 C/T 0.474 0.15 ± 0.06 10.56 ± 3.82 add ++‐+++‐ 6.39E‐05 rs6767721 3 87630433 G/T 0.071 0.29 ± 0.12 14.74 ± 8 dom +++++++ 5.90E‐05 rs843532 3 196482211 PAK2 C/T 0.057 0.29 ± 0.12 29.38 ± 9.08 dom +++++++ 9.23E‐06 rs10007938 4 32452973 G/A 0.241 0.20 ± 0.08 15.78 ± 5.5 dom ++++++‐ 4.74E‐05 rs10023791 4 99425353 TSPAN5 A/G 0.426 0.15 ± 0.06 9.35 ± 3.86 add +‐+++++ 4.31E‐05 rs1602084 4 128843480 MFSD8 G/A 0.042 0.43 ± 0.16 20.7 ± 9.19 dom +++++++ 5.20E‐07

15 Diabetes Page 52 of 127

rs34766684 4 146023924 ABCE1 C/T 0.008 0.79 ± 0.3 43.66 ± 28.57 dom ++++00+ 5.11E‐05 rs6815953 4 183109012 ODZ3 T/G 0.431 0.19 ± 0.06 9.47 ± 3.97 add +++++++ 3.14E‐05 rs16894006 5 24833120 C/T 0.020 ‐0.48 ± 0.18 ‐31.85 ± 15.38 dom ‐‐‐‐‐0‐ 4.38E‐05 rs7732393 5 114018075 AK097686 C/T 0.087 0.30 ± 0.10 16.44 ± 7.86 dom +++++0‐ 4.40E‐05 rs7724522 5 142081559 C/T 0.038 ‐0.57 ± 0.13 ‐18.32 ± 11.87 dom ‐‐‐‐+0+ 5.11E‐05 rs29848 5 151449400 AK001582 T/G 0.328 0.17 ± 0.06 15.44 ± 4.21 add ++++++‐ 5.08E‐05 rs3129963 6 32380208 G/A 0.138 0.28 ± 0.09 22.25 ± 6.51 dom +++++++ 4.47E‐05 rs9268530 6 32383223 C/T 0.128 0.27 ± 0.09 23.44 ± 6.66 dom +++++++ 3.71E‐05 rs3135382 6 32383441 G/T 0.128 0.27 ± 0.09 23.09 ± 6.67 dom +++++++ 4.41E‐05 rs2001098 6 32383837 A/G 0.128 0.27 ± 0.09 23.51 ± 6.66 dom +++++++ 3.82E‐05 rs2001097 6 32383858 T/G 0.128 0.27 ± 0.09 23.45 ± 6.65 dom +++++++ 3.69E‐05 rs2227138 6 32384500 T/C 0.110 0.22 ± 0.10 24.9 ± 7 dom +++++++ 7.04E‐05 rs3135376 6 32385470 G/A 0.128 0.27 ± 0.09 23.45 ± 6.65 dom +++++++ 3.69E‐05 rs3135375 6 32385573 A/G 0.128 0.27 ± 0.09 23.41 ± 6.66 dom +++++++ 3.78E‐05 rs3135374 6 32385605 A/C 0.128 0.27 ± 0.09 23.45 ± 6.65 dom +++++++ 3.69E‐05 rs3135372 6 32385782 A/C 0.128 0.27 ± 0.09 23.45 ± 6.65 dom +++++++ 4.21E‐05 rs2187820 6 32385873 T/C 0.128 0.27 ± 0.09 23.46 ± 6.66 dom +++++++ 3.71E‐05 rs2395161 6 32387752 C/A 0.128 0.27 ± 0.09 23.45 ± 6.65 dom +++++++ 3.79E‐05 rs2395162 6 32387780 T/G 0.128 0.27 ± 0.09 23.45 ± 6.65 dom +++++++ 3.70E‐05 rs3135366 6 32388709 C/T 0.129 0.27 ± 0.09 23.27 ± 6.65 dom +++++++ 3.61E‐05 rs3135356 6 32391516 A/G 0.127 0.28 ± 0.09 20.36 ± 6.67 dom +++++++ 1.01E‐04 rs1041885 6 32412809 HLA‐DRA A/T 0.140 0.27 ± 0.09 20.45 ± 6.51 dom +++++++ 1.01E‐04 rs7749057 6 32448904 G/A 0.131 0.21 ± 0.09 21.37 ± 6.6 dom +++++++ 4.18E‐05 rs7785730 7 28096199 JAZF1 G/A 0.131 ‐0.17 ± 0.09 ‐17.84 ± 6.61 dom ‐‐‐‐‐+‐ 8.23E‐05 rs24003 7 30748323 INMT C/T 0.471 ‐0.14 ± 0.06 ‐12.91 ± 4.15 add ‐‐‐‐‐0+ 6.24E‐05 rs2726051 7 36155071 C/A 0.223 0.25 ± 0.08 14.29 ± 5.53 dom +++++++ 5.27E‐05 rs17141982 7 70133502 AUTS2 T/C 0.340 0.20 ± 0.08 9.1 ± 5.58 dom ++++++‐ 9.89E‐05 rs10268984 7 98963340 ARPC1A T/C 0.103 ‐0.20 ± 0.10 ‐16.38 ± 7.12 dom ‐‐‐‐‐‐‐ 5.59E‐05 rs3177186 7 98984399 ARPC1A T/C 0.105 ‐0.19 ± 0.10 ‐16.45 ± 7.12 dom ‐‐‐‐‐‐‐ 6.58E‐05 rs7799219 7 123895098 EU233817 T/C 0.228 0.24 ± 0.08 14.82 ± 5.58 dom +++++++ 6.95E‐05 rs12682418 8 62891832 A/G 0.065 0.24 ± 0.12 25.42 ± 8.47 dom +++++++ 1.01E‐04 rs12675420 8 62924308 T/C 0.069 0.27 ± 0.12 23.61 ± 8.33 dom +++++++ 8.87E‐05 rs6475448 9 20497142 MLLT3 G/A 0.303 ‐0.06 ± 0.06 ‐18.68 ± 4.43 add ‐‐‐+‐0‐ 3.31E‐05

16 Page 53 of 127 Diabetes

rs10966384 9 24672959 C/T 0.057 ‐0.24 ± 0.12 ‐23.3 ± 9.47 dom ‐‐‐‐‐‐‐ 9.06E‐05 rs4817 9 33917498 UBE2R2 C/T 0.314 ‐0.14 ± 0.06 ‐8.04 ± 4.3 add ‐‐‐‐‐‐+ 7.96E‐05 rs10739874 9 105991203 BC035187 C/T 0.092 0.22 ± 0.10 27.16 ± 8.11 dom +++++0+ 1.00E‐04 rs4837024 9 128739400 T/C 0.465 0.16 ± 0.09 22.18 ± 5.96 dom +++++++ 8.73E‐05 rs10904919 10 17334745 T/C 0.374 ‐0.27 ± 0.06 ‐10.32 ± 10.74 add ‐0‐‐0‐‐ 1.03E‐04 rs2688789 10 17733014 STAM G/A 0.419 ‐0.08 ± 0.06 ‐14.73 ± 3.84 add ‐‐‐+‐‐‐ 9.47E‐05 rs12413935 10 85453920 G/T 0.020 ‐0.73 ± 0.23 ‐44.19 ± 19.71 dom ‐‐‐‐00+ 4.11E‐05 rs1223629 10 95906315 PLCE1 A/G 0.039 ‐0.74 ± 0.17 ‐17.55 ± 11.1 dom ‐‐‐‐‐0‐ 3.05E‐06 rs10870303 10 134191811 LRRC27 G/A 0.429 ‐0.13 ± 0.06 ‐4.07 ± 3.89 add ‐‐+‐+‐‐ 1.02E‐04 rs10160242 11 108498885 C/T 0.058 0.41 ± 0.11 5.25 ± 9.53 dom +‐+++0+ 6.26E‐05 rs948178 11 113195595 TTC12 A/G 0.337 0.21 ± 0.08 13.09 ± 5.42 dom +++++++ 9.43E‐05 rs3781827 11 121411041 SORL1 G/A 0.434 0.10 ± 0.06 10.77 ± 5.33 add +0++++‐ 6.12E‐05 rs1479451 12 23836547 SOX5 A/C 0.199 0.21 ± 0.08 10.02 ± 5.65 dom +++++++ 3.79E‐05 rs11180162 12 75081042 C/T 0.189 0.20 ± 0.08 7.9 ± 5.74 dom +++++‐+ 8.30E‐05 rs11108203 12 96100594 NTN4 T/C 0.069 ‐0.47 ± 0.12 ‐17.93 ± 8.36 dom ‐‐‐‐‐0‐ 4.07E‐05 rs10860482 12 100038835 ANKS1B C/T 0.372 0.09 ± 0.06 13.33 ± 4.09 add +++++++ 9.80E‐05 rs7974375 12 118585698 T/G 0.104 ‐0.13 ± 0.10 ‐23.88 ± 6.93 dom ‐‐+‐‐‐+ 8.96E‐05 rs17512574 12 118788003 TAOK3 T/C 0.110 ‐0.08 ± 0.09 ‐29.28 ± 6.72 dom ‐‐+‐‐‐+ 3.19E‐05 rs673078 12 118791441 TAOK3 C/A 0.125 ‐0.08 ± 0.09 ‐30.26 ± 6.55 dom ‐‐+‐‐‐+ 4.71E‐06 rs884844 12 118814838 SUDS3 T/C 0.113 ‐0.07 ± 0.09 ‐28.67 ± 6.67 dom ‐‐+‐‐‐+ 6.71E‐05 rs7305647 12 118855566 SUDS3 A/G 0.105 ‐0.08 ± 0.09 ‐29.15 ± 6.88 dom ‐‐+‐‐‐+ 5.90E‐05 rs4772128 13 99385553 SLC15A1 A/G 0.029 ‐0.51 ± 0.18 ‐20.52 ± 12.21 dom ‐‐‐‐‐0‐ 5.57E‐05 rs12717423 14 52940827 TXNDC16 G/A 0.253 ‐0.21 ± 0.08 ‐10.05 ± 5.5 dom ‐‐‐‐‐‐‐ 3.87E‐05 rs10129385 14 52959478 TXNDC16 C/T 0.253 ‐0.21 ± 0.08 ‐9.92 ± 5.48 dom ‐‐‐‐‐‐‐ 5.48E‐05 rs2617235 15 42758738 ZFP106 C/T 0.366 0.14 ± 0.06 14.3 ± 4.02 add +++++++ 9.05E‐05 rs10454039 15 42832534 C/T 0.429 0.14 ± 0.06 13.79 ± 3.94 add +++++++ 7.78E‐06 rs10851411 15 42859235 HAUS2 T/G 0.428 0.14 ± 0.06 12.78 ± 3.93 add +++++++ 5.64E‐06 rs2241998 15 42869028 STARD9 A/G 0.417 0.12 ± 0.06 11.94 ± 3.93 add +++++++ 7.70E‐05 rs7497796 15 55136506 A/C 0.376 0.17 ± 0.08 21.92 ± 5.65 dom +++++++ 2.63E‐05 rs12438945 15 55226570 C/A 0.230 0.19 ± 0.08 23.49 ± 5.54 dom +++++++ 5.38E‐05 rs11631474 15 67934167 MAP2K5 G/A 0.262 ‐0.24 ± 0.08 ‐6.71 ± 5.56 dom ‐‐‐‐‐+‐ 3.72E‐05 rs884202 15 68054388 MAP2K5 A/G 0.381 ‐0.10 ± 0.06 ‐8.87 ± 4.16 add ‐‐‐‐‐‐‐ 9.64E‐05 rs7178383 15 99159956 C/T 0.332 ‐0.16 ± 0.08 ‐19.57 ± 5.48 dom ‐‐‐‐‐‐+ 8.42E‐05

17 Diabetes Page 54 of 127

rs4624233 17 38955961 KRT28 A/G 0.137 ‐0.28 ± 0.09 ‐17.68 ± 6.28 dom ‐‐‐‐+‐+ 2.46E‐05 rs7219451 17 38957002 C/T 0.380 ‐0.17 ± 0.06 ‐15.91 ± 4.04 add ‐‐‐‐‐‐+ 3.92E‐06 rs10558 17 38991003 TMEM99 C/T 0.138 ‐0.31 ± 0.09 ‐16.19 ± 6.25 dom ‐‐‐‐+‐+ 1.48E‐05 rs9303297 17 39005990 T/C 0.138 ‐0.31 ± 0.09 ‐17.14 ± 6.28 dom ‐‐‐‐+‐+ 9.98E‐06 rs3760333 17 39023875 C/T 0.173 ‐0.31 ± 0.09 ‐13.41 ± 5.81 dom ‐‐‐‐+‐‐ 2.09E‐05 rs2291447 17 43212963 ACBD4 T/G 0.346 ‐0.24 ± 0.06 ‐10.49 ± 4.16 add ‐‐‐‐‐‐‐ 7.95E‐05 rs2192990 17 68801676 A/C 0.122 0.12 ± 0.10 15.54 ± 6.44 dom +++++++ 1.04E‐04 rs691336 17 76518426 DNAH17 T/C 0.263 ‐0.27 ± 0.08 ‐7.68 ± 5.54 dom ‐‐‐‐+‐‐ 2.77E‐05 rs759635 19 3351890 C/T 0.460 0.20 ± 0.06 12.32 ± 3.92 add +++++++ 1.20E‐05 rs3108582 19 37221835 G/A 0.293 0.21 ± 0.08 17.6 ± 5.5 dom +++++++ 1.01E‐04 rs6133145 20 4576230 A/C 0.400 0.15 ± 0.08 13.34 ± 6.02 dom +++++0‐ 4.52E‐05 rs6139486 20 4578080 A/G 0.366 0.14 ± 0.08 12.06 ± 5.52 dom ++++++‐ 7.29E‐05 rs6075733 20 20856254 C/T 0.346 ‐0.06 ± 0.06 ‐18.29 ± 4.13 add ‐‐+‐‐‐‐ 3.40E‐05 rs8130631 21 35535498 T/C 0.101 0.26 ± 0.10 16.36 ± 7.38 dom +++++0+ 5.21E‐05 rs1061325 22 19184095 CLTCL1 C/T 0.451 0.12 ± 0.10 ‐13.72 ± 9.23 rec ‐‐‐‐00‐ 9.96E‐05

18 Page 55 of 127 Diabetes

c. SI (nmax=2,549)

Direction of Association (BetaGene, IRAS, Ref Allele IRASFS, Best p‐ Marker Chr Position Gene ref/nonref Freq β±SE Best model TRIPOD) value rs880554 1 19954014 MINOS1 T/G 0.278 0.21 ± 0.08 dom +‐++ 3.87E‐05 rs17385225 1 164475201 A/G 0.134 0.28 ± 0.10 dom ++++ 4.87E‐05 rs1256941 1 201392764 TNNI1 A/C 0.126 0.33 ± 0.09 dom ++++ 1.03E‐04 rs6719442 2 2722295 A/G 0.18 ‐0.29 ± 0.08 dom ‐‐‐‐ 1.53E‐05 rs12620694 2 2763051 A/G 0.162 ‐0.38 ± 0.08 dom ‐‐‐‐ 3.42E‐05 rs1978648 2 43371542 T/C 0.328 0.2 ± 0.06 add ++++ 5.31E‐07 rs4952971 2 43373119 A/G 0.438 0.18 ± 0.06 add ++++ 2.31E‐05 rs10167465 2 43397176 G/A 0.419 0.19 ± 0.06 add ++++ 9.30E‐05 rs12464602 2 43397614 G/A 0.424 0.38 ± 0.10 rec ++++ 7.28E‐06 rs1044710 2 211297355 LANCL1 A/G 0.395 ‐0.2 ± 0.06 add ‐‐‐‐ 8.93E‐05 rs6782551 3 74922055 A/G 0.014 0.57 ± 0.22 dom ++++ 9.04E‐05 rs1872552 3 85049088 CADM2 A/G 0.444 ‐0.20 ± 0.06 add ‐‐‐‐ 8.59E‐05 rs716975 4 38349236 T/C 0.226 ‐0.27 ± 0.08 dom ‐‐‐‐ 9.86E‐06 rs7690543 4 68056613 T/C 0.177 0.28 ± 0.09 dom ++++ 2.34E‐06 rs1848056 4 125755019 T/C 0.484 0.09 ± 0.06 add +‐++ 3.21E‐05 rs9997902 4 125763629 A/G 0.49 0.10 ± 0.06 add +‐++ 2.29E‐05 rs1602084 4 128843480 MFSD8 G/A 0.038 0.43 ± 0.16 dom ++++ 3.10E‐06 rs11943562 4 167652786 C/T 0.130 ‐0.25 ± 0.09 dom ‐‐‐+ 6.27E‐05 rs17069175 4 181226698 A/G 0.241 ‐0.27 ± 0.08 dom ‐‐‐‐ 7.04E‐05 rs6868526 5 5399472 C/T 0.188 0.27 ± 0.09 dom +++‐ 2.22E‐05 rs16875556 5 5402163 A/G 0.167 0.26 ± 0.09 dom +++‐ 3.47E‐05 rs7717247 5 27839258 C/A 0.136 ‐0.33 ± 0.09 dom ‐‐‐+ 4.16E‐05 rs462647 5 81080808 C/T 0.334 0.32 ± 0.08 dom ++++ 8.79E‐05 rs6880017 5 81185254 G/A 0.314 ‐0.17 ± 0.06 add ‐‐‐+ 7.51E‐05 rs17155849 5 103142399 T/C 0.290 ‐0.29 ± 0.08 dom ‐‐‐‐ 7.13E‐05

19 Diabetes Page 56 of 127

rs1898910 5 124555847 A/C 0.161 ‐0.38 ± 0.09 dom ‐‐‐+ 6.60E‐06 rs1042711 5 148206348 SH3TC2 C/T 0.212 0.31 ± 0.08 dom ++++ 9.07E‐05 rs12194985 6 6892411 T/G 0.032 ‐0.40 ± 0.17 dom ‐‐‐‐ 8.50E‐05 rs10080664 6 15864284 A/G 0.384 0.15 ± 0.06 add ++++ 9.95E‐05 rs4716224 6 18161563 KDM1B A/G 0.306 ‐0.19 ± 0.08 dom ‐‐‐‐ 9.37E‐05 rs724941 6 76723011 IMPG1 C/T 0.446 0.17 ± 0.06 add +++‐ 9.34E‐05 rs2148261 6 76736996 IMPG1 T/C 0.449 0.15 ± 0.06 add ++++ 3.41E‐05 rs943086 6 76755221 IMPG1 G/A 0.449 0.15 ± 0.06 add ++++ 6.49E‐05 rs196705 6 80138778 T/C 0.123 ‐0.36 ± 0.10 dom ‐‐‐+ 9.35E‐06 rs196701 6 80147187 C/T 0.128 ‐0.35 ± 0.10 dom ‐‐‐‐ 1.37E‐06 rs17062582 6 133789961 EYA4 A/G 0.144 ‐0.18 ± 0.09 dom ‐‐‐‐ 1.02E‐04 rs7803642 7 21641629 DNAH11 T/C 0.321 ‐0.18 ± 0.06 add ‐‐‐‐ 9.92E‐05 rs9406428 9 11463799 C/T 0.132 0.33 ± 0.09 dom ++++ 7.63E‐05 rs10964496 9 20248264 A/G 0.091 0.34 ± 0.10 dom +++‐ 5.14E‐05 rs10811340 9 20283406 G/A 0.098 0.27 ± 0.10 dom +++‐ 7.35E‐05 rs1581979 9 23407435 C/A 0.310 ‐0.18 ± 0.06 add ‐‐‐‐ 8.14E‐05 rs10780305 9 81978708 A/G 0.431 0.15 ± 0.06 add ++++ 8.69E‐06 rs10867395 9 82118185 C/T 0.304 0.13 ± 0.08 dom ++++ 6.04E‐05 rs1885984 9 119078249 PAPPA T/C 0.009 ‐0.79 ± 0.25 dom ‐?‐‐ 9.14E‐05 rs2819042 10 10230151 A/C 0.455 ‐0.18 ± 0.06 add ‐‐‐‐ 1.38E‐05 rs2819039 10 10232363 C/T 0.456 ‐0.19 ± 0.06 add ‐‐‐‐ 1.61E‐05 rs359297 10 17333680 A/G 0.213 ‐0.28 ± 0.08 dom ‐‐‐‐ 5.10E‐05 rs11817459 10 17594247 G/T 0.396 ‐0.14 ± 0.06 add ‐‐‐‐ 7.01E‐05 rs12256421 10 17614097 A/G 0.387 ‐0.2 ± 0.06 add ‐‐‐‐ 9.07E‐05 rs945296 10 26704514 C/T 0.305 0.2 ± 0.06 add ++++ 1.02E‐04 rs1223629 10 95906315 PLCE1 A/G 0.038 ‐0.74 ± 0.17 dom ‐‐‐‐ 4.72E‐06 rs10870301 10 134186772 LRRC27 C/T 0.435 ‐0.12 ± 0.06 add ‐+‐‐ 7.93E‐05 rs4443996 10 134191005 LRRC27 C/A 0.441 ‐0.11 ± 0.06 add ‐+‐‐ 9.70E‐05 rs10870302 10 134191738 LRRC27 T/G 0.436 ‐0.13 ± 0.06 add ‐+‐‐ 9.64E‐05 rs10870303 10 134191811 LRRC27 G/A 0.436 ‐0.13 ± 0.06 add ‐+‐‐ 6.94E‐05 rs4568920 10 134324451 T/C 0.077 ‐0.29 ± 0.12 dom ‐+‐‐ 7.13E‐05 rs7117567 11 7715079 OVCH2 G/A 0.356 ‐0.21 ± 0.06 add ‐‐‐‐ 8.87E‐05 rs121704 11 17904634 SERGEF G/A 0.474 0.15 ± 0.06 add +++‐ 5.97E‐05

20 Page 57 of 127 Diabetes

rs10160242 11 108498885 C/T 0.060 0.41 ± 0.11 dom ++++ 4.33E‐06 rs2368785 12 260682 IQSEC3 C/T 0.150 0.19 ± 0.09 dom +‐++ 4.51E‐05 rs1947234 12 39450491 A/C 0.197 0.13 ± 0.08 dom ++++ 7.83E‐05 rs7136587 12 39487541 A/G 0.136 0.17 ± 0.09 dom +‐++ 1.01E‐04 rs10785139 12 75089475 C/T 0.307 0.19 ± 0.06 add ++++ 5.31E‐05 rs9554019 13 27951711 A/G 0.061 ‐0.36 ± 0.13 dom ‐‐‐‐ 2.76E‐05 rs17376318 13 108013050 FAM155A C/T 0.119 ‐0.41 ± 0.10 dom ‐‐‐‐ 4.00E‐05 rs9559508 13 109805793 MYO16 T/C 0.240 ‐0.17 ± 0.08 dom ‐+‐‐ 9.54E‐05 rs2383580 14 34749512 A/C 0.161 0.29 ± 0.08 dom ++++ 7.06E‐05 rs10129961 14 34767305 A/G 0.146 0.33 ± 0.09 dom ++++ 2.25E‐05 rs17123946 14 51929722 G/A 0.251 ‐0.29 ± 0.08 dom ‐‐‐‐ 9.17E‐05 rs10498430 14 51942961 T/C 0.243 ‐0.30 ± 0.08 dom ‐‐‐‐ 4.05E‐05 rs17123969 14 51946458 G/A 0.245 ‐0.30 ± 0.08 dom ‐‐‐‐ 5.36E‐05 rs4901281 14 52980190 TXNDC16 A/C 0.148 ‐0.29 ± 0.09 dom ‐‐‐‐ 5.98E‐05 rs11631474 15 67934167 MAP2K5 G/A 0.272 ‐0.24 ± 0.08 dom ‐‐‐‐ 3.36E‐05 rs896598 15 74036629 C15orf59 A/G 0.119 0.37 ± 0.10 dom ++++ 5.83E‐07 rs4887140 15 74046663 G/T 0.143 0.31 ± 0.10 add ++++ 6.91E‐08 rs2415230 15 74059081 A/G 0.171 0.26 ± 0.09 dom ++++ 7.20E‐06 rs27230 16 3434699 ZNF434 G/A 0.107 ‐0.23 ± 0.09 dom ‐‐‐+ 5.85E‐05 rs16530 17 37357034 RPL19 T/C 0.102 ‐0.33 ± 0.10 dom ‐‐‐‐ 2.97E‐05 rs691336 17 76518426 DNAH17 T/C 0.261 ‐0.27 ± 0.08 dom ‐‐‐‐ 2.91E‐05 rs6139479 20 4566415 A/G 0.308 0.23 ± 0.08 dom ++++ 9.73E‐05 rs6100794 20 58799036 AX747739 T/C 0.012 ‐0.63 ± 0.24 dom ‐‐‐+ 4.80E‐06

21 Diabetes Page 58 of 127

d. M (nmax=1,604)

Direction of Association (HTN, Ref Allele Best MACAD, Best p‐ Marker Chr Position Gene ref/nonref Freq β±SE model NIDDM) value rs2235438 1 4849384 BC037321 T/C 0.357 15.45 ± 4.12 add +++ 3.95E‐05 rs2744761 1 26040514 MAN1C1 G/T 0.229 ‐21.75 ± 5.8 dom ‐‐‐ 5.54E‐05 rs11209072 1 67908644 G/A 0.393 ‐22.54 ± 5.52 dom ‐‐‐ 7.60E‐05 rs12135476 1 69649328 A/G 0.118 ‐31.54 ± 6.61 dom ‐‐‐ 3.75E‐06 rs10493454 1 69659840 G/A 0.136 ‐29.41 ± 6.22 dom ‐‐‐ 6.08E‐06 rs4650135 1 69684997 C/T 0.157 ‐29.56 ± 6.00 dom ‐‐‐ 2.31E‐06 rs6685355 1 79458347 ELTD1 C/A 0.311 ‐18.36 ± 4.25 add ‐‐‐ 1.33E‐05 rs1886644 1 85350658 LPAR3 C/A 0.295 ‐22.90 ± 5.42 dom ‐‐‐ 6.28E‐06 rs13375429 1 112103322 ADORA3 A/G 0.015 107.86 ± 27.77 dom ?+? 1.03E‐04 rs11582424 1 154363985 C/A 0.292 20.19 ± 5.41 dom +++ 1.02E‐04 rs6665426 1 200148319 A/G 0.309 ‐19.74 ± 5.46 dom ‐‐‐ 8.31E‐05 rs17047682 1 218523025 TGFB2 G/A 0.078 ‐31.01 ± 7.63 dom ‐‐‐ 1.19E‐05 rs6681101 1 242243325 A/G 0.401 ‐23.30 ± 6.08 dom ‐‐? 9.80E‐05 rs10926618 1 242251696 PLD5 T/C 0.386 ‐23.32 ± 6.02 dom ‐‐? 8.79E‐05 rs7558483 2 11537452 T/C 0.244 ‐19.51 ± 5.58 dom ‐‐‐ 7.39E‐05 rs17031893 2 44283172 G/A 0.101 27.41 ± 6.78 dom +++ 9.83E‐05 rs7595513 2 46687867 G/A 0.198 ‐22.09 ± 5.80 dom ‐‐‐ 6.66E‐05 rs2138397 2 86974049 RMND5A A/G 0.442 ‐24.39 ± 5.86 dom ‐‐‐ 3.71E‐05 rs10179986 2 134864344 G/A 0.467 ‐17.78 ± 3.89 add ‐‐‐ 7.95E‐06 rs1996589 2 134865196 C/T 0.230 ‐21.95 ± 5.57 dom ‐‐‐ 3.97E‐05 rs4953902 2 134876049 C/A 0.140 ‐25.81 ± 6.31 dom ‐‐‐ 1.41E‐05 rs1111961 2 134880830 G/A 0.158 ‐25.37 ± 6.10 dom ‐‐‐ 1.40E‐05 rs13030335 2 142231898 LRP1B A/G 0.382 ‐33.45 ± 8.00 rec ‐‐? 4.13E‐05 rs10178963 2 142349495 LRP1B C/A 0.446 24.53 ± 6.30 dom ++? 9.64E‐05 rs1546676 2 154509239 A/G 0.325 23.62 ± 5.49 dom +++ 8.00E‐06 rs2178704 2 227579207 G/A 0.244 25.31 ± 5.41 dom +++ 8.83E‐05

22 Page 59 of 127 Diabetes

rs11683087 2 227586606 G/A 0.412 20.54 ± 3.87 add +++ 7.42E‐07 rs2251692 2 227589780 A/G 0.483 17.31 ± 3.84 add +++ 1.98E‐05 rs10205233 2 227614005 IRS1 T/C 0.185 23.19 ± 4.75 add ‐++ 2.35E‐05 rs16822640 2 227647907 IRS1 T/G 0.210 20.51 ± 4.61 add ‐++ 1.04E‐04 rs11130721 3 6008503 C/A 0.070 ‐33.07 ± 8.52 dom ‐‐‐ 7.00E‐05 rs2596937 3 9480906 SETD5 C/T 0.238 ‐17.41 ± 4.43 add ‐‐‐ 9.76E‐05 rs2279440 3 9518511 SETD5 T/C 0.203 ‐21.57 ± 4.63 add ‐‐‐ 3.31E‐06 rs17050395 3 9533974 G/A 0.235 ‐17.84 ± 4.48 add ‐‐‐ 8.31E‐05 rs3806667 3 9860880 ARPC4‐TTLL3 G/T 0.272 ‐20.45 ± 5.51 dom ‐‐+ 2.79E‐05 rs13106 3 12624580 MKRN2 A/G 0.028 126.46 ± 30.51 dom ??+ 3.41E‐05 rs635787 3 32466487 CMTM7 A/G 0.453 ‐22.82 ± 5.22 add ?‐‐ 1.24E‐05 rs9682976 3 60118879 FHIT T/C 0.152 ‐24.49 ± 6.11 dom ‐‐‐ 5.93E‐05 rs17062321 3 60122156 FHIT T/C 0.163 ‐24.84 ± 5.99 dom ‐‐‐ 2.39E‐05 rs12493716 3 106777359 LOC100302640 G/A 0.253 ‐16.3 ± 4.47 add ‐‐‐ 9.21E‐05 rs3773155 3 127438528 MGLL G/A 0.110 25.12 ± 6.87 dom +++ 4.27E‐05 rs12487584 3 132300293 ACAD11 T/C 0.284 19.13 ± 4.34 add +++ 2.87E‐05 rs13094259 3 142444625 TRPC1 T/G 0.091 ‐29.40 ± 7.77 dom ‐‐? 9.10E‐05 rs9824464 3 167635899 LOC646168 T/C 0.468 27.97 ± 7.05 rec ++‐ 8.41E‐05 rs11920292 3 188246257 LPP T/C 0.509 28.44 ± 6.08 add ?+? 2.90E‐06 rs11709891 3 188248624 LPP C/T 0.510 27.77 ± 6.06 add ?+? 4.54E‐06 rs1426260 3 188260703 LPP T/C 0.501 27.98 ± 6.08 add ?+? 4.25E‐06 rs10937355 3 188289697 LPP T/C 0.306 ‐23.26 ± 5.41 dom ‐‐‐ 4.12E‐05 rs12511127 4 5142212 STK32B G/A 0.325 ‐16.49 ± 4.07 add ‐‐‐ 6.59E‐05 rs6448852 4 12017993 C/T 0.468 15.04 ± 3.88 add +++ 5.55E‐05 rs1025877 4 12074137 G/A 0.455 ‐14.32 ± 3.91 add ‐‐‐ 9.65E‐05 rs4834882 4 12108239 T/C 0.314 18.23 ± 4.13 add +++ 2.08E‐05 rs1382751 4 12138827 C/T 0.316 17.13 ± 4.16 add +++ 7.86E‐05 rs9997603 4 66438114 EPHA5 T/G 0.080 ‐31.75 ± 7.58 dom ‐‐‐ 1.54E‐05 rs4320186 4 66483593 EPHA5 A/G 0.079 ‐30.58 ± 7.68 dom ‐‐‐ 2.41E‐05 rs11930824 4 161451545 A/G 0.445 29.13 ± 5.90 dom ++? 7.46E‐05 rs4627838 4 175602762 GLRA3 A/C 0.427 19.97 ± 5.71 dom ++‐ 7.25E‐05 rs4695784 4 175608905 GLRA3 T/C 0.426 19.97 ± 5.71 dom ++‐ 7.25E‐05 rs2448425 5 55917956 C/T 0.494 ‐15.23 ± 3.95 add ‐‐‐ 3.69E‐05

23 Diabetes Page 60 of 127

rs6877846 5 81160103 A/G 0.328 20.99 ± 5.55 dom +++ 5.27E‐05 rs4835696 5 137972584 A/G 0.383 35.18 ± 8.27 rec ++? 1.74E‐05 rs13361457 5 152797679 T/C 0.477 23.81 ± 5.60 add ?++ 9.63E‐06 rs1019507 5 152798614 C/A 0.409 ‐18.01 ± 4.10 add ‐‐‐ 2.10E‐05 rs1465417 5 153790531 GALNT10 T/C 0.198 ‐20.39 ± 5.87 dom ‐‐+ 7.72E‐05 rs322394 5 172157768 C/T 0.360 ‐15.83 ± 4.02 add ‐‐‐ 3.38E‐05 rs241439 6 32797537 TAP2 G/T 0.426 18.67 ± 5.34 add ?++ 9.23E‐05 rs16884633 6 53902171 MLIP A/G 0.234 ‐23.78 ± 5.58 dom ‐‐‐ 3.67E‐05 rs987672 6 77410315 G/A 0.358 ‐17.03 ± 3.98 add ‐‐‐ 9.05E‐05 rs665791 6 106674850 ATG5 G/A 0.328 18.17 ± 4.21 add +++ 8.39E‐06 rs484621 6 106734408 ATG5 T/C 0.323 18.89 ± 4.22 add +++ 4.12E‐06 rs490010 6 106740458 ATG5 A/G 0.316 18.72 ± 4.23 add +++ 5.91E‐06 rs510432 6 106774030 T/C 0.341 16.93 ± 4.17 add +++ 2.61E‐05 rs9637984 6 170275554 G/A 0.245 19.29 ± 4.45 add +++ 3.63E‐05 rs4134409 6 170279658 A/G 0.245 19.26 ± 4.45 add +++ 3.79E‐05 rs2282909 7 28844815 CREB5 T/G 0.409 22.37 ± 5.70 dom +++ 1.05E‐04 rs11768415 7 52347667 A/G 0.519 ‐17.74 ± 4.17 add ‐‐? 2.80E‐05 rs11764734 7 52356515 T/C 0.520 ‐18.43 ± 4.20 add ‐‐? 1.41E‐05 rs296307 7 52432938 T/C 0.470 ‐15.67 ± 4.05 add ‐‐‐ 8.25E‐05 rs296316 7 52439967 T/C 0.369 ‐16.72 ± 4.15 add ‐‐‐ 9.52E‐05 rs2188256 7 88213062 C/T 0.179 ‐21.95 ± 5.85 dom ‐‐‐ 6.79E‐05 rs1588422 7 97329406 T/C 0.278 44.15 ± 10.17 rec ++? 3.19E‐05 rs2968865 7 124810399 AX746567 G/A 0.459 29.85 ± 7.01 rec ++? 1.40E‐05 rs441606 8 17903046 A/G 0.462 26.11 ± 6.49 dom ++? 9.48E‐05 rs17197236 8 25193338 DOCK5 G/A 0.034 54.29 ± 11.11 dom +++ 7.13E‐06 rs13267838 8 25196710 DOCK5 T/G 0.035 54.96 ± 10.96 dom +++ 4.03E‐06 rs13252932 8 25198091 DOCK5 T/C 0.049 47.71 ± 9.20 dom +++ 5.17E‐06 rs11780263 8 27823832 SCARA5 A/G 0.210 ‐16.34 ± 4.67 add ‐‐+ 6.64E‐05 rs9650426 8 27827391 SCARA5 C/T 0.334 15.63 ± 4.06 add +++ 6.38E‐05 rs4732617 8 27829251 SCARA5 G/A 0.330 20.45 ± 5.52 dom +++ 1.02E‐04 rs1715350 8 50396852 T/G 0.258 ‐19.15 ± 4.39 add ‐‐‐ 7.31E‐05 rs4737430 8 57303823 A/G 0.404 17.9 ± 5.57 dom ++‐ 6.71E‐05 rs660416 8 102465300 A/G 0.337 ‐16.42 ± 4.07 add ‐‐‐ 5.79E‐05

24 Page 61 of 127 Diabetes

rs633142 8 102466767 T/G 0.337 ‐16.14 ± 4.08 add ‐‐‐ 8.10E‐05 rs618854 8 102467706 T/C 0.343 ‐16.61 ± 4.06 add ‐‐‐ 5.04E‐05 rs4333664 9 6556948 GLDC T/C 0.432 16.94 ± 3.95 add +++ 1.15E‐05 rs224025 9 20309831 T/C 0.449 ‐23.94 ± 5.98 dom ‐‐? 4.00E‐05 rs6475448 9 20497142 MLLT3 G/A 0.316 ‐18.68 ± 4.43 add ‐‐? 1.89E‐05 rs17781302 9 24142314 C/A 0.178 21.35 ± 5.03 add +++ 6.10E‐05 rs17060946 9 77808519 G/A 0.068 37.86 ± 8.30 dom +++ 2.56E‐06 rs7030420 9 77809075 G/A 0.080 29.63 ± 7.63 dom +++ 5.75E‐05 rs12001098 9 110407586 A/G 0.106 27.75 ± 7.15 dom ++? 1.00E‐04 rs1888221 9 117778355 A/G 0.310 19.08 ± 4.30 add +++ 2.52E‐06 rs10828046 10 20676173 A/G 0.157 ‐23.63 ± 6.04 dom ‐‐‐ 4.18E‐05 rs17100713 10 84510336 NRG3 T/C 0.017 104.22 ± 24.6 dom ?+? 2.28E‐05 rs11202465 10 89366214 G/A 0.007 146.07 ± 36.66 dom ?+? 6.76E‐05 rs17099236 10 92484110 A/G 0.114 28.87 ± 6.89 dom +++ 5.13E‐05 rs1488933 11 17267029 T/C 0.448 30.81 ± 7.44 rec ++‐ 2.76E‐05 rs10841497 12 20524202 PDE3A G/T 0.356 17.05 ± 4.02 add +++ 3.17E‐05 rs7964191 12 20551038 PDE3A C/T 0.150 24.85 ± 6.10 dom +++ 5.20E‐05 rs10770655 12 20574060 PDE3A C/A 0.180 23.56 ± 5.90 dom +++ 9.20E‐05 rs7311799 12 84718394 A/C 0.469 ‐27.14 ± 6.83 rec ‐‐? 9.33E‐05 rs17512574 12 118788003 TAOK3 T/C 0.11 ‐29.28 ± 6.72 dom ‐‐‐ 7.24E‐06 rs673078 12 118791441 TAOK3 C/A 0.124 ‐30.26 ± 6.55 dom ‐‐‐ 2.41E‐06 rs884844 12 118814838 SUDS3 T/C 0.111 ‐28.67 ± 6.67 dom ‐‐‐ 6.48E‐06 rs7305647 12 118855566 SUDS3 A/G 0.103 ‐29.15 ± 6.88 dom ‐‐‐ 6.15E‐06 rs11059101 12 127874250 C/T 0.100 ‐25.34 ± 7.18 dom ‐‐‐ 9.30E‐05 rs4760067 12 130611682 T/C 0.432 ‐23.40 ± 5.73 dom ‐‐‐ 2.54E‐05 rs2874868 13 36356679 MAB21L1 G/T 0.233 16.78 ± 5.49 dom ++‐ 6.40E‐05 rs7329452 13 39000963 G/T 0.498 ‐23.70 ± 6.11 dom ‐‐‐ 3.64E‐05 rs4520736 13 59174647 C/T 0.415 ‐21.75 ± 5.23 add ‐?‐ 2.56E‐05 rs4885169 13 74900793 A/G 0.239 ‐23.04 ± 5.58 dom ‐‐‐ 5.31E‐06 rs1041515 13 74905950 C/T 0.243 ‐21.78 ± 4.53 add ‐‐‐ 5.14E‐07 rs7992923 13 74907043 A/G 0.427 ‐13.94 ± 3.94 add ‐‐‐ 7.86E‐05 rs1331765 13 74907933 G/A 0.372 ‐15.35 ± 4.04 add ‐‐‐ 2.15E‐05 rs10492494 13 74920186 A/C 0.240 ‐22.02 ± 4.55 add ‐‐‐ 5.04E‐07

25 Diabetes Page 62 of 127

rs2325620 13 74927727 T/C 0.069 ‐34.55 ± 8.40 dom ‐‐? 3.28E‐05 rs2325622 13 74932425 A/C 0.247 ‐21.66 ± 4.51 add ‐‐‐ 5.61E‐07 rs9543599 13 74937657 C/T 0.433 ‐13.69 ± 3.94 add ‐‐‐ 8.26E‐05 rs555647 13 98632349 IPO5 G/A 0.403 20.89 ± 5.72 dom +++ 8.65E‐05 rs9559222 13 108699887 A/G 0.424 ‐43.53 ± 11.20 rec ?‐? 1.01E‐04 rs6572117 14 42360633 LRFN5 T/C 0.374 ‐29.20 ± 7.08 dom ‐?‐ 9.45E‐05 rs17120327 14 49073392 A/G 0.199 ‐22.43 ± 5.65 dom ‐‐‐ 3.06E‐05 rs7154149 14 49075564 A/G 0.204 ‐21.10 ± 5.62 dom ‐‐‐ 1.01E‐04 rs12050106 14 49084116 A/G 0.204 ‐21.07 ± 5.63 dom ‐‐‐ 1.04E‐04 rs7165441 15 27828539 G/A 0.408 22.79 ± 5.63 dom +++ 6.52E‐05 rs2222314 15 46405908 T/G 0.455 ‐25.24 ± 5.89 dom ‐‐‐ 1.64E‐05 rs7497796 15 55136506 A/C 0.384 21.92 ± 5.65 dom +++ 4.56E‐05 rs12438478 15 55159177 G/T 0.248 22.72 ± 5.49 dom +++ 2.98E‐05 rs17818867 15 55175350 C/T 0.255 19.09 ± 4.48 add +++ 1.24E‐05 rs11637842 15 55200927 A/G 0.225 20.78 ± 4.62 add +++ 1.43E‐05 rs12438945 15 55226570 C/A 0.230 21.63 ± 4.59 add +++ 4.34E‐06 rs17238052 15 55259099 G/A 0.235 22.68 ± 5.53 dom +++ 9.39E‐05 rs1076471 16 54100518 FTO A/G 0.244 ‐21.36 ± 5.52 dom ‐‐‐ 1.01E‐04 rs17175749 16 86343912 T/G 0.036 47.74 ± 11.31 dom ++? 2.46E‐05 rs3826347 17 64970002 CACNG4 G/A 0.424 25.26 ± 6.14 dom ++? 4.44E‐05 rs740559 17 64971249 CACNG4 A/G 0.446 24.31 ± 6.28 dom ++? 1.04E‐04 rs907900 17 77345200 RBFOX3 C/T 0.011 126.16 ± 30.94 dom ?+? 4.54E‐05 rs6501303 17 77430593 RBFOX3 A/G 0.046 33.3 ± 10.26 dom ++‐ 4.32E‐05 rs11872936 18 7352783 T/C 0.009 152.75 ± 35.1 dom ?+? 1.35E‐05 rs626410 18 65855591 A/C 0.398 16.55 ± 3.99 add +++ 2.88E‐05 rs12961613 18 66309996 T/C 0.229 ‐22.84 ± 5.59 dom ‐‐‐ 6.23E‐05 rs10408924 19 9253139 ZNF317 G/T 0.370 22.59 ± 5.62 dom +++ 9.94E‐05 rs892024 19 33399344 CEP89 A/G 0.168 ‐23.28 ± 5.87 dom ‐‐‐ 8.92E‐05 rs864140 20 3088010 LOC100134015 A/G 0.294 21.29 ± 5.54 dom +++ 1.04E‐04 rs913555 20 3090124 LOC100134015 A/G 0.295 21.8 ± 5.54 dom +++ 6.92E‐05 rs911112 20 3144664 ProSAPiP1 T/C 0.254 22.86 ± 5.65 dom +++ 6.70E‐05 rs6075733 20 20856254 C/T 0.346 ‐18.29 ± 4.13 add ‐‐‐ 8.61E‐06 rs11907984 20 20862068 T/C 0.370 ‐16.12 ± 4.10 add ‐‐‐ 9.28E‐05

26 Page 63 of 127 Diabetes

rs4813402 20 20889803 C/T 0.366 ‐16.68 ± 4.03 add ‐‐‐ 5.21E‐05 rs6137217 20 20997702 T/C 0.349 24.96 ± 5.54 dom +++ 9.01E‐06 rs1028444 20 22267058 C/T 0.404 26.33 ± 6.24 dom ++? 5.22E‐06 rs4813452 20 22276813 G/T 0.382 24.54 ± 6.20 dom ++? 2.16E‐05 rs17192831 20 22281954 T/C 0.386 24.83 ± 6.21 dom ++? 1.64E‐05 rs819136 20 32848719 ASIP A/G 0.103 29.44 ± 7.35 dom ++? 8.26E‐05 rs6018406 20 45941326 ZMYND8 C/A 0.247 18.51 ± 4.50 add +++ 5.91E‐05 rs155004 20 57870356 G/A 0.283 ‐24.33 ± 5.43 dom ‐‐‐ 2.48E‐05 rs2277827 21 47986001 DIP2A G/T 0.435 29.78 ± 7.30 rec ++? 1.02E‐04 rs763040 22 44763606 BC037321 A/G 0.205 22.54 ± 5.70 dom +++ 6.91E‐05

27 Diabetes Page 64 of 127

e. AIRg (nmax=2,548)

Direction of Association (BetaGene, IRAS, Ref Allele Best IRASFS, Best p‐ Marker Chr Position Gene ref/nonref Freq β±SE model TRIPOD) value rs2784739 1 8497558 RERE G/T 0.243 ‐1.98 ± 0.45 dom ‐‐‐‐ 1.91E‐05 rs11121182 1 8522553 RERE A/C 0.270 ‐1.92 ± 0.44 dom ‐‐‐‐ 5.01E‐05 rs10492966 1 8598005 RERE T/C 0.273 ‐1.96 ± 0.44 dom ‐‐‐‐ 4.70E‐05 rs10492965 1 8598127 RERE A/G 0.271 ‐1.93 ± 0.44 dom ‐‐‐‐ 5.08E‐05 rs11121203 1 8648240 RERE C/T 0.286 ‐1.86 ± 0.44 dom ‐‐‐‐ 4.42E‐05 rs12061717 1 55024928 ACOT11 T/C 0.080 ‐2.10 ± 0.61 dom ‐+‐‐ 2.66E‐05 rs7537721 1 88514479 A/G 0.010 8.45 ± 1.80 dom +?++ 2.92E‐05 rs11185362 1 104561488 G/A 0.309 ‐1.65 ± 0.44 dom ‐‐‐‐ 3.21E‐05 rs961490 1 227219076 CDC42BPA T/C 0.003 43.04 ± 10.6 dom ?+?? 6.62E‐05 rs17018659 2 4211781 G/A 0.004 10.57 ± 2.50 dom +++? 5.39E‐05 rs2053797 2 46370892 PRKCE A/G 0.162 1.89 ± 0.49 dom +‐++ 5.02E‐05 rs4953320 2 46374529 PRKCE C/T 0.099 2.13 ± 0.57 dom +‐++ 8.13E‐05 rs10200604 2 56575020 CCDC85A A/G 0.314 ‐1.33 ± 0.34 add ‐‐‐‐ 8.09E‐05 rs1345516 2 64703286 A/C 0.420 1.04 ± 0.32 add ++++ 4.11E‐05 rs6756027 2 64720254 A/G 0.432 1.09 ± 0.31 add ++++ 6.05E‐05 rs6546079 2 64725466 G/T 0.438 1.08 ± 0.31 add +‐++ 6.66E‐05 rs13002043 2 64726449 A/G 0.437 1.07 ± 0.31 add +‐++ 7.92E‐05 rs7594935 2 235255122 T/C 0.116 1.91 ± 0.54 dom ++++ 2.88E‐05 rs9809000 3 154268934 G/A 0.080 2.17 ± 0.65 dom +++‐ 2.76E‐05 rs6803803 3 180116563 C/T 0.002 17.53 ± 3.72 dom +++? 1.64E‐06 rs17013808 4 89004957 A/G 0.056 ‐3.15 ± 0.80 dom ‐‐‐‐ 4.05E‐05 rs11943562 4 167652786 C/T 0.130 1.71 ± 0.51 dom +‐++ 2.39E‐05 rs3893856 5 111163 A/G 0.096 2.09 ± 0.58 dom +++‐ 7.21E‐05 rs10041174 5 11710193 CTNND2 G/A 0.080 ‐2.59 ± 0.65 dom ‐‐‐‐ 2.36E‐05 rs11750248 5 52153066 ITGA1 T/C 0.068 2.43 ± 0.62 dom ++++ 2.88E‐05

28 Page 65 of 127 Diabetes

rs1545696 5 122102442 A/G 0.282 ‐1.60 ± 0.44 dom ‐‐‐‐ 4.93E‐05 rs6887101 5 122109207 A/G 0.270 ‐1.70 ± 0.44 dom ‐‐‐‐ 1.24E‐05 rs10071705 5 122132725 SNX2 T/C 0.273 ‐1.65 ± 0.44 dom ‐‐‐‐ 1.52E‐05 rs193541 5 122253304 SNX24 C/T 0.253 ‐1.71 ± 0.44 dom ‐‐‐‐ 7.64E‐06 rs17149748 5 122267367 SNX24 G/A 0.093 ‐2.14 ± 0.57 dom ‐‐‐‐ 5.70E‐05 rs6891052 5 122358015 T/G 0.092 ‐2.31 ± 0.56 dom ‐‐‐‐ 2.32E‐05 rs10476419 5 162296335 G/A 0.010 4.71 ± 2.26 dom +‐++ 8.86E‐05 rs10078423 5 162312823 G/A 0.005 7.29 ± 2.36 dom +?+? 4.94E‐05 rs10051450 5 162378040 T/C 0.005 7.39 ± 2.36 dom +?+? 3.14E‐05 rs12198482 6 15218671 C/A 0.213 1.65 ± 0.46 dom ++++ 8.95E‐05 rs4712523 6 20657564 CDKAL1 G/A 0.315 ‐1.17 ± 0.33 add ‐‐‐‐ 1.60E‐05 rs6456369 6 20660365 CDKAL1 C/T 0.350 ‐0.98 ± 0.32 add ‐+‐‐ 5.17E‐05 rs7754840 6 20661250 CDKAL1 C/G 0.310 ‐1.26 ± 0.33 add ‐‐‐‐ 3.83E‐06 rs7756992 6 20679709 CDKAL1 G/A 0.309 ‐1.13 ± 0.34 add ‐‐‐‐ 1.01E‐04 rs9368222 6 20686996 CDKAL1 A/C 0.262 ‐1.46 ± 0.35 add ‐‐‐‐ 1.28E‐06 rs2206734 6 20694884 CDKAL1 T/C 0.194 ‐2.05 ± 0.45 dom ‐‐‐‐ 1.02E‐06 rs1040558 6 20713706 CDKAL1 G/A 0.218 ‐1.92 ± 0.44 dom ‐‐‐‐ 5.52E‐06 rs6935599 6 20717095 CDKAL1 G/A 0.245 ‐1.73 ± 0.44 dom ‐‐‐‐ 5.83E‐05 rs10946403 6 20717404 CDKAL1 G/A 0.242 ‐1.74 ± 0.44 dom ‐‐‐‐ 5.56E‐05 rs9358357 6 20719145 CDKAL1 G/A 0.247 ‐1.77 ± 0.44 dom ‐‐‐+ 3.60E‐05 rs9356746 6 20720279 CDKAL1 C/T 0.193 ‐1.73 ± 0.45 dom ‐‐‐+ 3.29E‐05 rs3873380 6 31262438 HLA‐B T/C 0.408 1.55 ± 0.46 dom +‐++ 4.50E‐05 rs236358 6 36800611 CPNE5 A/C 0.427 1.05 ± 0.32 add +++‐ 3.39E‐05 rs35473403 6 43480822 YIPF3 T/C 0.002 16.32 ± 4.38 dom ++?? 7.58E‐05 rs7750450 6 55714563 BMP5 C/T 0.322 1.40 ± 0.34 add ++++ 6.21E‐05 rs17082388 6 120892140 G/A 0.236 1.67 ± 0.45 dom ++‐+ 1.49E‐05 rs11963462 6 121021878 C/T 0.232 1.60 ± 0.45 dom ++‐+ 6.06E‐05 rs2358010 6 121028021 A/C 0.232 1.59 ± 0.45 dom ++‐+ 6.50E‐05 rs9321207 6 130397238 L3MBTL3 A/G 0.365 ‐0.97 ± 0.32 add ‐‐‐+ 7.43E‐05 rs4897370 6 130466676 SAMD3 G/A 0.346 1.43 ± 0.44 dom ++++ 3.80E‐05 rs11970367 6 138544807 KIAA1244 A/G 0.006 11.97 ± 3.94 dom ++++ 9.07E‐05 rs2038586 6 158091108 ZDHHC14 T/C 0.184 1.97 ± 0.48 dom ++++ 1.49E‐05 rs9295206 6 163326692 PACRG G/A 0.400 ‐1.18 ± 0.32 add ‐‐‐‐ 4.78E‐05

29 Diabetes Page 66 of 127

rs7779074 7 22986107 FAM126A A/G 0.101 2.13 ± 0.60 dom ++++ 9.56E‐05 rs10230193 7 50364626 IKZF1 A/G 0.479 ‐1.79 ± 0.53 rec ‐+‐‐ 7.09E‐06 rs10232215 7 92097166 G/A 0.248 1.96 ± 0.44 dom ++++ 4.41E‐05 rs2111200 7 92140397 PEX1 T/C 0.251 1.96 ± 0.44 dom ++++ 3.21E‐05 rs10237822 7 93760001 G/T 0.025 3.94 ± 1.18 dom +++‐ 3.53E‐05 rs10242768 7 93784157 C/T 0.022 3.94 ± 1.13 dom +++‐ 6.87E‐05 rs17881463 7 100495687 T/C 0.003 43.04 ± 10.60 dom ?+?? 6.62E‐05 rs11779094 8 10666813 SOX7 A/G 0.075 ‐2.18 ± 0.64 dom ‐‐‐+ 8.16E‐05 rs11203714 8 15477945 TUSC3 G/T 0.217 1.11 ± 0.46 dom +‐+‐ 1.00E‐04 rs4645564 8 15494159 TUSC3 T/C 0.210 1.04 ± 0.46 dom +‐+‐ 1.04E‐04 rs7000560 8 16993943 C/A 0.476 2.00 ± 0.49 dom ++++ 3.35E‐05 rs4922265 8 16996435 A/C 0.469 2.11 ± 0.49 dom ++++ 6.61E‐06 rs6988635 8 95744466 DPY19L4 G/A 0.444 1.18 ± 0.31 add ++++ 7.73E‐05 rs7018475 9 22137685 G/T 0.323 ‐1.64 ± 0.34 add ‐‐‐‐ 4.90E‐06 rs13301551 9 25683697 T/C 0.075 2.39 ± 0.62 dom ++++ 8.39E‐05 rs2295926 9 101593825 GALNT12 C/T 0.348 ‐1.61 ± 0.44 dom ‐‐‐‐ 2.21E‐05 rs7341705 9 107651348 ABCA1 C/T 0.003 13.32 ± 4.28 dom +‐++ 1.77E‐05 rs9696881 9 109274146 BC017988 G/A 0.233 ‐1.47 ± 0.45 dom ‐‐‐‐ 6.80E‐05 rs1602111 9 109277184 BC017988 C/A 0.233 ‐1.53 ± 0.45 dom ‐‐‐‐ 2.16E‐05 rs2287005 9 113791313 LPAR1 C/T 0.068 2.61 ± 0.66 dom +++‐ 6.49E‐05 rs7036846 9 119798885 ASTN2 C/T 0.005 10.86 ± 2.43 dom ++++ 9.25E‐06 rs12348950 9 123327435 CDK5RAP2 C/T 0.469 1.95 ± 0.53 rec ++++ 5.73E‐05 rs1128905 9 139253839 GPSM1 T/C 0.435 ‐1.05 ± 0.32 add ‐‐‐‐ 8.83E‐05 rs10870202 9 139257411 DNLZ T/C 0.430 ‐1.04 ± 0.32 add ‐‐‐+ 5.37E‐05 rs10781496 9 139261086 CARD9 A/G 0.493 ‐1.07 ± 0.32 add ‐‐‐‐ 6.97E‐05 rs2855022 10 70849959 SRGN G/A 0.465 ‐1.72 ± 0.53 rec ‐‐‐+ 2.73E‐05 rs7919192 10 93660727 C/T 0.216 ‐1.45 ± 0.46 dom ‐‐‐+ 5.00E‐05 rs10509794 10 107460228 C/T 0.004 7.64 ± 2.29 dom +‐+‐ 1.02E‐04 rs6584696 10 107578214 C/T 0.026 4.14 ± 0.99 dom ++++ 2.66E‐05 rs2129969 11 45586169 G/A 0.477 1.14 ± 0.32 add ++++ 2.10E‐05 rs10838488 11 45596965 C/T 0.479 1.14 ± 0.32 add ++++ 2.70E‐05 rs510398 11 66054823 YIF1A C/T 0.003 12.63 ± 2.96 dom +?++ 4.37E‐06 rs11227856 11 67377758 NDUFV1 T/C 0.005 6.51 ± 2.48 dom +‐++ 5.34E‐05

30 Page 67 of 127 Diabetes

rs12295232 11 67379575 NDUFV1 A/G 0.005 6.51 ± 2.48 dom +‐++ 5.38E‐05 rs10082595 11 67383433 T/C 0.005 6.51 ± 2.48 dom +‐++ 5.40E‐05 rs11227870 11 67400566 TBX10 A/G 0.005 6.63 ± 2.50 dom +‐++ 6.28E‐05 rs10898909 11 72952496 A/G 0.404 1.41 ± 0.33 add +++‐ 4.03E‐06 rs3847554 11 92668826 T/C 0.343 ‐1.64 ± 0.32 add ‐‐‐‐ 1.08E‐06 rs1387153 11 92673828 T/C 0.220 ‐2.55 ± 0.45 dom ‐‐‐‐ 2.21E‐09 rs2166706 11 92691532 C/T 0.308 ‐1.70 ± 0.33 add ‐‐‐‐ 1.24E‐06 rs10830961 11 92694757 G/A 0.331 ‐1.59 ± 0.33 add ‐‐‐‐ 1.91E‐06 rs10830963 11 92708710 MTNR1B G/C 0.220 ‐2.76 ± 0.45 dom ‐‐‐‐ 5.23E‐12 rs686413 11 117537710 DSCAML1 A/G 0.327 ‐1.19 ± 0.33 add ‐‐‐‐ 5.67E‐05 rs12292105 11 117983479 TMPRSS4 G/T 0.024 3.77 ± 1.18 dom ++++ 3.77E‐05 rs11216770 11 117983801 TMPRSS4 T/C 0.024 3.78 ± 1.18 dom ++++ 3.67E‐05 rs7927108 11 134038949 NCAPD3 T/G 0.004 10.54 ± 2.49 dom +++‐ 4.35E‐05 rs7962050 12 1031454 RAD52 G/A 0.323 1.20 ± 0.33 add +++‐ 7.67E‐05 rs247352 12 14900457 C/T 0.013 4.42 ± 1.49 dom +‐++ 9.24E‐05 rs12816878 12 23155705 AK094733 T/C 0.283 1.31 ± 0.35 add ++++ 9.69E‐05 rs3847896 12 23159966 AK094733 C/T 0.453 1.12 ± 0.31 add +++‐ 6.47E‐05 rs1489076 12 29129874 T/C 0.377 ‐1.37 ± 0.33 add ‐‐‐‐ 1.97E‐05 rs11049971 12 29130200 T/C 0.376 ‐1.37 ± 0.33 add ‐‐‐‐ 1.78E‐05 rs1489078 12 29141413 G/A 0.376 ‐1.34 ± 0.33 add ‐‐‐‐ 2.48E‐05 rs11113214 12 107588082 G/A 0.219 ‐1.93 ± 0.47 dom ‐‐‐‐ 6.21E‐05 rs3026485 12 110782027 ATP2A2 C/T 0.002 15.24 ± 5.06 dom +?+? 6.78E‐06 rs16940879 12 110928719 G/A 0.003 11.03 ± 4.51 dom +?+‐ 6.21E‐05 rs10774579 12 121405210 C/T 0.252 1.59 ± 0.44 dom ++++ 7.01E‐05 rs10744163 12 124383950 DNAH10 T/C 0.200 1.75 ± 0.46 dom ++++ 2.66E‐05 rs9553849 13 27082326 A/G 0.199 1.57 ± 0.47 dom +‐++ 6.70E‐05 rs9670049 13 31692454 C/T 0.176 1.81 ± 0.47 dom ++++ 9.20E‐05 rs9585660 13 101962642 NALCN A/G 0.006 8.29 ± 2.16 dom +?++ 2.60E‐05 rs7158254 14 37264674 SLC25A21 C/T 0.007 7.18 ± 1.90 dom +++‐ 3.91E‐05 rs1690356 15 55301874 A/C 0.003 13.41 ± 3.63 dom +??+ 1.47E‐05 rs2701405 15 87539918 AGBL1 A/C 0.485 0.91 ± 0.30 add +++‐ 8.78E‐05 rs2570133 15 87604296 C/T 0.416 ‐1.00 ± 0.31 add ‐‐‐+ 6.64E‐05 rs428233 16 1085393 C/A 0.295 1.54 ± 0.44 dom ++++ 9.59E‐05

31 Diabetes Page 68 of 127

rs12921387 16 25978823 HS3ST4 C/T 0.223 ‐1.76 ± 0.45 dom ‐‐‐‐ 9.72E‐05 rs7192071 16 78953857 WWOX G/A 0.024 4.34 ± 1.03 dom ++++ 7.30E‐05 rs16953087 17 420033 VPS53 C/T 0.13 ‐1.81 ± 0.52 dom ‐‐‐‐ 3.26E‐05 rs1006703 17 3865399 ATP2A3 T/C 0.087 2.13 ± 0.57 dom +++‐ 2.65E‐06 rs2619996 17 71703758 T/C 0.042 3.15 ± 0.81 dom ++++ 7.69E‐05 rs899596 17 71735485 G/A 0.230 2.20 ± 0.45 dom ++++ 2.64E‐06 rs9947929 18 6662650 T/C 0.193 1.87 ± 0.45 dom +++‐ 2.15E‐05 rs9955097 18 7965469 PTPRM C/A 0.004 11.62 ± 2.75 dom +?++ 3.10E‐05 rs9950590 18 8043661 PTPRM T/C 0.005 11.99 ± 2.72 dom +?++ 5.19E‐06 rs2068732 18 26236729 C/A 0.120 2.42 ± 0.53 dom ++++ 6.85E‐05 rs12608167 18 71893294 G/A 0.264 1.36 ± 0.35 add ++++ 2.48E‐05 rs4567819 18 74894653 T/C 0.469 1.09 ± 0.31 add ++++ 1.01E‐04 rs153508 19 34009392 PEPD T/C 0.362 1.01 ± 0.33 add ++++ 7.18E‐05 rs33845 19 34014316 A/G 0.361 1.00 ± 0.33 add ++++ 7.03E‐05 rs6030572 20 41598995 PTPRT C/A 0.175 ‐1.96 ± 0.47 dom ‐‐‐‐ 8.83E‐05 rs17646111 21 34954782 DONSON A/G 0.237 ‐1.57 ± 0.45 dom ‐‐‐‐ 3.16E‐05 rs1892700 21 35016137 DONSON A/G 0.236 ‐1.52 ± 0.45 dom ‐‐‐‐ 5.02E‐05 rs5752933 22 29902192 C/A 0.230 2.11 ± 0.45 dom ++++ 1.36E‐05

32 Page 69 of 127 Diabetes

f. DI (nmax=3,083)

Direction of Association (BetaGene, IRAS, IRASFS, MACAD, Ref Allele NIDDM, Best p‐ Marker Chr Position Gene ref/nonref Freq β±SE Best model TRIPOD) value rs2985125 1 17004186 G/A 0.052 3.11 ± 0.85 dom ++++?+ 3.02E‐05 rs16866049 1 35836440 ZMYM4 G/A 0.002 21.17 ± 5.11 dom +?+??? 3.08E‐05 rs513553 1 182494063 RGSL1 G/A 0.262 ‐1.83 ± 0.49 dom ‐‐‐+‐‐ 8.14E‐05 rs185580 1 182519861 RGSL1 A/G 0.227 ‐1.47 ± 0.50 dom ‐+‐‐‐‐ 9.30E‐05 rs266549 1 182528269 RGSL1 T/C 0.229 ‐1.59 ± 0.50 dom ‐‐‐‐‐‐ 6.29E‐05 rs474939 1 182538615 A/G 0.239 ‐1.69 ± 0.49 dom ‐‐‐‐‐‐ 3.59E‐05 rs10919851 1 200187504 C/T 0.442 ‐1.16 ± 0.36 add ‐‐‐‐?+ 5.29E‐05 rs6427807 1 200189305 A/C 0.462 1.15 ± 0.36 add ++++?‐ 6.79E‐05 rs7603311 2 49041322 C/T 0.441 1.44 ± 0.36 add ++++?+ 2.30E‐05 rs4482537 2 49052255 T/C 0.404 1.38 ± 0.36 add ++++?+ 5.52E‐05 rs17492567 2 50212116 NRXN1 C/T 0.089 2.54 ± 0.65 dom ++++?+ 4.51E‐05 rs12986646 2 52372389 A/G 0.044 2.64 ± 0.89 dom +‐++?‐ 8.76E‐05 rs881952 2 60888202 C/T 0.477 ‐2.30 ± 0.52 dom ‐‐‐‐++ 4.59E‐06 rs1366828 2 83753456 T/C 0.452 ‐1.99 ± 0.53 dom ‐‐‐‐?‐ 9.92E‐05 rs6753918 2 137214258 C/T 0.012 6.77 ± 1.65 dom ++++?+ 2.54E‐05 rs7560169 2 142148511 LRP1B T/C 0.388 1.57 ± 0.49 dom +++++‐ 8.79E‐05 rs684428 2 220505265 SLC4A3 T/C 0.170 1.61 ± 0.52 dom ++++‐‐ 8.27E‐05 rs7559293 2 236422975 AGAP1 A/G 0.408 1.95 ± 0.51 dom +++++‐ 6.75E‐05 rs28415051 3 66008918 MAGI1 G/A 0.003 15.79 ± 6.09 dom +++??‐ 5.80E‐05 rs7629006 3 96801930 EPHA6 A/G 0.371 2.25 ± 0.49 dom ++++‐+ 1.33E‐05 rs9832209 3 96825782 EPHA6 A/G 0.356 2.00 ± 0.49 dom ++++++ 5.13E‐05 rs602149 3 185244569 LIPH T/G 0.059 ‐2.95 ± 0.81 dom ‐‐‐‐?+ 4.20E‐05 rs612304 3 185251001 LIPH C/T 0.059 ‐3.25 ± 0.81 dom ‐‐‐‐?‐ 3.31E‐05

33 Diabetes Page 70 of 127

rs233991 4 104665738 A/C 0.457 ‐2.07 ± 0.65 rec ‐‐‐‐?‐ 8.69E‐05 rs1520323 4 125146503 T/C 0.021 ‐3.68 ± 1.19 dom ‐‐‐‐?‐ 6.82E‐05 rs467650 5 97969453 C/T 0.271 1.94 ± 0.49 dom +++‐++ 3.33E‐05 rs4712428 6 10203618 MRDS1 T/C 0.326 2.08 ± 0.48 dom +++‐‐+ 3.43E‐05 rs9470003 6 35337931 PPARD C/G 0.011 8.07 ± 2.39 dom ++++?+ 3.92E‐05 rs13193467 6 85211681 T/C 0.132 ‐2.10 ± 0.57 dom ‐‐‐‐?‐ 4.66E‐05 rs1510292 6 124371914 NKAIN2 A/G 0.060 ‐3.05 ± 0.81 dom ‐+‐‐?‐ 5.10E‐05 rs17086954 6 156337304 G/A 0.220 2.02 ± 0.49 dom +++‐++ 2.71E‐05 rs10225719 7 12691988 SCIN T/C 0.418 ‐2.17 ± 0.62 dom ‐‐‐?‐+ 3.17E‐05 rs10267836 7 30755583 INMT T/C 0.041 3.20 ± 0.90 dom +‐++?‐ 6.27E‐06 rs1346111 7 49742459 C/T 0.226 ‐2.04 ± 0.49 dom ‐‐‐‐‐‐ 2.28E‐05 rs10278107 7 125278195 C/T 0.477 ‐1.90 ± 0.53 dom ‐‐‐‐‐‐ 5.14E‐05 rs12539028 7 154812950 A/G 0.435 ‐1.74 ± 0.52 dom ‐‐‐‐‐‐ 8.46E‐05 rs1077489 8 6635669 T/C 0.072 ‐2.37 ± 0.75 dom ‐+‐‐?‐ 9.47E‐05 rs12546336 8 39620015 ADAM2 A/G 0.333 1.65 ± 0.48 dom ++++++ 9.24E‐05 rs13253406 8 143200557 G/T 0.390 ‐1.77 ± 0.46 add ‐‐‐??‐ 6.65E‐05 rs2382470 9 14387817 NFIB A/G 0.255 ‐1.59 ± 0.49 dom ‐‐‐‐‐+ 2.02E‐05 rs2020927 9 107553185 ABCA1 G/A 0.161 ‐1.74 ± 0.53 dom ‐+‐‐‐‐ 5.74E‐05 rs10121901 9 107553524 ABCA1 G/A 0.161 ‐1.74 ± 0.53 dom ‐+‐‐‐‐ 5.63E‐05 rs2066720 9 107554069 ABCA1 T/C 0.161 ‐1.74 ± 0.53 dom ‐+‐‐‐‐ 5.74E‐05 rs11145750 9 139259249 CARD9 A/G 0.474 ‐1.69 ± 0.53 dom ‐+‐‐‐+ 2.71E‐05 rs3812560 9 139269905 T/C 0.465 ‐1.83 ± 0.52 dom ‐+‐‐?+ 6.16E‐06 rs3812570 9 139275204 SNAPC4 A/C 0.461 ‐1.87 ± 0.52 dom ‐+‐‐?+ 1.72E‐06 rs4266763 9 139289825 SNAPC4 A/G 0.489 ‐2.00 ± 0.54 dom ‐+‐‐?+ 3.46E‐06 rs8413 9 139323311 INPP5E T/C 0.470 ‐1.77 ± 0.52 dom ‐‐‐‐?+ 2.83E‐05 rs10870194 9 139327034 INPP5E A/G 0.446 ‐1.58 ± 0.51 dom ‐+‐‐?+ 5.86E‐05 rs10781542 9 139327439 INPP5E A/G 0.446 ‐1.59 ± 0.51 dom ‐+‐‐?+ 5.77E‐05 rs1148233 10 31461599 T/C 0.008 8.86 ± 2.17 dom ++++?+ 9.09E‐06 rs1414894 10 89785190 C/T 0.286 1.67 ± 0.48 dom ++++‐+ 4.62E‐05 rs2488069 10 94505421 G/T 0.002 ‐18.48 ± 5.14 dom ‐‐‐??‐ 5.73E‐05 rs7081634 10 94685886 EXOC6 G/A 0.002 ‐22.06 ± 5.64 dom ‐?‐??‐ 2.62E‐05 rs17108007 10 94711701 EXOC6 C/T 0.002 ‐21.94 ± 5.65 dom ‐?‐??‐ 2.84E‐05 rs7909248 10 94721776 EXOC6 T/G 0.002 ‐22.02 ± 5.65 dom ‐?‐??‐ 2.70E‐05

34 Page 71 of 127 Diabetes

rs17093817 10 94740586 EXOC6 G/A 0.002 ‐22.00 ± 5.63 dom ‐?‐??‐ 2.66E‐05 rs835252 10 94749417 EXOC6 G/A 0.002 ‐22.01 ± 5.65 dom ‐?‐??‐ 2.72E‐05 rs835237 10 94754464 EXOC6 A/G 0.002 ‐21.96 ± 5.65 dom ‐?‐??‐ 2.84E‐05 rs835242 10 94756734 EXOC6 C/T 0.002 ‐22.02 ± 5.64 dom ‐?‐??‐ 2.69E‐05 rs835243 10 94757548 EXOC6 G/A 0.002 ‐21.99 ± 5.66 dom ‐?‐??‐ 2.80E‐05 rs835246 10 94761707 EXOC6 A/G 0.002 ‐22.01 ± 5.65 dom ‐?‐??‐ 2.71E‐05 rs835254 10 94763426 EXOC6 G/A 0.002 ‐22.01 ± 5.65 dom ‐?‐??‐ 2.71E‐05 rs835255 10 94765333 EXOC6 A/G 0.002 ‐22.01 ± 5.65 dom ‐?‐??‐ 2.71E‐05 rs9420601 10 94771867 EXOC6 A/G 0.002 ‐22.76 ± 6.29 dom ‐?‐??? 7.36E‐05 rs7068036 10 95315193 T/C 0.156 1.94 ± 0.55 dom +‐++?+ 6.79E‐05 rs2237896 11 2858440 KCNQ1 A/G 0.247 1.64 ± 0.51 dom ++++?‐ 1.57E‐05 rs2237897 11 2858546 KCNQ1 T/C 0.251 1.75 ± 0.51 dom ++++?‐ 7.04E‐06 rs5241 11 14990543 CALCA T/G 0.016 5.81 ± 1.55 dom +++‐?+ 9.58E‐05 rs4756016 11 45699134 G/A 0.416 1.50 ± 0.51 dom +‐++++ 4.61E‐05 rs744434 11 65847982 PACS1 G/T 0.003 15.07 ± 3.98 dom +++??+ 5.45E‐05 rs3847554 11 92668826 T/C 0.339 ‐2.19 ± 0.48 dom ‐‐‐++‐ 1.03E‐04 rs1387153 11 92673828 T/C 0.220 ‐3.20 ± 0.51 dom ‐‐‐+?‐ 1.32E‐09 rs2166706 11 92691532 C/T 0.308 ‐2.29 ± 0.48 dom ‐‐‐++‐ 4.46E‐05 rs10830961 11 92694757 G/A 0.328 ‐2.37 ± 0.48 dom ‐‐‐++‐ 7.43E‐06 rs10830963 11 92708710 MTNR1B G/C 0.218 ‐3.40 ± 0.51 dom ‐‐‐+?‐ 1.03E‐11 rs1351571 11 98408860 T/C 0.472 ‐1.31 ± 0.44 add ‐+‐??+ 4.20E‐05 rs17108749 11 108796817 DDX10 G/T 0.009 ‐9.79 ± 2.41 dom ‐‐‐??‐ 7.57E‐05 rs7971324 12 3098924 TEAD4 C/A 0.056 3.44 ± 0.81 dom ++++?+ 5.00E‐05 rs17107718 12 70488764 T/C 0.054 2.52 ± 0.85 dom ++++?‐ 6.92E‐05 rs7304911 12 129705400 TMEM132D T/C 0.223 ‐1.40 ± 0.49 dom ‐+‐‐‐‐ 2.69E‐05 rs1537435 13 27909319 T/C 0.316 1.61 ± 0.48 dom ++++++ 5.12E‐05 rs17085484 13 27930039 C/T 0.318 1.52 ± 0.49 dom ++++++ 8.64E‐05 rs17085485 13 27936526 G/T 0.228 1.51 ± 0.49 dom ++++++ 7.43E‐05 rs870767 13 27938560 G/A 0.233 1.53 ± 0.49 dom +‐++++ 5.87E‐05 rs2764026 13 36291051 MAB21L1 G/A 0.282 ‐1.77 ± 0.48 dom ‐‐‐‐‐+ 6.43E‐05 rs9575380 13 36708286 G/A 0.281 1.66 ± 0.48 dom ++++++ 7.91E‐05 rs9575437 13 36731208 G/A 0.296 2.02 ± 0.48 dom ++++++ 2.08E‐05 rs9575445 13 36731586 A/G 0.285 1.88 ± 0.48 dom ++++++ 1.48E‐05

35 Diabetes Page 72 of 127

rs1328641 13 36745029 SOHLH2 T/C 0.227 1.96 ± 0.49 dom ++++++ 1.96E‐05 rs2149423 13 36772381 SOHLH2 G/A 0.315 2.18 ± 0.48 dom ++++++ 3.67E‐07 rs2054715 15 59607007 MYO1E C/T 0.172 ‐1.35 ± 0.55 dom ‐+‐‐?+ 6.02E‐05 rs11073891 15 90363995 C/A 0.274 1.37 ± 0.48 dom +‐++‐+ 9.68E‐05 rs4238710 16 84546021 A/G 0.310 ‐2.08 ± 0.48 dom ‐‐‐‐‐‐ 3.68E‐05 rs2326274 16 84546108 T/G 0.308 ‐2.1 ± 0.48 dom ‐‐‐‐‐‐ 3.97E‐05 rs9891963 17 2875114 RAP1GAP2 T/C 0.038 ‐3.23 ± 1.01 dom ‐‐‐+?+ 8.32E‐05 rs654136 18 48464204 ME2 T/C 0.359 ‐1.43 ± 0.49 dom ‐+‐‐‐‐ 9.26E‐05 rs4073064 18 59532727 RNF152 C/T 0.010 ‐10.09 ± 2.54 dom ‐‐‐??‐ 7.42E‐05 rs2541872 18 63632952 A/G 0.385 ‐1.93 ± 0.5 dom ‐‐‐‐?‐ 9.90E‐05 rs2587374 18 63638807 A/G 0.250 ‐2.07 ± 0.48 dom ‐‐‐‐‐‐ 5.93E‐05 rs4802566 19 49632309 PPFIA3 T/C 0.392 1.77 ± 0.50 dom ++++++ 2.84E‐05 rs1217356 20 4170187 G/A 0.450 ‐2.35 ± 0.63 dom ‐‐‐??‐ 5.21E‐05 rs6076157 20 23862844 G/A 0.479 2.09 ± 0.55 dom ++++?+ 9.63E‐05 rs8128305 21 27861993 CYYR1 A/G 0.250 1.61 ± 0.49 dom +++++‐ 1.63E‐05 rs219628 21 27865420 CYYR1 C/T 0.255 1.4 ± 0.49 dom +++++‐ 5.01E‐05 rs2833555 21 33285149 HUNK T/C 0.079 ‐2.93 ± 0.73 dom ‐‐‐‐?‐ 6.09E‐05 rs133937 22 33395851 SYN3 C/A 0.335 1.65 ± 0.50 dom ++++++ 6.74E‐05

36 Page 73 of 127 Diabetes

g. SG (nmax=2,542)

Direction of Association (BetaGene, IRAS, IRASFS, MACAD, Ref Allele NIDDM, Best p‐ Marker Chr Position Gene ref/nonref Freq β±SE Best model TRIPOD) value rs1674879 1 4497217 T/C 0.079 0.19 ± 0.05 dom ++++ 5.99E‐05 rs780593 1 4507743 C/T 0.081 0.19 ± 0.05 dom ++++ 1.03E‐04 rs1572823 1 19889959 T/C 0.125 ‐0.14 ± 0.04 dom ‐‐‐‐ 6.36E‐05 rs11805807 1 155064844 T/C 0.004 1.14 ± 0.27 dom +??? 2.89E‐05 rs563988 1 182474160 RGSL1 C/T 0.268 ‐0.11 ± 0.04 dom ‐+‐‐ 9.29E‐05 rs471910 1 182474704 RGSL1 C/T 0.269 ‐0.11 ± 0.04 dom ‐+‐‐ 5.55E‐05 rs7570259 2 23202248 A/C 0.002 1.59 ± 0.35 dom +??? 5.51E‐06 rs1049817 2 27550967 GTF3C2 A/G 0.464 0.11 ± 0.03 add ++++ 1.89E‐05 rs11684134 2 27558252 GTF3C2 A/G 0.436 0.1 ± 0.03 add ++++ 5.99E‐05 rs10205219 2 27568565 GTF3C2 T/C 0.463 0.11 ± 0.03 add ++++ 3.42E‐05 rs4665969 2 27574953 GTF3C2 T/C 0.468 0.11 ± 0.03 add ++++ 1.44E‐05 rs6716894 2 27583273 A/G 0.468 0.11 ± 0.03 add ++++ 3.40E‐05 rs7586601 2 27584666 A/G 0.425 0.11 ± 0.03 add ++++ 3.20E‐05 rs11695549 2 27586155 C/A 0.479 ‐0.11 ± 0.03 add ‐‐‐‐ 3.21E‐05 rs2280737 2 27589810 EIF2B4 T/C 0.469 0.11 ± 0.03 add ++++ 3.38E‐05 rs7602534 2 27592423 EIF2B4 C/T 0.465 0.11 ± 0.03 add ++++ 5.06E‐05 rs12475426 2 27599132 SNX17 G/A 0.459 0.11 ± 0.03 add ++++ 8.93E‐05 rs13472 2 27600239 ZNF513 G/A 0.469 0.11 ± 0.03 add ++++ 4.28E‐05 rs1260342 2 27663416 NRBP1 G/T 0.46 0.11 ± 0.03 add ++++ 1.02E‐04 rs4803 2 27667297 KRTCAP3 A/G 0.459 0.11 ± 0.03 add ++++ 8.09E‐05 rs11126999 2 27670307 IFT172 G/A 0.474 0.11 ± 0.03 add ++++ 3.09E‐05 rs704795 2 27716494 FNDC4 G/A 0.460 0.11 ± 0.03 add ++++ 7.12E‐05 rs1260320 2 27722416 GCKR G/A 0.467 0.11 ± 0.03 add ++++ 9.73E‐05

37 Diabetes Page 74 of 127

rs2293571 2 27729480 GCKR G/A 0.476 0.12 ± 0.03 add ++++ 1.98E‐05 rs1260326 2 27730940 GCKR T/C 0.335 0.13 ± 0.03 add ++++ 4.04E‐06 rs780094 2 27741237 GCKR T/C 0.341 0.14 ± 0.03 add ++++ 1.97E‐06 rs780093 2 27742603 GCKR T/C 0.341 0.14 ± 0.03 add ++++ 1.12E‐06 rs11681351 2 27743423 GCKR G/A 0.479 0.11 ± 0.03 add ++++ 3.35E‐05 rs4852424 2 70283210 PCBP1‐AS1 G/A 0.382 ‐0.15 ± 0.04 dom ‐‐‐‐ 5.50E‐05 rs3755388 2 70310878 PCBP1‐AS1 G/A 0.388 ‐0.15 ± 0.04 dom ‐‐‐‐ 6.51E‐05 rs6743318 2 70373677 G/T 0.392 ‐0.15 ± 0.04 dom ‐‐‐‐ 4.91E‐05 rs14234 2 70524142 FAM136A A/G 0.412 0.10 ± 0.03 add ++++ 2.34E‐05 rs9816690 3 82046207 BC031255 A/G 0.055 0.23 ± 0.06 dom ++++ 7.44E‐05 rs11927192 3 183730657 ABCC5 A/G 0.004 0.77 ± 0.2 dom +?++ 5.32E‐05 rs523079 3 187615862 T/C 0.069 0.25 ± 0.06 dom +‐++ 1.53E‐07 rs13059988 3 187624906 T/G 0.063 0.22 ± 0.06 dom +‐++ 3.40E‐07 rs10000105 4 53623677 A/G 0.002 1.32 ± 0.34 dom +?++ 7.67E‐05 rs3775781 4 70595637 SULT1B1 T/C 0.027 ‐0.38 ± 0.10 dom ‐‐‐‐ 3.26E‐05 rs1011631 4 82440730 T/C 0.328 0.09 ± 0.03 add +‐++ 9.08E‐05 rs6871313 5 2397617 G/A 0.372 0.1 ± 0.03 add ++++ 4.12E‐05 rs6885718 5 31657655 PDZD2 G/A 0.081 0.22 ± 0.05 dom ++++ 4.62E‐05 rs17165293 5 126183502 A/G 0.041 0.28 ± 0.07 dom ++++ 8.94E‐05 rs7708035 5 161834699 A/G 0.003 1.71 ± 0.45 dom +++? 1.99E‐05 rs28011 5 179407229 RNF130 C/T 0.325 ‐0.08 ± 0.03 add ‐+‐‐ 8.59E‐05 rs4700708 5 179529895 RASGEF1C A/G 0.419 ‐0.08 ± 0.03 add ‐+‐‐ 6.82E‐05 rs2064197 6 8998811 G/A 0.164 ‐0.19 ± 0.04 dom ‐‐‐‐ 7.23E‐06 rs699986 6 49731027 G/A 0.472 ‐0.18 ± 0.05 rec ‐‐‐‐ 6.24E‐05 rs696718 6 49752742 T/G 0.473 ‐0.18 ± 0.05 rec ‐‐‐‐ 9.37E‐05 rs367274 6 90622187 T/C 0.418 0.12 ± 0.03 add ++++ 2.51E‐05 rs7744034 6 135143748 A/G 0.253 0.13 ± 0.04 dom +++‐ 5.45E‐05 rs11752655 6 135160309 G/A 0.081 0.19 ± 0.05 dom +++‐ 1.12E‐05 rs12536973 7 10062341 G/A 0.312 ‐0.11 ± 0.03 add ‐‐‐‐ 5.09E‐05 rs4720914 7 10915448 C/T 0.132 ‐0.17 ± 0.04 dom ‐‐‐‐ 8.42E‐05 rs16876733 7 10945193 C/A 0.129 ‐0.17 ± 0.04 dom ‐‐‐‐ 5.24E‐05 rs539518 7 73753250 CLIP2 T/C 0.366 0.09 ± 0.03 add +‐+‐ 9.40E‐05 rs1421221 8 97004203 C/T 0.385 ‐0.11 ± 0.03 add ‐‐‐‐ 9.91E‐05

38 Page 75 of 127 Diabetes

rs883952 9 71514651 PIP5K1B G/A 0.478 0.10 ± 0.03 add ++++ 5.56E‐05 rs12313180 12 30308868 T/C 0.336 0.14 ± 0.03 add ++++ 5.88E‐06 rs4931283 12 30334071 G/A 0.322 0.16 ± 0.04 dom ++++ 1.34E‐05 rs909013 12 30334754 G/A 0.317 0.16 ± 0.04 dom ++++ 1.75E‐05 rs17518256 12 30339648 C/A 0.295 0.17 ± 0.04 dom ++++ 1.32E‐05 rs10843647 12 30341934 T/G 0.331 0.17 ± 0.04 dom ++++ 4.13E‐06 rs11837387 12 73467487 C/T 0.001 2.02 ± 0.42 dom ++?? 2.22E‐05 rs17042107 12 76600231 C/T 0.038 0.3 ± 0.08 dom ++++ 1.03E‐04 rs11104268 12 76627445 G/A 0.042 0.33 ± 0.08 dom ++++ 6.74E‐06 rs7296900 12 104177668 NT5DC3 T/C 0.453 0.12 ± 0.03 add ++++ 4.05E‐05 rs11113179 12 107452785 CRY1 T/C 0.286 ‐0.12 ± 0.03 add ‐‐‐‐ 1.28E‐05 rs7319628 13 34502705 RFC3 A/G 0.006 0.95 ± 0.23 dom +++‐ 2.21E‐05 rs17081477 13 35134265 C/T 0.013 0.44 ± 0.13 dom +++‐ 3.83E‐05 rs1748124 13 52455098 C/T 0.480 ‐0.11 ± 0.03 add ‐‐‐+ 8.53E‐05 rs9550193 13 113324324 C13orf35 T/G 0.351 ‐0.12 ± 0.03 add ‐‐‐‐ 3.19E‐05 rs2145516 14 26129412 A/G 0.457 0.09 ± 0.03 add +‐++ 8.88E‐05 rs12432901 14 26494469 A/G 0.105 ‐0.18 ± 0.05 dom ‐‐‐‐ 4.44E‐05 rs7140895 14 49724328 C/T 0.123 0.17 ± 0.05 dom ++++ 9.31E‐05 rs2353498 15 24150918 T/C 0.329 0.1 ± 0.03 add +‐++ 4.06E‐05 rs1429751 15 34116858 RYR3 C/T 0.253 0.14 ± 0.04 dom ++++ 9.22E‐05 rs17650440 15 52504036 MYO5C A/G 0.004 2.09 ± 0.44 dom ???+ 6.17E‐06 rs9964 15 102194288 TARSL2 C/T 0.450 0.16 ± 0.05 rec ++++ 8.62E‐05 rs516667 15 102204031 TARSL2 G/A 0.448 0.16 ± 0.05 rec ++++ 5.02E‐05 rs12901450 15 102224341 TARSL2 A/G 0.449 0.17 ± 0.05 rec ++++ 4.27E‐05 rs2456491 15 102305129 T/C 0.461 0.18 ± 0.05 rec ++++ 2.47E‐05 rs1115936 16 7171923 RBFOX1 G/A 0.363 ‐0.13 ± 0.04 dom ‐+‐‐ 5.22E‐05 rs7203944 16 54438254 G/A 0.314 0.12 ± 0.03 add ++++ 1.03E‐04 rs4783122 16 82535037 G/A 0.243 ‐0.16 ± 0.04 dom ‐‐‐‐ 3.56E‐05 rs7202949 16 82593560 G/A 0.474 ‐0.09 ± 0.03 add ‐‐‐‐ 9.47E‐05 rs4299147 16 82883338 CDH13 T/C 0.410 0.10 ± 0.03 add ++++ 8.86E‐05 rs1559310 16 82918371 CDH13 G/T 0.437 ‐0.11 ± 0.03 add ‐‐‐‐ 4.08E‐05 rs11150514 16 82923464 CDH13 G/T 0.414 0.10 ± 0.03 add ++++ 4.41E‐05 rs12933472 16 82924685 CDH13 A/G 0.435 ‐0.12 ± 0.03 add ‐‐‐‐ 8.16E‐06

39 Diabetes Page 76 of 127

rs11150519 16 82934307 CDH13 G/A 0.441 ‐0.11 ± 0.03 add ‐‐‐‐ 4.32E‐05 rs6565127 16 83152261 CDH13 G/A 0.373 0.09 ± 0.03 add ++++ 6.14E‐05 rs1559438 16 83308559 CDH13 C/T 0.476 0.09 ± 0.03 add +‐++ 6.67E‐05 rs7499978 16 85065085 KIAA0513 A/G 0.434 0.11 ± 0.03 add ++++ 5.49E‐05 rs16947417 17 13143819 G/T 0.053 0.26 ± 0.06 dom ++++ 2.24E‐05 rs9896748 17 64939574 T/G 0.070 0.27 ± 0.06 dom +++‐ 2.37E‐05 rs94312 18 7806492 PTPRM G/A 0.049 ‐0.27 ± 0.07 dom ‐‐‐‐ 8.39E‐05 rs2048132 18 73694904 T/G 0.225 0.16 ± 0.04 dom ++++ 2.16E‐05 rs6566045 18 75650801 C/T 0.289 0.14 ± 0.04 dom ++++ 4.52E‐05 rs1106581 19 293934 A/G 0.451 0.10 ± 0.03 add ++++ 9.35E‐05 rs2291004 19 37997952 ZNF793 A/C 0.153 0.16 ± 0.04 dom +++‐ 3.82E‐05 rs788338 19 50778543 MYH14 C/T 0.287 ‐0.17 ± 0.04 dom ‐‐‐+ 1.66E‐06 rs788332 19 50782462 MYH14 A/C 0.264 ‐0.16 ± 0.04 dom ‐‐‐‐ 1.77E‐05 rs2278998 19 50939737 MYBPC2 C/A 0.343 0.11 ± 0.03 add ++++ 1.00E‐04 rs2004423 19 50939867 MYBPC2 A/G 0.325 0.12 ± 0.03 add ++++ 4.51E‐05 rs4802723 19 51172786 SHANK1 G/A 0.150 ‐0.16 ± 0.04 dom ‐‐‐‐ 1.90E‐05 rs4802724 19 51173218 SHANK1 C/A 0.151 ‐0.16 ± 0.04 dom ‐‐‐‐ 1.81E‐05 rs2825882 21 21283010 C/T 0.474 ‐0.10 ± 0.03 add ‐‐‐+ 9.16E‐05 rs9974077 21 43835771 UBASH3A T/G 0.259 0.13 ± 0.04 dom ++++ 3.44E‐05

40 Page 77 of 127 Diabetes

Supplementary Table 3. Top Discovery hits from the GUARDIAN Consortium ordered by trait.

Model 1§ Model 2|| SNP Chr Position* Gene Name Alleles† RAF‡ Trait Beta P-value Beta P-value rs2302063 19 3150418 GNA15 A/C 0.34 MCRI -0.29 7.31E-08 -0.19 1.47E-05 rs1602084 4 128843480 MFSD8 G/A 0.041 SI+M 8.97 5.20E-07 11.15 7.29E-05 rs896232 2 2732877 MYT1L / TSSC1 T/C 0.29 SI+M -5.28 1.26E-06 -6.44 4.43E-04 rs6719442 2 2722295 MYT1L / TSSC1 A/G 0.18 SI+M -5.03 1.53E-06 -4.79 5.06E-04 ¶ rs1978648 2 43371542 HAAO / ZFP36L2 / THADA T/C 0.32 SI 0.20 5.31E-07 0.10 2.11E-05 rs896598 15 74036629 C15orf59 A/G 0.12 SI 0.37 5.83E-07 0.28 7.14E-07 rs4887140 15 74046663 C15orf59 / TBC1D21 G/T 0.14 SI 0.31 6.91E-08 0.18 1.35E-06 rs196701 6 80147187 HMGN3 / LCA5 C/T 0.13 SI -0.35 1.37E-06 -0.10 9.02E-03 rs10492494 13 74920186 KLF12 / LINC00347 A/C 0.24 M -22.00 5.04E-07 -15.71 8.82E-05 rs11683087 2 227586606 LOC646736 / IRS1# G/A 0.41 M 20.54 7.42E-07 17.45 8.25E-06 ** rs10830963 11 92708710 MTNR1B G/C 0.22 AIRg -2.76 5.23E-12 -2.81 3.22E-13 †† rs1387153 11 92673828 FAT3 / MTNR1B T/C 0.22 AIRg -2.55 2.21E-09 -2.62 2.16E-10 ‡‡ rs2206734 6 20694884 CDKAL1 T/C 0.20 AIRg -2.05 1.02E-06 -1.90 5.03E-06 §§ rs3847554 11 92668826 FAT3 / MTNR1B A/G 0.34 AIRg -1.64 1.08E-06 -1.70 1.27E-07 |||| rs9368222 6 20686996 CDKAL1 A/C 0.26 AIRg -1.46 1.28E-06 -1.36 4.74E-06 rs6803803 3 180116563 PEX5L / TTC14 C/T 0.0030 AIRg 17.53 1.64E-06 17.25 9.29E-07 rs10830963 11 92708710 MTNR1B** G/C 0.23 DI -3.40 1.03E-11 -3.36 3.25E-12 rs1387153 11 92673828 FAT3 / MTNR1B†† T/C 0.22 DI -3.20 1.32E-09 -3.11 7.51E-10 rs2149423 13 36772381 CCDC169-SOHLH2; SOHLH2 G/A 0.32 DI 2.18 3.67E-07 2.07 7.35E-07 rs3812570 9 139275204 SNAPC4 A/C 0.46 DI -1.87 1.72E-06 -1.63 5.89E-06 rs523079 3 187615862 BCL6 / LPP T/C 0.069 SG 0.25 1.53E-07 0.25 3.82E-08 ¶¶ rs780093 2 27742603 GCKR T/C 0.34 SG 0.14 1.12E-06 0.13 3.11E-06 rs788338 19 50778543 MYH14 C/T 0.29 SG -0.17 1.66E-06 -0.17 1.98E-06 Independent signals (r2<0.80) with evidence of association (P<2.00E-06) with the nearest annotated RefSeq gene(s) listed. *Build hg19, †Reference Allele/Other Allele, ‡Reference Allele Frequency, §Model 1 covariates included age, gender, study site (in multi- center recruitment studies), and admixture proportions, ||Model 2 covariates included age, gender, study site (in multi-center recruitment studies), admixture proportions, and BMI, ¶Previously identified T2D locus (THADA rs7578597; r2=0.0079, #Previously identified T2D locus (IRS1 rs2943641; r2=0.04), **Previously identified T2D locus (MTNR1B rs1387153; r2=0.69), ††Previously identified T2D locus (MTNR1B rs1387153), ‡‡Previously identified T2D locus (CDKAL1 rs7754840; r2=0.42), §§Previously identified T2D locus (MTNR1B rs1387153; r2=0.54), ||||Previously identified T2D locus (CDKAL1 rs7754840; r2=0.72), ¶¶Previously identified T2D locus (GCKR rs780094; r2=0.98)

41 Diabetes Page 78 of 127

Conditional Analysis SNP Chr:Position* Gene Name Alleles† RAF‡ Trait Beta P-value SNP r2§ P-value rs2302063 19:3150418 GNA15 A/C 0.336 MCRI -0.29 7.31E-08 rs1602084 4:128843480 MFSD8 G/A 0.041 SI+M 8.97 5.20E-07 rs896232 2:2732877 MYT1L / TSSC1 T/C 0.291SI+M -5.28 1.26E-06 rs6719442 2:2722295 MYT1L / TSSC1 A/G 0.184 SI+M -5.03 1.53E-06 rs896232 0.37 8.21E-03 || || rs1978648 2:43371542 HAAO / ZFP36L2 / THADA T/C 0.324 SI 0.20 5.31E-07 rs7578597 0.0079 6.88E-07 rs896598 15:74036629 C15orf59 A/G 0.116 SI 0.37 5.83E-07 rs4887140 15:74046663 C15orf59 / TBC1D21 G/T 0.139 SI 0.31 6.91E-08 rs896598 0.79 3.41E-02 rs196701 6:80147187 HMGN3 / LCA5 C/T 0.132 SI -0.35 1.37E-06 rs10492494 13:74920186 KLF12 / LINC00347 A/C 0.240 M -22.02 5.04E-07 rs11683087 2:227586606 LOC646736 / IRS1|| G/A 0.412M 20.547.42E-07 rs2943641|| 0.04 1.29E-06 || || rs10830963 11:92708710 MTNR1B G/C 0.220AIRg -2.76 5.23E-12 rs1387153 0.69 8.67E-05 || || rs1387153 11:92673828 FAT3 / MTNR1B T/C 0.220AIRg -2.55 2.21E-09 rs10830963 0.69 8.27E-01 || || rs2206734 6:20694884 CDKAL1 T/C 0.198AIRg -2.05 1.02E-06 rs7754840 0.42 9.37E-03 || || rs3847554 11:92668826 FAT3 / MTNR1B A/G 0.341AIRg -1.64 1.08E-06 rs1387153 0.54 3.66E-01 rs10830963 0.36 5.95E-01 || || rs9368222 6:20686996 CDKAL1 A/C 0.264AIRg -1.46 1.28E-06 rs7754840 0.72 8.19E-02 rs2206734 0.57 3.06E-01 rs6803803 3:180116563 PEX5L / TTC14 C/T 0.003 AIRg 17.53 1.64E-06 rs10830963 11:92708710 MTNR1B|| G/C 0.230DI -3.401.03E-11 rs1387153|| 0.69 4.31E-04 rs1387153 11:92673828 FAT3 / MTNR1B|| T/C 0.220DI -3.201.32E-09 rs10830963|| 0.69 7.27E-01 rs2149423 13:36772381 CCDC169-SOHLH2; SOHLH2 G/A 0.315 DI 2.18 3.67E-07 rs3812570 9:139275204 SNAPC4 A/C 0.461 DI -1.87 1.72E-06 rs523079 3:187615862 BCL6 / LPP T/C 0.069 SG 0.25 1.53E-07 || || rs780093 2:27742603 GCKR T/C 0.341SG 0.14 1.12E-06 rs780094 0.98 1.05E-01 rs788338 19:50778543 MYH14 C/T 0.287 SG -0.17 1.66E-06 Independent signals (r2<0.80) with evidence of association (P<2.00E-06) with the nearest annotated RefSeq gene(s) listed. *Build hg19, †Reference Allele/Other Allele, ‡Reference Allele Frequency, §Correlation from the largest set of unrelated individuals from BetaGene ||Previously identified T2D locus

42 Page 79 of 127 Diabetes

Supplementary Table 5A. Association with reported type 2 diabetes (T2D) susceptibility loci with MCRI in GUARDIAN Hispanic Americans (nmax=3,787). Index SNPs reaching genome‐wide significance (P<5.0E‐08) for association with T2D were selected from the NHGRI GWAS catalog (http://www.genome.gov/gwastudies). When the index variable was unavailable in GUARDIAN, a suitable proxy was selected using the HapMap 3 MEX (Mexican ancestry in Los Angeles, California) population.

2 Index r Position Alleles Heterogeneity Additive Ref Proxy Gene(s) Beta SE SNP (MEX) (hg19) Risk Ref/Alt P-value P-value rs10923931 1 rs2793831 1.00 1:120523902 NOTCH2 T T/C 0.05 0.09 0.10 0.80 rs2075423 29 1:212221342 PROX1 G - - - - - rs17106184 28 rs1278516 1.00 1:50900021 FAF1 G G/A 0.22 0.12 0.072 0.71 rs6723108 30 2:135479980 TMEM163 T T/G 0.08 0.07 0.012 0.68 rs7560163 2 2:151637936 RND3 / FABP5P10 C - - - - - rs7593730 3 2:161171454 RBMS1 C - - - - - rs3923113 4 2:165501849 EIF3EP3 / SNORA70F A - - - - - rs7578326 5 rs13405357 0.90 2:227022036 LOC646736 A A/G -0.12 0.06 0.53 0.048 rs2943641 31 2:227093745 IRS1 C C/T -0.16 0.06 0.15 0.24 rs780094 29 2:27741237 GCKR C C/T -0.09 0.05 0.82 0.050 rs7578597 1 2:43732823 THADA T T/C 0.12 0.11 0.42 0.52 rs243021 5 2:60584819 BCL11A A A/G -0.07 0.05 0.017 0.18 rs11708067 29 3:123065778 ADCY5 A A/G 0.03 0.06 0.20 0.37 rs1801282 3:12393125 PPARG C C/G -0.11 0.08 0.67 0.38 rs4402960 6 3:185511687 IGF2BP2 T T/G 0.05 0.06 0.25 0.92 rs16861329 4 rs16861317 1.00 3:186664728 ST6GAL1 G G/A 0.12 0.05 0.0050 0.71 rs6808574 28 3:187740523 LPP C C/T -0.01 0.06 0.086 0.43 rs7612463 32 3:23336450 UBE2E2 C C/A -0.19 0.11 0.52 0.081 rs831571 8 rs35837 0.92 3:64013249 PSMD6 / PRICKLE2-AS1 C C/T 0.05 0.09 0.67 0.72 rs4607103 1 3:64711904 ADAMTS9-AS2 C C/T 0.07 0.05 0.24 0.090 rs7656416 9 4:1254535 CTBP1-AS1 / MAEA C - - - - - rs6815464 8 4:1309901 MAEA C - - - - - rs6813195 28 4:153739925 TMEM154 C - - - - - rs1801214 5 4:6303022 WFS1 T - - - - - rs702634 28 5:53271420 ARL15 A A/G -0.02 0.07 0.31 0.77 rs459193 33 5:55842508 ANKRD55 G - - - - - rs4457053 5 5:76424949 ZBED3-AS1 G G/A -0.02 0.05 0.36 0.48 rs10946398 12 rs7754840 0.96 6:20661250 CDKAL1 C C/G 0.16 0.05 0.0025 0.0087 rs3130501 28 6:31136453 POU5F1-TCF19 G G/A -0.11 0.06 0.81 0.061

43 Diabetes Page 80 of 127 rs9470794 8 rs3800364 0.83 6:38121211 ZFAND3 C G/A 0.04 0.12 0.82 0.94 rs1535500 8 6:39284050 KCNK16 T - - - - - rs1048886 15 6:71289189 C6orf57 G G/A -0.01 0.07 0.92 0.62 rs9505118 28 6:7290437 SSR1-RREB1 A A/G 0.05 0.05 0.14 0.82 rs6467136 8 7:127164958 ZNF800 / GCC1 G - - - - - rs10229583 16 7:127246903 FSCN3 / PAX4 G G/A 0.09 0.07 0.88 0.27 rs972283 5 7:130466854 KLF14 / MIR29A G G/A -0.02 0.05 0.14 0.50 rs17168486 29 7:14898282 DGKB T T/C 0.08 0.05 0.34 0.084 rs864745 1 rs1635852 1.00 7:28189411 JAZF1 T T/C -0.06 0.07 0.68 0.16 rs10278336 29 7:44211888 GCK A - - - - - rs13266634 11 8:118184783 SLC30A8 C C/T 0.09 0.06 0.41 0.11 rs515071 9 rs508419 1.00 8:41522991 ANK1 C G/A 0.05 0.06 0.65 0.60 rs896854 5 rs4735337 0.81 8:95973465 TP53INP1 T T/C 0.04 0.05 0.83 0.33 rs10811661 6 9:22134094 CDKN2B-AS1 / DMRTA1 T - - - - - rs7018475 18 9:22137685 CDKN2B-AS1 / DMRTA1 T T/G -0.11 0.06 0.26 0.030 rs7041847 8 9:4287466 GLIS3 A - - - - - rs13292136 5 9:81952128 KRT18P24 / CHCHD2P9 C - - - - - rs2796441 33 9:84308948 TLE1 G G/A 0.07 0.06 0.87 0.39 rs17584499 20 9:8879118 PTPRD T T/C 0.12 0.06 0.82 0.11 rs7903146 22 10:114758349 TCF7L2 T T/C 0.04 0.06 0.64 0.92 rs10886471 19 10:121149403 GRK5 C C/T -0.06 0.07 0.25 0.17 rs12779790 1 10:12328010 CDC123 / MIR4480 G - - - - - rs1802295 4 10:70931474 VPS26A A A/G -0.10 0.06 0.43 0.064 rs12571751 33 10:80612637 ZMIZ1 A - - - - - rs1111875 11 rs10882101 1.00 10:94462427 HHEX / EXOC6 C C/T -0.06 0.05 0.33 0.23 rs2334499 35 11:1696849 DUSP8 T T/C 0.05 0.05 0.22 0.46 rs5219 6 11:17409572 KCNJ11 T T/C -0.06 0.05 0.93 0.27 rs231362 5 11:2691471 KCNQ1;KCNQ1OT1 G G/A 0.09 0.05 0.92 0.13 rs2237892 24 11:2839751 KCNQ1 C C/T -0.10 0.06 0.47 0.096 rs1552224 5 11:72433098 ARAP1 A A/C 0.12 0.11 0.14 0.12 rs1387153 5 11:92673828 FAT3 / MTNR1B T T/C -0.02 0.06 0.88 0.35 rs7305618 17 12:121402932 RPL12P33 / HNF1A-AS1 C C/T 0.10 0.07 0.54 0.24 rs7957197 5 12:121460686 OASL T - - - - - rs4275659 28 12:123447928 MPHOSPH9 C C/T -0.02 0.05 0.32 0.25 rs10842994 33 12:27965150 KLHDC5 C C/T 0.02 0.07 0.51 0.67 rs11063069 34 12:4374373 CCND2 G G/A -0.09 0.08 0.66 0.48

44 Page 81 of 127 Diabetes

rs1531343 5 rs2612067 1.00 12:66170163 RPSAP52 C G/T 0.08 0.10 0.73 0.15 rs2261181 5 12:66212318 HMGA2 T T/C 0.06 0.11 0.94 0.40 rs7961581 1 12:71663102 TSPAN8 / LGR5 C C/T -0.11 0.07 0.20 0.11 rs9552911 26 13:23864657 SGCG G - - - - - rs1359790 23 13:80717156 NDFIP2 / SPRY2 G - - - - - rs7403531 19 15:38822905 RASGRP1 T T/C 0.02 0.05 0.20 0.24 rs7172432 27 15:62396389 C2CD4A / C2CD4B A - - - - - rs7178572 4 rs11857294 0.86 15:77596725 HMG20A G C/T -0.10 0.05 0.035 0.0053 rs11634397 5 15:80432222 ZFAND6 / FAH G G/A 0.13 0.05 0.054 0.093 rs2028299 4 15:90374257 AP3S2;C15orf38-AP3S2 C C/A 0.09 0.06 0.26 0.51 rs8042680 5 15:91521337 PRC1 A A/C 0.03 0.05 0.082 0.33 rs8050136 12 16:53816275 FTO A A/C -0.14 0.06 0.019 0.34 rs7202877 33 16:75247245 BCAR1 T T/G 0.17 0.10 0.46 0.057 rs391300 20 17:2216258 SRR G G/A -0.02 0.05 0.10 0.99 rs13342232 36 17:6945940 SLC16A11 G - - - - - rs4430796 19 17:36098040 HNF1B G G/A 0.05 0.05 0.89 0.28 rs12970134 33 18:57884750 MC4R A A/G -0.08 0.07 0.26 0.16 rs8090011 14 18:7068462 LAMA1 G - - - - - rs10401969 33 19:19407718 CILP2 C C/T 0.04 0.13 0.016 0.95 rs3786897 8 19:33893008 PEPD A A/G 0.03 0.06 0.68 0.18 rs6017317 8 20:42946966 FITM2 / R3HDML G - - - - - rs4812829 4 rs2144908 1.00 20:42985717 HNF4A A A/G 0.04 0.05 0.66 0.20 rs12010175 19 X:152862638 FAM58A G - - - - - rs5945326 5 X:152899922 KRT18P48 / DUSP9 A - - - - -

45 Diabetes Page 82 of 127

Supplementary Table 5B. Association with reported type 2 diabetes (T2D) susceptibility loci with SI+M in GUARDIAN Hispanic Americans (nmax=4,153). Index SNPs reaching genome‐wide significance (P<5.0E‐08) for association with T2D were selected from the NHGRI GWAS catalog (http://www.genome.gov/gwastudies). When the index SNP was unavailable in GUARDIAN, a suitable proxy was selected using the HapMap 3 MEX (Mexican ancestry in Los Angeles, California) population.

2 Index r Position Alleles Heterogeneity Additive Ref Proxy Gene(s) Beta SE SNP (MEX) (hg19) Risk Ref/Alt P-value P-value rs10923931 1 rs2793831 1.00 1:120523902 NOTCH2 T T/C 0.22 2.46 0.82 0.55 rs2075423 29 1:212221342 PROX1 G - - - - - rs17106184 28 rs1278516 1.00 1:50900021 FAF1 G G/A -0.70 3.64 0.85 0.26 rs6723108 30 2:135479980 TMEM163 T T/G -1.67 2.45 0.24 0.73 rs7560163 2 2:151637936 RND3 / FABP5P10 C - - - - - rs7593730 3 2:161171454 RBMS1 C - - - - - rs3923113 4 2:165501849 EIF3EP3 / SNORA70F A - - - - - rs7578326 5 rs13405357 0.90 2:227022036 LOC646736 A A/G 2.44 1.94 0.10 0.60 rs2943641 31 2:227093745 IRS1 C C/T 0.85 2.11 0.099 0.16 rs780094 29 2:27741237 GCKR C C/T -1.09 1.72 0.99 0.098 rs7578597 1 2:43732823 THADA T T/C 3.69 3.65 0.94 0.15 rs243021 5 2:60584819 BCL11A A A/G 1.24 1.69 0.12 0.53 rs11708067 29 3:123065778 ADCY5 A A/G 0.51 1.89 0.47 0.76 rs1801282 3:12393125 PPARG C C/G 2.70 2.75 0.51 0.64 rs4402960 6 3:185511687 IGF2BP2 T T/G -0.01 1.98 0.12 0.95 rs16861329 4 rs16861317 1.00 3:186664728 ST6GAL1 G G/A 0.07 1.80 0.14 0.072 rs6808574 28 3:187740523 LPP C C/T -1.95 2.14 0.12 0.66 rs7612463 32 3:23336450 UBE2E2 C C/A -2.64 3.13 0.52 0.26 rs831571 8 rs35837 0.92 3:64013249 PSMD6 / PRICKLE2-AS1 C C/T -0.74 2.90 0.97 0.71 rs4607103 1 3:64711904 ADAMTS9-AS2 C C/T -2.29 1.76 0.03 0.41 rs7656416 9 4:1254535 CTBP1-AS1 / MAEA C - - - - - rs6815464 8 4:1309901 MAEA C - - - - - rs6813195 28 4:153739925 TMEM154 C - - - - - rs1801214 5 4:6303022 WFS1 T - - - - - rs702634 28 5:53271420 ARL15 A A/G -4.60 2.22 0.73 0.041 rs459193 33 5:55842508 ANKRD55 G - - - - - rs4457053 5 5:76424949 ZBED3-AS1 G G/A 0.88 1.71 0.94 0.79 rs10946398 12 rs7754840 0.96 6:20661250 CDKAL1 C C/G 0.52 1.77 0.019 0.0081 rs3130501 28 6:31136453 POU5F1-TCF19 G G/A 1.43 1.95 0.57 0.75

46 Page 83 of 127 Diabetes

rs9470794 8 rs3800364 0.83 6:38121211 ZFAND3 C G/A 4.43 3.25 0.99 0.022 rs1535500 8 6:39284050 KCNK16 T - - - - - rs1048886 15 6:71289189 C6orf57 G G/A -0.15 2.09 0.40 0.36 rs9505118 28 6:7290437 SSR1-RREB1 A A/G 1.09 1.67 0.095 0.90 rs6467136 8 7:127164958 ZNF800 / GCC1 G - - - - - rs10229583 16 7:127246903 FSCN3 / PAX4 G G/A -1.64 2.24 0.73 0.80 rs972283 5 7:130466854 KLF14 / MIR29A G G/A -2.74 1.67 0.49 0.014 rs17168486 29 7:14898282 DGKB T T/C 1.28 1.68 0.71 0.21 rs864745 1 rs1635852 1.00 7:28189411 JAZF1 T T/C -4.20 1.62 0.41 0.068 rs10278336 29 7:44211888 GCK A - - - - - rs13266634 11 8:118184783 SLC30A8 C C/T 1.25 1.92 0.10 0.21 rs515071 9 rs508419 1.00 8:41522991 ANK1 C G/A 1.83 2.09 0.94 0.73 rs896854 5 rs4735337 0.81 8:95973465 TP53INP1 T T/C 2.08 1.54 0.67 0.35 rs10811661 6 9:22134094 CDKN2B-AS1 / DMRTA1 T - - - - - rs7018475 18 9:22137685 CDKN2B-AS1 / DMRTA1 T T/G -1.75 1.79 0.97 0.22 rs7041847 8 9:4287466 GLIS3 A - - - - - rs13292136 5 9:81952128 KRT18P24 / CHCHD2P9 C - - - - - rs2796441 33 9:84308948 TLE1 G G/A -2.14 1.65 0.41 0.86 rs17584499 20 9:8879118 PTPRD T T/C -1.01 1.98 0.15 0.41 rs7903146 22 10:114758349 TCF7L2 T T/C 0.33 1.87 0.76 0.34 rs10886471 19 10:121149403 GRK5 C C/T -0.16 1.48 0.60 0.30 rs12779790 1 10:12328010 CDC123 / MIR4480 G - - - - - rs1802295 4 10:70931474 VPS26A A A/G -4.82 1.94 0.32 0.0094 rs12571751 33 10:80612637 ZMIZ1 A - - - - - rs1111875 11 rs10882101 1.00 10:94462427 HHEX / EXOC6 C C/T -0.79 1.72 0.13 0.66 rs2334499 35 11:1696849 DUSP8 T T/C -2.48 1.59 0.16 0.31 rs5219 6 11:17409572 KCNJ11 T T/C 2.75 1.71 0.19 0.85 rs231362 5 11:2691471 KCNQ1;KCNQ1OT1 G G/A -0.81 1.79 0.23 0.18 rs2237892 24 11:2839751 KCNQ1 C C/T 1.75 1.84 0.36 0.48 rs1552224 5 11:72433098 ARAP1 A A/C 3.34 3.15 0.47 0.31 rs1387153 5 11:92673828 FAT3 / MTNR1B T T/C -2.52 1.87 0.61 0.013 rs7305618 17 12:121402932 RPL12P33 / HNF1A-AS1 C C/T 1.20 2.15 0.90 0.084 rs7957197 5 12:121460686 OASL T - - - - - rs4275659 28 12:123447928 MPHOSPH9 C C/T 0.55 1.64 0.61 0.37 rs10842994 33 12:27965150 KLHDC5 C C/T -1.58 2.47 0.079 0.95 rs11063069 34 12:4374373 CCND2 G G/A -1.71 2.31 0.99 0.15

47 Diabetes Page 84 of 127

rs1531343 5 rs2612067 1.00 12:66170163 RPSAP52 C G/T -0.11 3.01 0.30 0.26 rs2261181 5 12:66212318 HMGA2 T T/C 0.01 3.29 0.52 0.45 rs7961581 1 12:71663102 TSPAN8 / LGR5 C C/T -4.73 2.20 0.051 0.094 rs9552911 26 13:23864657 SGCG G - - - - - rs1359790 23 13:80717156 NDFIP2 / SPRY2 G - - - - - rs7403531 19 15:38822905 RASGRP1 T T/C 0.47 1.70 0.58 0.63 rs7172432 27 15:62396389 C2CD4A / C2CD4B A - - - - - rs7178572 4 rs11857294 0.86 15:77596725 HMG20A G C/T -2.51 1.70 0.40 0.067 rs11634397 5 15:80432222 ZFAND6 / FAH G G/A 1.41 1.55 0.79 0.14 rs2028299 4 15:90374257 AP3S2;C15orf38-AP3S2 C C/A 1.75 2.24 0.94 0.017 rs8042680 5 15:91521337 PRC1 A A/C 2.33 1.83 0.17 0.25 rs8050136 12 16:53816275 FTO A A/C -4.64 1.93 0.78 0.0019 rs7202877 33 16:75247245 BCAR1 T T/G -0.79 2.89 0.16 0.62 rs391300 20 17:2216258 SRR G G/A 1.39 1.71 0.31 0.24 rs13342232 36 17:6945940 SLC16A11 G - - - - - rs4430796 19 17:36098040 HNF1B G G/A 1.87 1.69 0.36 0.16 rs12970134 33 18:57884750 MC4R A A/G 1.96 2.36 0.36 0.65 rs8090011 14 18:7068462 LAMA1 G - - - - - rs10401969 33 19:19407718 CILP2 C C/T 4.84 3.67 0.015 0.48 rs3786897 8 19:33893008 PEPD A A/G -4.10 1.89 0.10 0.85 rs6017317 8 20:42946966 FITM2 / R3HDML G - - - - - rs4812829 4 rs2144908 1.00 20:42985717 HNF4A A A/G 3.58 1.72 0.56 0.0046 rs12010175 19 X:152862638 FAM58A G - - - - - rs5945326 5 X:152899922 KRT18P48 / DUSP9 A - - - - -

48 Page 85 of 127 Diabetes

Supplementary Table 5C. Association with reported type 2 diabetes (T2D) susceptibility loci with SI in GUARDIAN Hispanic Americans (nmax=2,549). Index SNPs reaching genome‐wide significance (P<5.0E‐08) for association with T2D were selected from the NHGRI GWAS catalog (http://www.genome.gov/gwastudies). When the index variable was unavailable in GUARDIAN, a suitable proxy was selected using the HapMap 3 MEX (Mexican ancestry in Los Angeles, California) population.

49 Diabetes Page 86 of 127 rs9470794 8 rs3800364 0.83 6:38121211 ZFAND3 C G/A 0.21 0.12 0.91 0.061 rs1535500 8 6:39284050 KCNK16 T - - - - - rs1048886 15 6:71289189 C6orf57 G G/A 0.08 0.08 0.42 0.37 rs9505118 28 6:7290437 SSR1-RREB1 A A/G -0.11 0.06 0.063 0.65 rs6467136 8 7:127164958 ZNF800 / GCC1 G - - - - - rs10229583 16 7:127246903 FSCN3 / PAX4 G G/A 0.09 0.08 0.75 0.37 rs972283 5 7:130466854 KLF14 / MIR29A G G/A -0.06 0.06 0.24 0.047 rs17168486 29 7:14898282 DGKB T T/C 0.09 0.06 0.65 0.22 rs864745 1 rs1635852 1.00 7:28189411 JAZF1 T T/C -0.03 0.06 0.82 0.44 rs10278336 29 7:44211888 GCK A - - - - - rs13266634 11 8:118184783 SLC30A8 C C/T 0.10 0.07 0.021 0.24 rs515071 9 rs508419 1.00 8:41522991 ANK1 C G/A 0.02 0.07 0.86 0.74 rs896854 5 rs4735337 0.81 8:95973465 TP53INP1 T T/C -0.03 0.06 0.54 0.87 rs10811661 6 9:22134094 CDKN2B-AS1 / DMRTA1 T - - - - - rs7018475 18 9:22137685 CDKN2B-AS1 / DMRTA1 T T/G -0.04 0.06 0.79 0.40 rs7041847 8 9:4287466 GLIS3 A - - - - - rs13292136 5 9:81952128 KRT18P24 / CHCHD2P9 C - - - - - rs2796441 33 9:84308948 TLE1 G G/A 0.03 0.06 0.56 0.30 rs17584499 20 9:8879118 PTPRD T T/C 0.12 0.07 0.83 0.10 rs7903146 22 10:114758349 TCF7L2 T T/C 0.03 0.06 0.39 0.27 rs10886471 19 10:121149403 GRK5 C C/T -0.09 0.06 0.47 0.26 rs12779790 1 10:12328010 CDC123 / MIR4480 G - - - - - rs1802295 4 10:70931474 VPS26A A A/G -0.07 0.07 0.86 0.085 rs12571751 33 10:80612637 ZMIZ1 A - - - - - rs1111875 11 rs10882101 1.00 10:94462427 HHEX / EXOC6 C C/T -0.05 0.06 0.17 0.54 rs2334499 35 11:1696849 DUSP8 T T/C -0.09 0.06 0.088 0.96 rs5219 6 11:17409572 KCNJ11 T T/C -0.03 0.06 0.57 0.11 rs231362 5 11:2691471 KCNQ1;KCNQ1OT1 G G/A 0.15 0.06 0.21 0.036 rs2237892 24 11:2839751 KCNQ1 C C/T 0.03 0.07 0.19 0.85 rs1552224 5 11:72433098 ARAP1 A A/C -0.02 0.10 0.38 0.65 rs1387153 5 11:92673828 FAT3 / MTNR1B T T/C -0.16 0.07 0.33 0.032 rs7305618 17 12:121402932 RPL12P33 / HNF1A-AS1 C C/T 0.06 0.08 0.82 0.12 rs7957197 5 12:121460686 OASL T - - - - - rs4275659 28 12:123447928 MPHOSPH9 C C/T -0.09 0.06 0.66 0.23 rs10842994 33 12:27965150 KLHDC5 C C/T 0.02 0.08 0.38 0.96 rs11063069 34 12:4374373 CCND2 G G/A -0.05 0.08 0.90 0.21

50 Page 87 of 127 Diabetes

rs1531343 5 rs2612067 1.00 12:66170163 RPSAP52 C G/T 0.23 0.11 0.14 0.19 rs2261181 5 12:66212318 HMGA2 T T/C 0.18 0.11 0.32 0.37 rs7961581 1 12:71663102 TSPAN8 / LGR5 C C/T 0.07 0.07 0.05 0.44 rs9552911 26 13:23864657 SGCG G - - - - - rs1359790 23 13:80717156 NDFIP2 / SPRY2 G - - - - - rs7403531 19 15:38822905 RASGRP1 T T/C 0.00 0.06 0.80 0.51 rs7172432 27 15:62396389 C2CD4A / C2CD4B A - - - - - rs7178572 4 rs11857294 0.86 15:77596725 HMG20A G C/T -0.04 0.06 0.95 0.19 rs11634397 5 15:80432222 ZFAND6 / FAH G G/A 0.06 0.06 0.89 0.22 rs2028299 4 15:90374257 AP3S2;C15orf38-AP3S2 C C/A 0.11 0.07 0.87 0.024 rs8042680 5 15:91521337 PRC1 A A/C -0.07 0.06 0.065 0.53 rs8050136 12 16:53816275 FTO A A/C -0.12 0.07 0.58 0.026 rs7202877 33 16:75247245 BCAR1 T T/G -0.03 0.11 0.066 0.42 rs391300 20 17:2216258 SRR G G/A 0.08 0.06 0.17 0.53 rs13342232 36 17:6945940 SLC16A11 G - - - - - rs4430796 19 17:36098040 HNF1B G G/A -0.04 0.06 0.18 0.48 rs12970134 33 18:57884750 MC4R A A/G 0.03 0.08 0.22 0.87 rs8090011 14 18:7068462 LAMA1 G - - - - - rs10401969 33 19:19407718 CILP2 C C/T 0.14 0.15 0.12 0.82 rs3786897 8 19:33893008 PEPD A A/G 0.04 0.06 0.36 0.20 rs6017317 8 20:42946966 FITM2 / R3HDML G - - - - - rs4812829 4 rs2144908 1.00 20:42985717 HNF4A A A/G 0.12 0.06 0.35 0.076 rs12010175 19 X:152862638 FAM58A G - - - - - rs5945326 5 X:152899922 KRT18P48 / DUSP9 A - - - - -

51 Diabetes Page 88 of 127

Supplementary Table 5D. Association with reported type 2 diabetes (T2D) susceptibility loci with M in GUARDIAN Hispanic Americans (nmax=1604). Index SNPs reaching genome‐wide significance (P<5.0E‐08) for association with T2D were selected from the NHGRI GWAS catalog (http://www.genome.gov/gwastudies). When the index variable was unavailable in GUARDIAN, a suitable proxy was selected using the HapMap 3 MEX (Mexican ancestry in Los Angeles, California) population.

2 Index r Position Alleles Heterogeneity Additive Ref Proxy Gene(s) Beta SE SNP (MEX) (hg19) Risk Ref/Alt P-value P-value rs10923931 1 rs2793831 1.00 1:120523902 NOTCH2 T T/C 0.62 6.68 0.35 1.00 rs2075423 29 1:212221342 PROX1 G - - - - - rs17106184 28 rs1278516 1.00 1:50900021 FAF1 G G/A -2.03 9.91 0.75 0.88 rs6723108 30 2:135479980 TMEM163 T T/G -4.00 5.82 0.48 0.35 rs7560163 2 2:151637936 RND3 / FABP5P10 C - - - - - rs7593730 3 2:161171454 RBMS1 C - - - - - rs3923113 4 2:165501849 EIF3EP3 / SNORA70F A - - - - - rs7578326 5 rs13405357 0.90 2:227022036 LOC646736 A A/G 5.87 4.59 0.058 0.20 rs2943641 31 2:227093745 IRS1 C C/T 2.18 5.00 0.11 0.63 rs780094 29 2:27741237 GCKR C C/T -2.51 4.09 0.91 0.48 rs7578597 1 2:43732823 THADA T T/C 8.55 8.66 0.54 0.40 rs243021 5 2:60584819 BCL11A A A/G 2.90 4.02 0.48 0.45 rs11708067 29 3:123065778 ADCY5 A A/G 1.30 4.48 0.47 0.96 rs1801282 3:12393125 PPARG C C/G 6.58 6.52 0.70 0.36 rs4402960 6 3:185511687 IGF2BP2 T T/G 0.00 4.70 0.45 0.85 rs16861329 4 rs16861317 1.00 3:186664728 ST6GAL1 G G/A 0.10 4.28 0.12 0.64 rs6808574 28 3:187740523 LPP C C/T -4.75 5.08 0.20 0.15 rs7612463 32 3:23336450 UBE2E2 C C/A -7.18 8.49 0.88 0.40 rs831571 8 rs35837 0.92 3:64013249 PSMD6 / PRICKLE2-AS1 C C/T -1.79 6.88 0.72 0.94 rs4607103 1 3:64711904 ADAMTS9-AS2 C C/T -5.49 4.18 0.11 0.40 rs7656416 9 4:1254535 CTBP1-AS1 / MAEA C - - - - - rs6815464 8 4:1309901 MAEA C - - - - - rs6813195 28 4:153739925 TMEM154 C - - - - - rs1801214 5 4:6303022 WFS1 T - - - - - rs702634 28 5:53271420 ARL15 A A/G -10.81 5.28 0.76 0.044 rs459193 33 5:55842508 ANKRD55 G - - - - - rs4457053 5 5:76424949 ZBED3-AS1 G G/A 2.12 4.06 0.60 0.43 rs10946398 12 rs7754840 0.96 6:20661250 CDKAL1 C C/G 1.13 4.21 0.72 0.93 rs3130501 28 6:31136453 POU5F1-TCF19 G G/A 3.49 4.62 0.23 0.67

52 Page 89 of 127 Diabetes

rs9470794 8 rs3800364 0.83 6:38121211 ZFAND3 C G/A 11.70 8.83 0.93 0.19 rs1535500 8 6:39284050 KCNK16 T - - - - - rs1048886 15 6:71289189 C6orf57 G G/A -0.45 4.96 0.19 0.73 rs9505118 28 6:7290437 SSR1-RREB1 A A/G 2.75 3.97 0.26 0.44 rs6467136 8 7:127164958 ZNF800 / GCC1 G - - - - - rs10229583 16 7:127246903 FSCN3 / PAX4 G G/A -4.01 5.32 0.56 0.47 rs972283 5 7:130466854 KLF14 / MIR29A G G/A -6.42 3.96 0.53 0.15 rs17168486 29 7:14898282 DGKB T T/C 2.91 3.99 0.37 0.63 rs864745 1 rs1635852 1.00 7:28189411 JAZF1 T T/C -13.90 5.39 0.20 0.021 rs10278336 29 7:44211888 GCK A - - - - - rs13266634 11 8:118184783 SLC30A8 C C/T 2.83 4.57 0.71 0.60 rs515071 9 rs508419 1.00 8:41522991 ANK1 C G/A 4.32 4.95 0.94 0.34 rs896854 5 rs4735337 0.81 8:95973465 TP53INP1 T T/C 5.71 4.18 0.74 0.18 rs10811661 6 9:22134094 CDKN2B-AS1 / DMRTA1 T - - - - - rs7018475 18 9:22137685 CDKN2B-AS1 / DMRTA1 T T/G -4.11 4.24 0.93 0.36 rs7041847 8 9:4287466 GLIS3 A - - - - - rs13292136 5 9:81952128 KRT18P24 / CHCHD2P9 C - - - - - rs2796441 33 9:84308948 TLE1 G G/A -7.03 5.36 0.86 0.17 rs17584499 20 9:8879118 PTPRD T T/C -2.55 4.69 0.053 0.45 rs7903146 22 10:114758349 TCF7L2 T T/C 0.75 4.45 0.97 0.87 rs10886471 19 10:121149403 GRK5 C C/T -0.41 6.44 1.00 0.95 rs12779790 1 10:12328010 CDC123 / MIR4480 G - - - - - rs1802295 4 10:70931474 VPS26A A A/G -11.34 4.60 0.050 0.045 rs12571751 33 10:80612637 ZMIZ1 A - - - - - rs1111875 11 rs10882101 1.00 10:94462427 HHEX / EXOC6 C C/T -1.81 4.08 0.10 0.96 rs2334499 35 11:1696849 DUSP8 T T/C -5.77 3.77 0.55 0.12 rs5219 6 11:17409572 KCNJ11 T T/C 6.57 4.05 0.55 0.083 rs231362 5 11:2691471 KCNQ1;KCNQ1OT1 G G/A -2.12 4.24 0.66 0.64 rs2237892 24 11:2839751 KCNQ1 C C/T 4.11 4.36 0.47 0.37 rs1552224 5 11:72433098 ARAP1 A A/C 7.96 7.47 0.32 0.28 rs1387153 5 11:92673828 FAT3 / MTNR1B T T/C -6.57 5.08 0.83 0.20 rs7305618 17 12:121402932 RPL12P33 / HNF1A-AS1 C C/T 2.77 5.10 0.56 0.41 rs7957197 5 12:121460686 OASL T - - - - - rs4275659 28 12:123447928 MPHOSPH9 C C/T 1.42 3.89 0.32 0.96 rs10842994 33 12:27965150 KLHDC5 C C/T -3.78 5.86 0.016 0.87 rs11063069 34 12:4374373 CCND2 G G/A -4.55 6.28 0.95 0.46

53 Diabetes Page 90 of 127

rs1531343 5 rs2612067 1.00 12:66170163 RPSAP52 C G/T -0.58 7.15 0.51 0.88 rs2261181 5 12:66212318 HMGA2 T T/C -0.23 7.80 0.49 0.94 rs7961581 1 12:71663102 TSPAN8 / LGR5 C C/T -11.34 5.21 0.14 0.09 rs9552911 26 13:23864657 SGCG G - - - - - rs1359790 23 13:80717156 NDFIP2 / SPRY2 G - - - - - rs7403531 19 15:38822905 RASGRP1 T T/C 1.10 4.03 0.17 0.96 rs7172432 27 15:62396389 C2CD4A / C2CD4B A - - - - - rs7178572 4 rs11857294 0.86 15:77596725 HMG20A G C/T -5.90 4.04 0.054 0.20 rs11634397 5 15:80432222 ZFAND6 / FAH G G/A 3.75 4.20 0.18 0.42 rs2028299 4 15:90374257 AP3S2;C15orf38-AP3S2 C C/A 4.00 5.32 0.73 0.32 rs8042680 5 15:91521337 PRC1 A A/C 5.63 4.35 0.44 0.28 rs8050136 12 16:53816275 FTO A A/C -10.84 4.58 0.57 0.028 rs7202877 33 16:75247245 BCAR1 T T/G -2.10 7.86 0.60 0.81 rs391300 20 17:2216258 SRR G G/A 3.19 4.05 0.40 0.28 rs13342232 36 17:6945940 SLC16A11 G - - - - - rs4430796 19 17:36098040 HNF1B G G/A 4.48 4.00 0.52 0.17 rs12970134 33 18:57884750 MC4R A A/G 4.60 5.60 0.46 0.35 rs8090011 14 18:7068462 LAMA1 G - - - - - rs10401969 33 19:19407718 CILP2 C C/T 12.91 9.96 0.0049 0.38 rs3786897 8 19:33893008 PEPD A A/G -9.78 4.48 0.35 0.054 rs6017317 8 20:42946966 FITM2 / R3HDML G - - - - - rs4812829 4 rs2144908 1.00 20:42985717 HNF4A A A/G 8.33 4.09 0.58 0.020 rs12010175 19 X:152862638 FAM58A G - - - - - rs5945326 5 X:152899922 KRT18P48 / DUSP9 A - - - - -

54 Page 91 of 127 Diabetes

Supplementary Table 5E. Association with reported type 2 diabetes (T2D) susceptibility loci with AIRg in GUARDIAN Hispanic Americans (nmax=2,548). Index SNPs reaching genome‐wide significance (P<5.0E‐08) for association with T2D were selected from the NHGRI GWAS catalog (http://www.genome.gov/gwastudies). When the index variable was unavailable in GUARDIAN, a suitable proxy was selected using the HapMap 3 MEX (Mexican ancestry in Los Angeles, California) population.

2 Index r Position Alleles Heterogeneity Additive Ref Proxy Gene(s) Beta SE SNP (MEX) (hg19) Risk Ref/Alt P-value P-value rs10923931 1 rs2793831 1.00 1:120523902 NOTCH2 T T/C -0.81 0.49 0.25 0.14 rs2075423 29 1:212221342 PROX1 G - - - - - rs17106184 28 rs1278516 1.00 1:50900021 FAF1 G G/A -1.32 0.77 0.64 0.021 rs6723108 30 2:135479980 TMEM163 T T/G -0.21 0.45 0.65 0.30 rs7560163 2 2:151637936 RND3 / FABP5P10 C - - - - - rs7593730 3 2:161171454 RBMS1 C - - - - - rs3923113 4 2:165501849 EIF3EP3 / SNORA70F A - - - - - rs7578326 5 rs13405357 0.90 2:227022036 LOC646736 A A/G 0.03 0.35 0.30 0.63 rs2943641 31 2:227093745 IRS1 C C/T 0.23 0.39 0.94 0.42 rs780094 29 2:27741237 GCKR C C/T -0.61 0.32 0.45 0.16 rs7578597 1 2:43732823 THADA T T/C -0.77 0.63 0.52 0.29 rs243021 5 2:60584819 BCL11A A A/G 0.31 0.32 0.66 0.52 8.85E- rs11708067 29 3:123065778 ADCY5 A A/G -1.01 0.37 0.097 05 rs1801282 3:12393125 PPARG C C/G 1.05 0.49 0.66 0.013 rs4402960 6 3:185511687 IGF2BP2 T T/G -0.76 0.35 0.81 0.016 rs16861329 4 rs16861317 1.00 3:186664728 ST6GAL1 G G/A -0.25 0.34 0.32 0.12 rs6808574 28 3:187740523 LPP C C/T -0.26 0.39 0.20 0.26 rs7612463 32 3:23336450 UBE2E2 C C/A 1.26 0.61 0.11 0.20 rs831571 8 rs35837 0.92 3:64013249 PSMD6 / PRICKLE2-AS1 C C/T 0.46 0.52 0.011 0.99 rs4607103 1 3:64711904 ADAMTS9-AS2 C C/T 0.36 0.34 0.64 0.093 rs7656416 9 4:1254535 CTBP1-AS1 / MAEA C - - - - - rs6815464 8 4:1309901 MAEA C - - - - - rs6813195 28 4:153739925 TMEM154 C - - - - - rs1801214 5 4:6303022 WFS1 T - - - - - rs702634 28 5:53271420 ARL15 A A/G -0.26 0.41 0.28 0.45 rs459193 33 5:55842508 ANKRD55 G - - - - - rs4457053 5 5:76424949 ZBED3-AS1 G G/A -0.69 0.33 0.71 0.027 rs10946398 12 rs7754840 0.96 6:20661250 CDKAL1 C C/G -1.26 0.33 0.72 3.8E-06 rs3130501 28 6:31136453 POU5F1-TCF19 G G/A 0.10 0.38 0.81 0.64 55 Diabetes Page 92 of 127 rs9470794 8 rs3800364 0.83 6:38121211 ZFAND3 C G/A 0.66 0.69 0.80 0.50 rs1535500 8 6:39284050 KCNK16 T - - - - - rs1048886 15 6:71289189 C6orf57 G G/A 0.07 0.41 0.044 0.61 rs9505118 28 6:7290437 SSR1-RREB1 A A/G 0.14 0.33 0.14 0.64 rs6467136 8 7:127164958 ZNF800 / GCC1 G - - - - - rs10229583 16 7:127246903 FSCN3 / PAX4 G G/A -1.12 0.43 0.58 0.0028 rs972283 5 7:130466854 KLF14 / MIR29A G G/A -0.11 0.33 0.31 0.94 rs17168486 29 7:14898282 DGKB T T/C -0.78 0.33 0.70 0.033 rs864745 1 rs1635852 1.00 7:28189411 JAZF1 T T/C 0.06 0.33 0.79 0.83 rs10278336 29 7:44211888 GCK A - - - - - rs13266634 11 8:118184783 SLC30A8 C C/T -0.50 0.37 0.30 0.021 rs515071 9 rs508419 1.00 8:41522991 ANK1 C G/A -0.30 0.40 0.93 0.61 rs896854 5 rs4735337 0.81 8:95973465 TP53INP1 T T/C -0.25 0.31 0.54 0.35 rs10811661 6 9:22134094 CDKN2B-AS1 / DMRTA1 T - - - - - rs7018475 18 9:22137685 CDKN2B-AS1 / DMRTA1 T T/G 1.64 0.34 0.18 4.9E-06 rs7041847 8 9:4287466 GLIS3 A - - - - - rs13292136 5 9:81952128 KRT18P24 / CHCHD2P9 C - - - - - rs2796441 33 9:84308948 TLE1 G G/A -0.31 0.31 0.68 0.46 rs17584499 20 9:8879118 PTPRD T T/C -1.27 0.38 0.20 0.0037 rs7903146 22 10:114758349 TCF7L2 T T/C -1.03 0.36 0.090 2.5E-04 rs10886471 19 10:121149403 GRK5 C C/T 0.43 0.32 0.45 0.15 rs12779790 1 10:12328010 CDC123 / MIR4480 G - - - - - rs1802295 4 10:70931474 VPS26A A A/G 0.51 0.37 0.91 0.17 rs12571751 33 10:80612637 ZMIZ1 A - - - - - rs1111875 11 rs10882101 1.00 10:94462427 HHEX / EXOC6 C C/T 0.29 0.33 0.58 0.51 rs2334499 35 11:1696849 DUSP8 T T/C 0.19 0.32 0.025 0.55 rs5219 6 11:17409572 KCNJ11 T T/C -0.10 0.32 0.91 0.86 rs231362 5 11:2691471 KCNQ1;KCNQ1OT1 G G/A -0.29 0.34 0.30 0.49 rs2237892 24 11:2839751 KCNQ1 C C/T -0.73 0.36 0.053 0.0077 rs1552224 5 11:72433098 ARAP1 A A/C -1.71 0.62 0.89 0.0015 rs1387153 5 11:92673828 FAT3 / MTNR1B T T/C -1.99 0.36 0.43 2.3E-08 rs7305618 17 12:121402932 RPL12P33 / HNF1A-AS1 C C/T -1.60 0.45 0.30 5.8E-04 rs7957197 5 12:121460686 OASL T - - - - - rs4275659 28 12:123447928 MPHOSPH9 C C/T 0.53 0.32 0.67 0.18 rs10842994 33 12:27965150 KLHDC5 C C/T -0.94 0.44 0.41 0.11 rs11063069 34 12:4374373 CCND2 G G/A -0.17 0.49 0.24 0.60

56 Page 93 of 127 Diabetes

rs1531343 5 rs2612067 1.00 12:66170163 RPSAP52 C G/T -0.82 0.60 0.84 0.21 rs2261181 5 12:66212318 HMGA2 T T/C -0.54 0.64 0.75 0.47 rs7961581 1 12:71663102 TSPAN8 / LGR5 C C/T -0.15 0.39 0.027 0.54 rs9552911 26 13:23864657 SGCG G - - - - - rs1359790 23 13:80717156 NDFIP2 / SPRY2 G - - - - - rs7403531 19 15:38822905 RASGRP1 T T/C -0.14 0.32 0.47 0.39 rs7172432 27 15:62396389 C2CD4A / C2CD4B A - - - - - rs7178572 4 rs11857294 0.86 15:77596725 HMG20A G C/T -0.05 0.33 0.59 0.88 rs11634397 5 15:80432222 ZFAND6 / FAH G G/A 0.14 0.31 0.26 0.35 rs2028299 4 15:90374257 AP3S2;C15orf38-AP3S2 C C/A -0.72 0.38 0.19 0.011 rs8042680 5 15:91521337 PRC1 A A/C -0.28 0.33 0.096 0.42 rs8050136 12 16:53816275 FTO A A/C 0.33 0.36 0.82 0.30 rs7202877 33 16:75247245 BCAR1 T T/G -0.94 0.63 0.0035 0.049 rs391300 20 17:2216258 SRR G G/A 0.08 0.34 0.80 0.82 rs13342232 36 17:6945940 SLC16A11 G - - - - - rs4430796 19 17:36098040 HNF1B G G/A -0.83 0.32 0.75 0.008 rs12970134 33 18:57884750 MC4R A A/G -0.18 0.43 0.24 0.95 rs8090011 14 18:7068462 LAMA1 G - - - - - rs10401969 33 19:19407718 CILP2 C C/T 0.37 0.81 0.62 0.25 rs3786897 8 19:33893008 PEPD A A/G -0.28 0.35 0.33 0.27 rs6017317 8 20:42946966 FITM2 / R3HDML G - - - - - rs4812829 4 rs2144908 1.00 20:42985717 HNF4A A A/G -0.12 0.31 0.92 0.70 rs12010175 19 X:152862638 FAM58A G - - - - - rs5945326 5 X:152899922 KRT18P48 / DUSP9 A - - - - -

57 Diabetes Page 94 of 127

Supplementary Table 5F. Association with reported type 2 diabetes (T2D) susceptibility loci with DI in GUARDIAN Hispanic Americans (nmax=3,083). Index SNPs reaching genome‐wide significance (P<5.0E‐08) for association with T2D were selected from the NHGRI GWAS catalog (http://www.genome.gov/gwastudies). When the index variable was unavailable in GUARDIAN, a suitable proxy was selected using the HapMap 3 MEX (Mexican ancestry in Los Angeles, California) population.

58 Page 95 of 127 Diabetes

rs9470794 8 rs3800364 0.83 6:38121211 ZFAND3 C G/A 1.40 0.79 0.92 0.10 rs1535500 8 6:39284050 KCNK16 T - - - - - rs1048886 15 6:71289189 C6orf57 G G/A -0.11 0.45 0.27 0.85 rs9505118 28 6:7290437 SSR1-RREB1 A A/G 0.03 0.36 0.071 0.79 rs6467136 8 7:127164958 ZNF800 / GCC1 G - - - - - rs10229583 16 7:127246903 FSCN3 / PAX4 G G/A -0.85 0.50 0.60 0.064 rs972283 5 7:130466854 KLF14 / MIR29A G G/A -0.67 0.36 0.27 0.033 rs17168486 29 7:14898282 DGKB T T/C -0.37 0.36 0.17 0.74 rs864745 1 rs1635852 1.00 7:28189411 JAZF1 T T/C -0.49 0.44 0.89 0.28 rs10278336 29 7:44211888 GCK A - - - - - rs13266634 11 8:118184783 SLC30A8 C C/T -0.77 0.40 0.79 0.018 rs515071 9 rs508419 1.00 8:41522991 ANK1 C G/A -0.07 0.44 0.92 0.79 rs896854 5 rs4735337 0.81 8:95973465 TP53INP1 T T/C -0.21 0.35 0.95 0.43 rs10811661 6 9:22134094 CDKN2B-AS1 / DMRTA1 T - - - - - rs7018475 18 9:22137685 CDKN2B-AS1 / DMRTA1 T T/G 1.32 0.37 0.17 3.9E-04 rs7041847 8 9:4287466 GLIS3 A - - - - - rs13292136 5 9:81952128 KRT18P24 / CHCHD2P9 C - - - - - rs2796441 33 9:84308948 TLE1 G G/A -0.01 0.34 0.36 0.63 rs17584499 20 9:8879118 PTPRD T T/C -0.58 0.42 0.70 0.33 rs7903146 22 10:114758349 TCF7L2 T T/C -1.06 0.40 0.08 5.8E-05 rs10886471 19 10:121149403 GRK5 C C/T 0.12 0.37 0.66 0.90 rs12779790 1 10:12328010 CDC123 / MIR4480 G - - - - - rs1802295 4 10:70931474 VPS26A A A/G 0.13 0.41 0.55 0.99 rs12571751 33 10:80612637 ZMIZ1 A - - - - - rs1111875 11 rs10882101 1.00 10:94462427 HHEX / EXOC6 C C/T 0.32 0.36 0.51 0.49 rs2334499 35 11:1696849 DUSP8 T T/C -0.49 0.35 0.07 0.39 rs5219 6 11:17409572 KCNJ11 T T/C -0.29 0.35 0.23 0.18 rs231362 5 11:2691471 KCNQ1;KCNQ1OT1 G G/A 0.71 0.37 0.12 0.19 rs2237892 24 11:2839751 KCNQ1 C C/T -0.88 0.41 0.0007 0.0035 rs1552224 5 11:72433098 ARAP1 A A/C -1.65 0.71 0.50 0.016 rs1387153 5 11:92673828 FAT3 / MTNR1B T T/C -2.69 0.42 0.0046 5.7E-09 rs7305618 17 12:121402932 RPL12P33 / HNF1A-AS1 C C/T -0.46 0.50 0.98 0.26 rs7957197 5 12:121460686 OASL T - - - - - rs4275659 28 12:123447928 MPHOSPH9 C C/T 0.06 0.35 0.82 0.96 rs10842994 33 12:27965150 KLHDC5 C C/T -0.91 0.50 0.70 0.21 rs11063069 34 12:4374373 CCND2 G G/A -0.79 0.56 0.69 0.40

59 Diabetes Page 96 of 127

rs1531343 5 rs2612067 1.00 12:66170163 RPSAP52 C G/T 0.19 0.68 0.15 0.68 rs2261181 5 12:66212318 HMGA2 T T/C 0.08 0.72 0.14 0.85 rs7961581 1 12:71663102 TSPAN8 / LGR5 C C/T -0.36 0.45 0.94 0.31 rs9552911 26 13:23864657 SGCG G - - - - - rs1359790 23 13:80717156 NDFIP2 / SPRY2 G - - - - - rs7403531 19 15:38822905 RASGRP1 T T/C -0.08 0.35 0.61 0.81 rs7172432 27 15:62396389 C2CD4A / C2CD4B A - - - - - rs7178572 4 rs11857294 0.86 15:77596725 HMG20A G C/T -0.33 0.36 0.16 0.28 rs11634397 5 15:80432222 ZFAND6 / FAH G G/A 0.51 0.36 0.80 0.052 rs2028299 4 15:90374257 AP3S2;C15orf38-AP3S2 C C/A 0.14 0.44 0.014 0.72 rs8042680 5 15:91521337 PRC1 A A/C -0.24 0.36 0.68 0.64 rs8050136 12 16:53816275 FTO A A/C -0.21 0.39 0.86 0.51 rs7202877 33 16:75247245 BCAR1 T T/G -0.51 0.72 0.48 0.48 rs391300 20 17:2216258 SRR G G/A 0.01 0.37 0.96 0.90 rs13342232 36 17:6945940 SLC16A11 G - - - - - rs4430796 19 17:36098040 HNF1B G G/A -0.72 0.35 0.038 0.20 rs12970134 33 18:57884750 MC4R A A/G -0.08 0.50 0.68 0.91 rs8090011 14 18:7068462 LAMA1 G - - - - - rs10401969 33 19:19407718 CILP2 C C/T 2.02 0.92 0.12 0.008 rs3786897 8 19:33893008 PEPD A A/G 0.29 0.38 0.68 0.86 rs6017317 8 20:42946966 FITM2 / R3HDML G - - - - - rs4812829 4 rs2144908 1.00 20:42985717 HNF4A A A/G 0.02 0.34 0.59 0.96 rs12010175 19 X:152862638 FAM58A G - - - - - rs5945326 5 X:152899922 KRT18P48 / DUSP9 A - - - - -

60 Page 97 of 127 Diabetes

Supplementary Table 5G. Association with reported type 2 diabetes (T2D) susceptibility loci with SG in GUARDIAN Hispanic Americans (nmax=2,542). Index SNPs reaching genome‐wide significance (P<5.0E‐08) for association with T2D were selected from the NHGRI GWAS catalog (http://www.genome.gov/gwastudies). When the index variable was unavailable in GUARDIAN, a suitable proxy was selected using the HapMap 3 MEX (Mexican ancestry in Los Angeles, California) population.

61 Diabetes Page 98 of 127 rs9470794 8 rs3800364 0.83 6:38121211 ZFAND3 C G/A 0.04 0.06 0.67 0.58 rs1535500 8 6:39284050 KCNK16 T - - - - - rs1048886 15 6:71289189 C6orf57 G G/A 0.04 0.04 0.21 0.48 rs9505118 28 6:7290437 SSR1-RREB1 A A/G -0.05 0.03 0.15 0.20 rs6467136 8 7:127164958 ZNF800 / GCC1 G - - - - - rs10229583 16 7:127246903 FSCN3 / PAX4 G G/A 0.00 0.04 0.88 0.98 rs972283 5 7:130466854 KLF14 / MIR29A G G/A -0.02 0.03 0.062 0.44 rs17168486 29 7:14898282 DGKB T T/C -0.03 0.03 0.80 0.22 rs864745 1 rs1635852 1.00 7:28189411 JAZF1 T T/C 0.03 0.03 0.33 0.29 rs10278336 29 7:44211888 GCK A - - - - - rs13266634 11 8:118184783 SLC30A8 C C/T -0.04 0.03 0.16 0.070 rs515071 9 rs508419 1.00 8:41522991 ANK1 C G/A 0.00 0.03 0.41 0.67 rs896854 5 rs4735337 0.81 8:95973465 TP53INP1 T T/C 0.00 0.03 0.28 0.93 rs10811661 6 9:22134094 CDKN2B-AS1 / DMRTA1 T - - - - - rs7018475 18 9:22137685 CDKN2B-AS1 / DMRTA1 T T/G 0.04 0.03 0.24 0.41 rs7041847 8 9:4287466 GLIS3 A - - - - - rs13292136 5 9:81952128 KRT18P24 / CHCHD2P9 C - - - - - rs2796441 33 9:84308948 TLE1 G G/A -0.01 0.03 0.20 0.93 rs17584499 20 9:8879118 PTPRD T T/C 0.00 0.03 0.91 0.85 rs7903146 22 10:114758349 TCF7L2 T T/C 0.01 0.03 0.20 0.96 rs10886471 19 10:121149403 GRK5 C C/T -0.04 0.03 0.91 0.19 rs12779790 1 10:12328010 CDC123 / MIR4480 G - - - - - rs1802295 4 10:70931474 VPS26A A A/G -0.02 0.03 0.44 0.44 rs12571751 33 10:80612637 ZMIZ1 A - - - - - rs1111875 11 rs10882101 1.00 10:94462427 HHEX / EXOC6 C C/T -0.01 0.03 0.51 0.62 rs2334499 35 11:1696849 DUSP8 T T/C -0.04 0.03 0.59 0.10 rs5219 6 11:17409572 KCNJ11 T T/C -0.06 0.03 0.29 0.0076 rs231362 5 11:2691471 KCNQ1;KCNQ1OT1 G G/A 0.04 0.03 0.66 0.15 rs2237892 24 11:2839751 KCNQ1 C C/T 0.00 0.03 0.44 0.95 rs1552224 5 11:72433098 ARAP1 A A/C 0.02 0.05 0.98 0.75 rs1387153 5 11:92673828 FAT3 / MTNR1B T T/C -0.12 0.03 0.39 3.0E-04 rs7305618 17 12:121402932 RPL12P33 / HNF1A-AS1 C C/T -0.08 0.04 0.71 0.049 rs7957197 5 12:121460686 OASL T - - - - - rs4275659 28 12:123447928 MPHOSPH9 C C/T 0.00 0.03 0.45 1.00 rs10842994 33 12:27965150 KLHDC5 C C/T -0.02 0.04 0.29 0.86 rs11063069 34 12:4374373 CCND2 G G/A -0.04 0.04 0.31 0.47

62 Page 99 of 127 Diabetes

rs1531343 5 rs2612067 1.00 12:66170163 RPSAP52 C G/T -0.04 0.05 0.25 0.56 rs2261181 5 12:66212318 HMGA2 T T/C -0.05 0.05 0.33 0.33 rs7961581 1 12:71663102 TSPAN8 / LGR5 C C/T -0.01 0.03 0.78 0.93 rs9552911 26 13:23864657 SGCG G - - - - - rs1359790 23 13:80717156 NDFIP2 / SPRY2 G - - - - - rs7403531 19 15:38822905 RASGRP1 T T/C 0.02 0.03 0.12 0.94 rs7172432 27 15:62396389 C2CD4A / C2CD4B A - - - - - rs7178572 4 rs11857294 0.86 15:77596725 HMG20A G C/T -0.04 0.03 0.29 0.42 rs11634397 5 15:80432222 ZFAND6 / FAH G G/A 0.01 0.03 0.35 0.32 rs2028299 4 15:90374257 AP3S2;C15orf38-AP3S2 C C/A -0.01 0.03 0.0055 0.93 rs8042680 5 15:91521337 PRC1 A A/C -0.01 0.03 0.73 0.78 rs8050136 12 16:53816275 FTO A A/C -0.02 0.03 0.21 0.48 rs7202877 33 16:75247245 BCAR1 T T/G 0.07 0.05 0.24 0.23 rs391300 20 17:2216258 SRR G G/A 0.01 0.03 0.67 0.52 rs13342232 36 17:6945940 SLC16A11 G - - - - - rs4430796 19 17:36098040 HNF1B G G/A -0.04 0.03 0.26 0.14 rs12970134 33 18:57884750 MC4R A A/G -0.03 0.04 0.76 0.51 rs8090011 14 18:7068462 LAMA1 G - - - - - rs10401969 33 19:19407718 CILP2 C C/T 0.06 0.07 0.13 0.27 rs3786897 8 19:33893008 PEPD A A/G 0.02 0.03 0.40 0.83 rs6017317 8 20:42946966 FITM2 / R3HDML G - - - - - rs4812829 4 rs2144908 1.00 20:42985717 HNF4A A A/G -0.02 0.03 0.49 0.57 rs12010175 19 X:152862638 FAM58A G - - - - - rs5945326 5 X:152899922 KRT18P48 / DUSP9 A - - - - -

63 Diabetes Page 100 of 127

REFERENCES

1. Zeggini et al. Meta‐analysis of genome‐wide association data and large‐scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet 40:638‐645, 2008 2. Palmer et al. A genome‐wide association search for type 2 diabetes genes in African Americans. PLoS One 7:e29202, 2012 3. Qi et al. Genetic variants at 2q24 are associated with susceptibility to type 2 diabetes. Hum Mol Genet 19:2706‐2715, 2010 4. Kooner et al. Genome‐wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci. Nat Genet 43:984‐989, 2011 5. Voight et al. Twelve type 2 diabetes susceptibility loci identified through large‐scale association analysis. Nat Genet 42:579‐589, 2010 6. Scott et al. A genome‐wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316:1341‐1345, 2007 7. Unoki et al. SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations. Nat Genet 40:1098‐1102, 2008 8. Cho et al. Meta‐analysis of genome‐wide association studies identifies eight new loci for type 2 diabetes in east Asians. Nat Genet 44:67‐72, 2012 9. Imamura et al. A single‐nucleotide polymorphism in ANK1 is associated with susceptibility to type 2 diabetes in Japanese populations. Hum Mol Genet 21:3042‐3049, 2012 10. Takeuchi et al. Confirmation of multiple risk Loci and genetic impacts by a genome‐wide association study of type 2 diabetes in the Japanese population. Diabetes 58:1690‐1699, 2009 11. Saxena et al. Genome‐wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316:1331‐1336, 2007 12. Zeggini et al. Replication of genome‐wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316:1336‐1341, 2007 13. Steinthorsdottir et al. A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet 39:770‐775, 2007 14. Perry et al. Stratifying type 2 diabetes cases by BMI identifies genetic risk variants in LAMA1 and enrichment for risk variants in lean compared to obese cases. PLoS Genet 8:e1002741, 2012 15. Sim et al. Transferability of type 2 diabetes implicated loci in multi‐ethnic cohorts from Southeast Asia. PLoS Genet 7:e1001363, 2011 16. Ma et al. Genome‐wide association study in a Chinese population identifies a susceptibility locus for type 2 diabetes at 7q32 near PAX4. Diabetologia 56:1291‐1305, 2013 17. Parra et al. Genome‐wide association study of type 2 diabetes in a sample from Mexico City and a meta‐analysis of a Mexican‐American sample from Starr County, Texas. Diabetologia 54:2038‐2046, 2011 18. Huang et al. 1000 Genomes‐based imputation identifies novel and refined associations for the Wellcome Trust Case Control Consortium phase 1 Data. Eur J Hum Genet 20:801‐805, 2012 19. Li et al. A genome‐wide association study identifies GRK5 and RASGRP1 as type 2 diabetes loci in Chinese Hans. Diabetes 62:291‐298, 2013 20. Tsai et al. A genome‐wide association study identifies susceptibility variants for type 2 diabetes in Han Chinese. PLoS Genet 6:e1000847, 2010 21. WTCCC Genome‐wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447:661‐678, 2007 22. Sladek at al. A genome‐wide association study identifies novel risk loci for type 2 diabetes. Nature 445:881‐885, 2007 23. Shu et al. Identification of new genetic risk variants for type 2 diabetes. PLoS Genet 6:e1001127, 2010 24. Yasuda et al. Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus. Nat Genet 40:1092‐1097, 2008 25. Cui et al. A genome‐wide association study confirms previously reported loci for type 2 diabetes in Han Chinese. PLoS One 6:e22353, 2011 26. Saxena et al. Genome‐wide association study identifies a novel locus contributing to type 2 diabetes susceptibility in Sikhs of Punjabi origin from India. Diabetes 62:1746‐1755, 2013 27. Yamauchi et al. A genome‐wide association study in the Japanese population identifies susceptibility loci for type 2 diabetes at UBE2E2 and C2CD4A‐C2CD4B. Nat Genet 42:864‐868, 2010

64 Page 101 of 127 Diabetes

Supplementary Table 6. All SNPs from GWAS of T2D-related quantitative traits with Translation to T2D in Mexican-origin cohorts ordered by trait from the Discovery stage.

Discovery Cohort Translational Cohort Discovery and Translational Marker Chr Position Gene RA/ RA Trait Beta P‐value OR (95%CI) P‐value Meta‐Analysis Nonref Frequency P‐value rs4350219 1 19858807 MCRI 0.24 7.45E‐05 T/C 0.244 0.93 (0.86‐1.00) 1.40E‐01 1.21E‐04 rs11247954 1 26741285 LIN28A MCRI 0.26 9.76E‐05 A/G 0.179 1.03 (0.93‐1.14) 4.97E‐01 2.29E‐02 rs2278979 1 26877708 RPS6KA1 MCRI 0.31 3.16E‐05 A/G 0.405 1.06 (0.99‐1.13) 4.33E‐01 1.69E‐02 rs3790645 1 26884864 RPS6KA1 MCRI 0.34 6.07E‐06 A/G 0.421 1.05 (0.98‐1.12) 8.57E‐01 2.13E‐03 rs1064196 1 26887592 RPS6KA1 MCRI 0.34 9.75E‐06 C/T 0.424 1.04 (0.97‐1.11) 7.54E‐01 3.66E‐03 rs282177 1 26899125 RPS6KA1 MCRI 0.34 3.30E‐05 T/C 0.451 1.07 (1.00‐1.15) 3.62E‐01 2.20E‐02 rs7549785 1 159277868 FCER1A MCRI 0.34 7.92E‐04 A/G 0.163 1.22 (1.11‐1.35) 1.66E‐03 8.82E‐01 rs12742834 1 240107121 MCRI 0.22 1.94E‐04 C/T 0.245 1.06 (0.98‐1.16) 8.27E‐01 1.31E‐02 rs6697598 1 241105515 RGS7 MCRI ‐0.60 1.88E‐05 C/T 0.042 0.99 (0.82‐1.19) 3.16E‐01 2.05E‐02 rs6718111 2 8201262 LINC00299 MCRI ‐0.19 9.33E‐05 C/T 0.487 0.99 (0.92‐1.06) 2.49E‐01 5.14E‐02 rs1044280 2 8871342 KIDINS220 MCRI 0.19 6.97E‐05 A/C 0.287 0.99 (0.92‐1.07) 8.72E‐01 3.43E‐03 rs7572039 2 31061392 MCRI 0.36 2.74E‐05 T/G 0.078 1.10 (0.97‐1.24) 1.59E‐01 4.88E‐02 rs10197417 2 70881592 ADD2 MCRI ‐0.15 7.00E‐04 T/C 0.411 0.98 (0.91‐1.05) 4.51E‐01 6.23E‐02 rs6745880 2 171105318 MYO3B MCRI ‐0.30 7.34E‐05 G/A 0.138 0.97 (0.88‐1.07) 6.61E‐01 1.84E‐03 rs13024014 2 173530946 MCRI ‐0.62 9.17E‐05 T/C 0.023 0.96 (0.77‐1.20) 4.36E‐01 2.67E‐02 rs11688831 2 199299078 MCRI ‐0.14 7.08E‐05 A/G 0.384 1.01 (0.94‐1.09) 7.27E‐01 2.24E‐03 rs12373582 2 209069303 MCRI 0.37 1.80E‐04 G/A 0.084 0.94 (0.81‐1.08) 7.64E‐01 4.22E‐03 rs6741187 2 222065721 MCRI 2.15 8.62E‐05 T/C 0.010 1.06 (0.54‐2.08) 9.35E‐01 6.54E‐03 rs6798029 3 10763460 MCRI ‐0.29 5.17E‐04 A/G 0.254 0.90 (0.84‐0.98) 2.33E‐02 3.95E‐01 rs13321674 3 51704721 MCRI ‐1.57 7.70E‐05 C/T 0.009 0.60 (0.35‐1.01) 1.96E‐01 5.99E‐02 rs381062 3 55267391 MCRI 0.43 3.11E‐04 A/G 0.061 1.11 (0.98‐1.26) 2.56E‐01 8.07E‐02 rs726737 3 142860107 MCRI ‐0.15 7.83E‐04 A/G 0.320 0.90 (0.83‐0.97) 7.54E‐03 6.27E‐01 rs13064954 3 156854742 MCRI 0.23 6.36E‐04 A/G 0.107 1.08 (0.96‐1.22) 7.68E‐02 2.44E‐01 rs13325944 3 157057390 VEPH1 MCRI 0.19 9.82E‐04 A/G 0.145 1.06 (0.96‐1.17) 6.37E‐02 3.08E‐01 rs9830704 3 187222367 MCRI 0.21 3.06E‐04 T/C 0.164 1.04 (0.95‐1.14) 8.69E‐01 7.61E‐03

65 Diabetes Page 102 of 127

rs16835397 4 4268642 MCRI ‐0.71 1.85E‐05 T/C 0.018 0.83 (0.64‐1.06) 5.52E‐01 9.12E‐03 rs2124794 4 62290634 LPHN3 MCRI ‐0.15 5.27E‐05 A/G 0.437 0.98 (0.92‐1.06) 9.53E‐01 3.73E‐03 rs6822279 4 99745705 MCRI ‐0.21 2.33E‐05 C/A 0.406 0.93 (0.87‐0.99) 1.50E‐02 2.04E‐01 rs7726659 5 74478078 ANKRD31 MCRI ‐0.90 4.58E‐05 G/A 0.015 0.97 (0.75‐1.26) 6.08E‐01 1.17E‐02 rs6874765 5 147298847 MCRI ‐4.50 2.02E‐04 A/G 0.005 1.16 (0.34‐4.01) 6.09E‐01 2.79E‐03 rs523848 6 15830025 MCRI 0.20 3.48E‐05 A/G 0.467 0.96 (0.90‐1.03) 3.56E‐01 3.44E‐04 rs220933 6 15845797 MCRI ‐0.19 9.83E‐05 C/T 0.421 1.07 (0.99‐1.14) 3.83E‐01 7.51E‐04 rs9370836 6 15856619 MCRI 0.23 1.19E‐04 C/T 0.442 0.94 (0.88‐1.00) 2.19E‐01 3.30E‐04 rs3749855 6 17283321 RBM24 MCRI ‐0.52 5.04E‐06 G/T 0.057 0.96 (0.82‐1.11) 6.94E‐01 4.56E‐04 rs6938736 6 22441270 MCRI 0.22 7.64E‐05 C/T 0.469 0.96 (0.90‐1.03) 1.42E‐01 1.26E‐04 rs9295552 6 22540765 MCRI ‐0.28 7.11E‐04 T/C 0.300 1.04 (0.97‐1.12) 2.64E‐01 1.45E‐03 rs9449095 6 81313076 MCRI 0.44 3.88E‐04 G/A 0.046 0.97 (0.84‐1.12) 2.04E‐01 6.58E‐04 rs13219760 6 110761189 SLC22A16 MCRI 0.35 3.15E‐06 G/A 0.111 0.94 (0.84‐1.05) 8.13E‐01 5.34E‐04 rs723685 6 110763875 SLC22A16 MCRI 0.33 8.04E‐06 G/A 0.114 1.04 (0.94‐1.15) 2.54E‐01 1.88E‐02 rs17166951 7 13302054 MCRI 0.42 8.25E‐05 A/C 0.060 0.93 (0.79‐1.10) 7.71E‐01 2.79E‐03 rs4629751 7 16825580 MCRI 0.26 9.58E‐05 G/T 0.284 0.97 (0.90‐1.05) 4.80E‐01 1.12E‐03 rs10251809 7 32044030 PDE1C MCRI ‐0.25 4.28E‐05 T/C 0.180 0.95 (0.86‐1.04) 4.06E‐01 2.12E‐02 rs10246021 7 100692680 MUC17 MCRI 0.29 2.01E‐04 T/G 0.470 0.96 (0.90‐1.03) 3.36E‐02 3.60E‐05 rs11136431 8 1791433 ARHGEF10 MCRI 0.14 6.90E‐05 T/C 0.383 0.99 (0.93‐1.07) 2.65E‐01 3.16E‐04 rs6651438 8 1794023 ARHGEF10 MCRI 0.20 9.10E‐05 C/T 0.377 0.90 (0.84‐0.96) 3.40E‐02 1.98E‐05 rs13258014 8 4165460 CSMD1 MCRI 0.26 7.99E‐05 T/C 0.392 0.98 (0.91‐1.05) 5.32E‐01 1.23E‐03 rs17128106 8 19146926 MCRI 2.97 1.37E‐04 A/G 0.003 0.53 (0.25‐1.13) 1.00E‐01 1.14E‐04 rs4434590 8 100860657 VPS13B MCRI ‐0.29 8.09E‐05 T/C 0.161 1.00 (0.92‐1.09) 5.65E‐01 1.73E‐02 rs13253073 8 100897383 COX6C MCRI ‐0.35 5.89E‐06 A/C 0.129 0.93 (0.85‐1.02) 2.08E‐01 2.07E‐02 rs12544943 8 100903890 COX6C MCRI ‐0.34 6.90E‐06 G/A 0.129 0.91 (0.83‐1.00) 1.44E‐01 3.19E‐02 rs13257834 8 122322450 MCRI ‐0.22 9.10E‐04 G/A 0.248 1.01 (0.94‐1.08) 4.27E‐01 3.65E‐03 rs7851513 9 9842176 PTPRD MCRI 0.38 2.72E‐05 A/C 0.129 0.98 (0.89‐1.07) 3.41E‐01 2.72E‐04 rs10960561 9 12275924 MCRI ‐0.19 4.19E‐04 A/G 0.256 1.03 (0.90‐1.17) 8.23E‐02 1.97E‐04 rs7025024 9 25816219 MCRI ‐0.18 8.33E‐05 G/A 0.342 0.94 (0.87‐1.01) 4.12E‐01 2.76E‐02 rs16923334 9 106556113 MCRI ‐0.54 6.75E‐04 C/T 0.028 0.94 (0.77‐1.14) 3.16E‐01 9.01E‐02 rs6602203 10 17596121 MCRI ‐0.32 4.80E‐06 T/C 0.403 1.02 (0.95‐1.09) 5.86E‐01 2.96E‐04 rs10825203 10 55798117 PCDH15 MCRI 0.23 5.80E‐05 A/C 0.268 0.94 (0.87‐1.01) 5.86E‐02 2.91E‐05

66 Page 103 of 127 Diabetes

rs1911409 10 55806316 PCDH15 MCRI 0.23 5.05E‐05 G/A 0.243 1.00 (0.93‐1.08) 2.89E‐01 3.00E‐04 rs716594 10 112006311 MXI1 MCRI ‐0.65 3.84E‐05 A/G 0.019 0.74 (0.57‐0.96) 7.50E‐02 9.85E‐02 rs11016332 10 130363802 MCRI 2.07 4.72E‐05 G/A 0.008 0.74 (0.37‐1.50) 7.84E‐01 7.30E‐03 rs7944706 11 10331311 MCRI 0.31 4.70E‐05 A/G 0.285 1.04 (0.97‐1.11) 9.33E‐02 9.07E‐02 rs2449501 11 20044696 NAV2 MCRI ‐0.22 1.27E‐05 G/A 0.198 0.97 (0.89‐1.07) 7.91E‐01 1.06E‐03 rs16918932 11 29309078 MCRI 3.45 4.38E‐05 G/T 0.003 0.43 (0.11‐1.70) 6.30E‐01 1.23E‐03 rs10400279 11 36270057 MCRI ‐0.31 8.87E‐05 G/A 0.058 1.06 (0.93‐1.20) 6.57E‐01 2.03E‐03 rs2510094 11 102981300 DYNC2H1 MCRI 0.45 5.69E‐05 C/T 0.044 0.88 (0.74‐1.05) 4.90E‐01 8.54E‐04 rs7131741 12 78251906 NAV3 MCRI 0.25 4.30E‐04 G/T 0.211 0.97 (0.89‐1.07) 6.72E‐01 2.85E‐02 rs2059765 12 115030724 MCRI ‐0.29 4.19E‐04 A/G 0.228 1.07 (0.98‐1.17) 1.25E‐01 3.44E‐04 rs17075764 13 52100949 MCRI 0.37 5.41E‐04 G/A 0.042 1.10 (0.83‐1.45) 4.00E‐01 2.35E‐03 rs1334870 13 54838415 MCRI ‐0.26 8.31E‐05 A/C 0.309 0.98 (0.90‐1.06) 4.44E‐01 8.86E‐04 rs9530368 13 75270057 MCRI ‐0.22 6.37E‐05 C/A 0.358 0.92 (0.86‐0.99) 2.43E‐01 4.54E‐02 rs1930224 13 96897559 HS6ST3 MCRI 0.25 3.69E‐04 T/C 0.131 0.99 (0.88‐1.10) 4.38E‐01 2.16E‐03 rs6576136 14 28737460 MCRI 0.18 9.18E‐05 C/T 0.381 1.01 (0.94‐1.08) 5.90E‐01 1.71E‐02 rs1680727 14 34507353 MCRI 0.19 5.13E‐04 C/T 0.336 1.06 (0.98‐1.14) 6.13E‐01 3.58E‐02 rs2031271 14 42344822 LRFN5 MCRI 0.23 3.73E‐05 C/A 0.158 1.10 (1.00‐1.21) 6.74E‐02 1.05E‐01 rs8003026 14 72482760 RGS6 MCRI 3.07 4.04E‐05 G/T 0.003 1.84 (0.85‐3.97) 1.17E‐01 7.25E‐02 rs8014528 14 91305899 MCRI ‐0.20 3.03E‐04 C/T 0.348 1.04 (0.96‐1.12) 5.45E‐02 9.07E‐05 rs10147864 14 97919601 MCRI 3.27 6.21E‐05 C/T 0.005 0.76 (0.12‐4.83) 5.88E‐01 1.31E‐03 rs637568 15 29692391 FAM189A1 MCRI ‐0.46 8.96E‐05 G/A 0.027 1.17 (0.92‐1.48) 6.61E‐01 2.07E‐03 rs10518808 15 55562142 RAB27A MCRI 0.22 4.70E‐04 A/G 0.215 0.94 (0.86‐1.02) 2.73E‐01 1.16E‐03 rs11853158 15 56364902 MCRI ‐0.18 6.96E‐05 A/G 0.320 0.91 (0.84‐0.98) 1.79E‐02 2.55E‐01 rs2718934 15 56557418 MCRI ‐0.17 2.50E‐05 G/A 0.466 0.94 (0.88‐1.01) 2.44E‐01 3.11E‐02 rs8032549 15 56572176 MCRI ‐0.18 7.52E‐05 G/A 0.328 0.92 (0.86‐0.99) 1.65E‐02 2.70E‐01 rs2244373 15 57622887 MCRI ‐0.15 4.42E‐04 C/T 0.212 1.06 (0.97‐1.15) 3.65E‐01 1.78E‐03 rs12441883 15 58456850 ALDH1A2 MCRI 0.23 3.60E‐05 A/G 0.370 1.00 (0.93‐1.08) 9.40E‐01 2.93E‐03 rs3784334 15 68610384 ITGA11 MCRI 0.25 4.38E‐04 G/T 0.183 1.03 (0.94‐1.13) 7.62E‐01 2.31E‐02 rs7172809 15 77819676 MCRI 0.18 9.20E‐06 A/G 0.484 1.12 (1.04‐1.20) 1.49E‐02 1.57E‐01 rs2701405 15 87539918 AGBL1 MCRI ‐0.23 2.15E‐05 A/C 0.486 1.02 (0.95‐1.09) 8.93E‐01 1.94E‐03 rs4843249 16 87652026 JPH3 MCRI 0.18 5.22E‐04 G/A 0.465 0.98 (0.91‐1.06) 2.90E‐01 8.83E‐02 rs781856 17 3950224 ZZEF1 MCRI 0.94 7.06E‐06 A/G 0.014 1.09 (0.83‐1.43) 7.79E‐01 2.91E‐03

67 Diabetes Page 104 of 127

rs4790177 17 4067900 ANKFY1 MCRI 0.95 4.21E‐05 T/C 0.012 1.26 (0.77‐2.06) 3.52E‐01 2.53E‐02 rs8065822 17 4171848 MCRI 1.21 2.19E‐04 C/A 0.009 1.42 (0.83‐2.43) 4.18E‐01 4.13E‐02 rs2325989 17 4199320 UBE2G1 MCRI 1.10 5.63E‐05 G/A 0.015 1.09 (0.85‐1.41) 3.55E‐01 2.82E‐02 rs1986507 17 10082301 GAS7 MCRI ‐0.26 9.92E‐05 A/G 0.152 1.02 (0.93‐1.12) 8.68E‐01 8.41E‐03 rs2274892 17 16852027 TNFRSF13B MCRI ‐0.16 7.67E‐05 G/T 0.372 0.92 (0.86‐0.98) 1.30E‐02 2.99E‐01 rs9911767 17 70376204 MCRI 0.12 6.78E‐04 A/G 0.386 0.99 (0.92‐1.07) 3.38E‐01 8.44E‐02 rs9912528 17 77387550 RBFOX3 MCRI 0.27 1.65E‐05 C/T 0.150 1.05 (0.95‐1.15) 4.48E‐01 1.21E‐02 rs2339345 18 49957255 DCC MCRI ‐0.25 7.80E‐06 A/C 0.343 1.05 (0.99‐1.13) 3.75E‐01 1.52E‐04 rs1008632 18 58869249 MCRI 0.22 4.19E‐04 T/C 0.312 0.99 (0.92‐1.07) 6.36E‐01 3.08E‐02 rs11872993 18 71104519 MCRI ‐1.74 8.65E‐05 T/C 0.006 0.44 (0.21‐0.90) 1.88E‐01 6.51E‐02 rs2276210 18 74587458 ZNF236 MCRI ‐0.89 9.92E‐05 A/G 0.015 0.90 (0.70‐1.17) 7.25E‐01 1.23E‐02 rs3786947 19 3114229 GNA11 MCRI ‐0.28 1.21E‐05 A/G 0.222 1.05 (0.95‐1.16) 2.42E‐01 8.79E‐05 rs7247790 19 5311412 PTPRS MCRI ‐0.28 6.88E‐05 G/T 0.185 0.95 (0.86‐1.06) 5.34E‐01 1.76E‐02 rs6013784 20 52365120 MCRI 0.18 9.56E‐04 T/C 0.167 1.04 (0.95‐1.14) 7.29E‐01 3.66E‐02 rs9983598 21 17903973 LINC00478 MCRI 3.86 1.06E‐04 T/C 0.002 0.51 (0.04‐6.14) 7.20E‐01 2.76E‐03 rs6685355 1 79458347 ELTD1 SI+M ‐7.81 6.27E‐05 C/A 0.326 0.97 (0.91‐1.05) 4.28E‐01 2.32E‐02 rs1507290 1 86684713 SI+M 5.01 6.54E‐05 G/A 0.206 0.98 (0.90‐1.07) 8.85E‐01 6.51E‐03 rs896232 2 2732877 SI+M ‐5.28 1.26E‐06 T/C 0.282 1.00 (0.92‐1.08) 4.05E‐01 4.54E‐03 rs13411840 2 29973281 ALK SI+M ‐14.39 2.69E‐06 C/A 0.046 0.87 (0.75‐1.00) 6.03E‐02 4.66E‐02 rs7581057 2 115958079 DPP10 SI+M ‐5.47 1.74E‐04 G/A 0.056 1.29 (1.10‐1.50) 6.67E‐03 4.82E‐06 rs207910 2 217018422 XRCC5 SI+M 7.26 4.51E‐05 G/A 0.150 0.95 (0.85‐1.07) 7.04E‐01 8.90E‐03 rs6767721 3 87630433 SI+M 6.37 5.90E‐05 G/T 0.071 1.08 (0.95‐1.23) 5.94E‐01 1.38E‐02 rs9853442 3 177191797 SI+M ‐5.68 4.21E‐04 A/G 0.485 1.00 (0.94‐1.08) 8.47E‐01 1.84E‐02 rs10007938 4 32452973 SI+M 6.76 4.74E‐05 G/A 0.241 1.00 (0.92‐1.08) 9.48E‐01 3.47E‐03 rs10023791 4 99425353 TSPAN5 SI+M 4.03 4.31E‐05 A/G 0.426 1.02 (0.96‐1.10) 3.04E‐01 3.03E‐02 rs6815953 4 183109012 ODZ3 SI+M 4.10 3.14E‐05 T/G 0.431 0.92 (0.86‐0.99) 1.25E‐02 2.47E‐06 rs16894006 5 24833120 SI+M ‐12.02 4.38E‐05 C/T 0.020 0.91 (0.68‐1.22) 4.62E‐01 1.78E‐02 rs7724522 5 142081559 SI+M ‐7.09 5.11E‐05 C/T 0.038 1.14 (0.94‐1.37) 1.10E‐01 6.51E‐05 rs29848 5 151449400 AK001582 SI+M 6.61 5.08E‐05 T/G 0.328 1.06 (0.98‐1.13) 3.27E‐01 2.99E‐02 rs2001097 6 32383858 SI+M 10.04 3.69E‐05 T/G 0.128 1.04 (0.75‐1.42) 8.29E‐01 5.70E‐03 rs2227138 6 32384500 SI+M 10.62 7.04E‐05 T/C 0.110 0.92 (0.62‐1.38) 3.55E‐01 5.31E‐04 rs3135376 6 32385470 SI+M 10.04 3.69E‐05 G/A 0.128 1.04 (0.75‐1.42) 8.32E‐01 5.65E‐03

68 Page 105 of 127 Diabetes

rs2395161 6 32387752 SI+M 10.04 3.79E‐05 C/A 0.128 1.04 (0.75‐1.42) 8.29E‐01 5.77E‐03

rs3135366 6 32388709 SI+M 9.96 3.61E‐05 C/T 0.129 0.95 (0.76‐1.18) 7.76E‐01 1.80E‐03

rs558015 6 137899792 SI+M ‐4.84 1.45E‐04 A/G 0.470 0.98 (0.92‐1.05) 8.86E‐01 9.73E‐03

rs24003 7 30748323 INMT SI+M ‐4.83 6.24E‐05 C/T 0.471 1.02 (0.95‐1.09) 2.81E‐01 3.27E‐04

rs2726051 7 36155071 SI+M 6.17 5.27E‐05 C/A 0.223 1.07 (0.98‐1.16) 1.77E‐01 5.68E‐02

rs17141982 7 70133502 AUTS2 SI+M 3.95 9.89E‐05 T/C 0.340 0.99 (0.92‐1.06) 2.23E‐01 3.01E‐04

rs10268984 7 98963340 ARPC1A SI+M ‐7.02 5.59E‐05 T/C 0.103 1.09 (0.99‐1.20) 1.96E‐01 1.67E‐04

rs3177186 7 98984399 ARPC1A SI+M ‐7.04 6.58E‐05 T/C 0.105 1.03 (0.73‐1.47) 8.64E‐01 3.24E‐03

rs7799219 7 123895098 EU233817 SI+M 6.38 6.95E‐05 T/C 0.228 0.94 (0.86‐1.04) 1.41E‐01 1.17E‐04

rs12675420 8 62924308 SI+M 10.10 8.87E‐05 T/C 0.069 1.10 (0.96‐1.27) 7.17E‐01 1.19E‐02

rs6475448 9 20497142 MLLT3 SI+M ‐6.91 3.31E‐05 G/A 0.303 0.98 (0.91‐1.06) 5.97E‐01 9.37E‐04

rs10966384 9 24672959 SI+M ‐9.96 9.06E‐05 C/T 0.057 0.86 (0.74‐1.01) 7.07E‐02 1.36E‐01

rs4817 9 33917498 UBE2R2 SI+M ‐3.47 7.96E‐05 C/T 0.314 0.93 (0.86‐1.00) 8.88E‐02 1.13E‐01

rs10739874 9 105991203 BC035187 SI+M 10.13 1.00E‐04 C/T 0.092 1.05 (0.95‐1.17) 5.58E‐01 1.95E‐02

rs1176191 9 105993267 BC035187 SI+M 10.03 1.77E‐04 T/C 0.090 1.05 (0.95‐1.15) 5.46E‐01 2.62E‐02

rs2688789 10 17733014 STAM SI+M ‐6.25 9.47E‐05 G/A 0.419 1.00 (0.93‐1.07) 4.65E‐01 1.05E‐03

rs12413935 10 85453920 SI+M ‐10.34 4.11E‐05 G/T 0.020 0.95 (0.75‐1.21) 6.14E‐01 1.13E‐03

rs948178 11 113195595 TTC12 SI+M 5.63 9.43E‐05 A/G 0.337 1.04 (0.96‐1.12) 6.89E‐01 2.33E‐03

rs3781827 11 121411041 SORL1 SI+M 3.38 6.12E‐05 G/A 0.434 0.97 (0.91‐1.04) 5.36E‐01 1.07E‐03

rs11180162 12 75081042 SI+M 3.44 8.30E‐05 C/T 0.189 1.05 (0.97‐1.15) 4.38E‐01 2.55E‐02

rs10860482 12 100038835 ANKS1B SI+M 5.67 9.80E‐05 C/T 0.372 1.07 (1.00‐1.15) 2.30E‐01 5.68E‐02

rs7974375 12 118585698 SI+M ‐10.14 8.96E‐05 T/G 0.104 0.91 (0.82‐1.03) 1.93E‐01 6.45E‐02

rs17512574 12 118788003 TAOK3 SI+M ‐12.38 3.19E‐05 T/C 0.110 0.96 (0.87‐1.07) 2.92E‐01 2.81E‐02

rs673078 12 118791441 TAOK3 SI+M ‐12.79 4.71E‐06 C/A 0.125 0.88 (0.80‐0.98) 6.71E‐02 5.21E‐02

rs884844 12 118814838 SUDS3 SI+M ‐12.12 6.71E‐05 T/C 0.113 0.90 (0.81‐1.01) 1.84E‐02 2.50E‐01

rs7305647 12 118855566 SUDS3 SI+M ‐12.32 5.90E‐05 A/G 0.105 0.96 (0.86‐1.06) 2.40E‐01 4.45E‐02

rs4772128 13 99385553 SLC15A1 SI+M ‐7.87 5.57E‐05 A/G 0.029 0.81 (0.58‐1.14) 5.32E‐01 1.60E‐02

rs12717423 14 52940827 TXNDC16 SI+M ‐4.35 3.87E‐05 G/A 0.253 1.02 (0.94‐1.10) 7.64E‐01 1.79E‐03

rs10129385 14 52959478 TXNDC16 SI+M ‐4.30 5.48E‐05 C/T 0.253 1.03 (0.96‐1.11) 3.47E‐01 4.35E‐04

rs2617235 15 42758738 ZFP106 SI+M 6.10 9.05E‐05 C/T 0.366 0.95 (0.88‐1.02) 5.46E‐01 1.40E‐03

rs10851411 15 42859235 HAUS2 SI+M 5.46 5.64E‐06 T/G 0.428 0.96 (0.89‐1.03) 7.23E‐01 5.40E‐04

rs2241998 15 42869028 STARD9 SI+M 5.10 7.70E‐05 A/G 0.417 1.00 (0.94‐1.07) 4.71E‐01 2.23E‐02

69 Diabetes Page 106 of 127

rs7497796 15 55136506 SI+M 9.33 2.63E‐05 A/C 0.376 0.99 (0.92‐1.06) 7.74E‐01 5.61E‐03 rs12438945 15 55226570 SI+M 10.00 5.38E‐05 C/A 0.230 1.01 (0.93‐1.10) 3.51E‐01 2.81E‐02 rs884202 15 68054388 MAP2K5 SI+M ‐3.79 9.64E‐05 A/G 0.381 0.97 (0.90‐1.04) 5.72E‐01 1.84E‐02 rs7178383 15 99159956 SI+M ‐8.34 8.42E‐05 C/T 0.332 1.00 (0.93‐1.09) 5.91E‐01 1.64E‐02 rs4624233 17 38955961 KRT28 SI+M ‐7.61 2.46E‐05 A/G 0.137 1.02 (0.92‐1.14) 4.08E‐01 3.60E‐04 rs7219451 17 38957002 SI+M ‐6.80 3.92E‐06 C/T 0.380 1.08 (1.00‐1.16) 1.06E‐02 3.97E‐07 rs10558 17 38991003 TMEM99 SI+M ‐7.00 1.48E‐05 C/T 0.138 1.06 (0.96‐1.17) 1.18E‐01 3.08E‐05 rs9303297 17 39005990 SI+M ‐7.40 9.98E‐06 T/C 0.138 1.06 (0.96‐1.16) 1.73E‐01 4.34E‐05 rs3760333 17 39023875 SI+M ‐5.83 2.09E‐05 C/T 0.173 1.05 (0.96‐1.15) 9.73E‐02 2.90E‐05 rs2291447 17 43212963 ACBD4 SI+M ‐4.56 7.95E‐05 T/G 0.346 1.00 (0.93‐1.07) 8.85E‐01 3.82E‐03 rs6133145 20 4576230 SI+M 6.23 4.52E‐05 A/C 0.400 0.99 (0.92‐1.07) 4.24E‐01 5.60E‐04 rs6139486 20 4578080 SI+M 5.16 7.29E‐05 A/G 0.366 0.96 (0.89‐1.03) 4.80E‐01 9.53E‐04 rs6075733 20 20856254 SI+M ‐7.74 3.40E‐05 C/T 0.346 0.99 (0.92‐1.06) 9.15E‐01 2.65E‐03 rs1061325 22 19184095 CLTCL1 SI+M ‐3.28 9.96E‐05 C/T 0.451 1.02 (0.95‐1.09) 5.01E‐01 1.25E‐03 rs17385225 1 164475201 SI 0.28 4.87E‐05 A/G 0.134 0.99 (0.84‐1.17) 5.60E‐01 1.39E‐02 rs6719442 2 2722295 SI ‐0.29 1.53E‐05 A/G 0.180 1.05 (0.96‐1.15) 4.33E‐01 3.03E‐04 rs12620694 2 2763051 SI ‐0.38 3.42E‐05 A/G 0.162 1.03 (0.95‐1.13) 7.09E‐01 1.40E‐03 rs1978648 2 43371542 SI 0.20 5.31E‐07 T/C 0.328 1.03 (0.96‐1.11) 3.08E‐01 4.72E‐03 rs4952971 2 43373119 SI 0.18 2.31E‐05 A/G 0.438 1.00 (0.93‐1.07) 8.08E‐01 1.55E‐03 rs10167465 2 43397176 SI 0.19 9.30E‐05 G/A 0.419 0.98 (0.91‐1.06) 8.93E‐01 4.25E‐03 rs1044710 2 211297355 LANCL1 SI ‐0.20 8.93E‐05 A/G 0.395 1.03 (0.96‐1.11) 5.43E‐01 1.37E‐03 rs6782551 3 74922055 SI 0.57 9.04E‐05 A/G 0.014 0.80 (0.42‐1.54) 7.97E‐02 6.14E‐05 rs1872552 3 85049088 CADM2 SI ‐0.20 8.59E‐05 A/G 0.444 1.01 (0.95‐1.07) 6.62E‐01 2.03E‐03 rs716975 4 38349236 SI ‐0.27 9.86E‐06 T/C 0.226 1.03 (0.95‐1.12) 8.57E‐01 2.71E‐03 rs7690543 4 68056613 SI 0.28 2.34E‐06 T/C 0.177 1.05 (0.96‐1.15) 3.76E‐01 6.67E‐03 rs1848056 4 125755019 SI 0.09 3.21E‐05 T/C 0.484 0.98 (0.91‐1.05) 3.41E‐01 3.02E‐04 rs9997902 4 125763629 SI 0.10 2.29E‐05 A/G 0.490 0.95 (0.89‐1.00) 1.15E‐01 3.98E‐05 rs1602084 4 128843480 MFSD8 SI 0.43 3.10E‐06 G/A 0.038 1.05 (0.85‐1.29) 5.78E‐01 3.68E‐03 rs11943562 4 167652786 SI ‐0.25 6.27E‐05 C/T 0.130 0.96 (0.86‐1.07) 2.49E‐01 4.39E‐02 rs17069175 4 181226698 SI ‐0.27 7.04E‐05 A/G 0.241 0.99 (0.91‐1.07) 4.28E‐01 7.49E‐04 rs6868526 5 5399472 SI 0.27 2.22E‐05 C/T 0.188 1.05 (0.96‐1.14) 6.91E‐01 6.56E‐03 rs16875556 5 5402163 SI 0.26 3.47E‐05 A/G 0.167 1.01 (0.92‐1.12) 7.85E‐01 1.81E‐03

70 Page 107 of 127 Diabetes

rs7717247 5 27839258 SI ‐0.33 4.16E‐05 C/A 0.136 0.99 (0.89‐1.10) 7.57E‐01 1.83E‐03

rs462647 5 81080808 SI 0.32 8.79E‐05 C/T 0.334 1.07 (0.99‐1.15) 4.37E‐02 1.78E‐01

rs6880017 5 81185254 SI ‐0.17 7.51E‐05 G/A 0.314 0.97 (0.90‐1.04) 5.61E‐01 1.69E‐02

rs17155849 5 103142399 SI ‐0.29 7.13E‐05 T/C 0.290 1.02 (0.94‐1.10) 5.96E‐01 1.46E‐03

rs1898910 5 124555847 SI ‐0.38 6.60E‐06 A/C 0.161 1.02 (0.93‐1.12) 7.04E‐01 3.52E‐03

rs1042711 5 148206348 SH3TC2 SI 0.31 9.07E‐05 C/T 0.212 1.04 (0.97‐1.11) 6.40E‐01 1.48E‐02

rs12194985 6 6892411 SI ‐0.40 8.50E‐05 T/G 0.032 1.17 (0.97‐1.43) 3.04E‐01 4.55E‐04

rs10080664 6 15864284 SI 0.15 9.95E‐05 A/G 0.384 0.95 (0.89‐1.02) 3.04E‐01 5.04E‐04

rs4716224 6 18161563 KDM1B SI ‐0.19 9.37E‐05 A/G 0.306 1.00 (0.93‐1.07) 8.23E‐01 9.20E‐03

rs724941 6 76723011 IMPG1 SI 0.17 9.34E‐05 C/T 0.446 0.93 (0.87‐1.00) 7.11E‐01 2.49E‐03

rs943086 6 76755221 IMPG1 SI 0.15 6.49E‐05 G/A 0.449 1.00 (0.93‐1.07) 3.15E‐01 3.46E‐02

rs196701 6 80147187 SI ‐0.35 1.37E‐06 C/T 0.128 0.93 (0.84‐1.03) 5.03E‐02 4.23E‐02

rs7803642 7 21641629 DNAH11 SI ‐0.18 9.92E‐05 T/C 0.321 1.05 (0.98‐1.13) 9.62E‐01 6.55E‐03

rs9406428 9 11463799 SI 0.33 7.63E‐05 C/T 0.132 0.96 (0.86‐1.06) 7.62E‐02 5.10E‐05

rs10964496 9 20248264 SI 0.34 5.14E‐05 A/G 0.091 0.95 (0.85‐1.06) 9.58E‐01 3.73E‐03

rs10811340 9 20283406 SI 0.27 7.35E‐05 G/A 0.098 0.93 (0.83‐1.03) 8.57E‐01 3.38E‐03

rs1581979 9 23407435 SI ‐0.18 8.14E‐05 C/A 0.310 0.95 (0.89‐1.03) 4.25E‐01 2.63E‐02

rs10780305 9 81978708 SI 0.15 8.69E‐06 A/G 0.431 0.97 (0.91‐1.04) 5.95E‐01 4.31E‐04

rs1885984 9 119078249 PAPPA SI ‐0.79 9.14E‐05 T/C 0.009 0.64 (0.35‐1.19) 1.90E‐01 6.57E‐02

rs2819042 10 10230151 SI ‐0.18 1.38E‐05 A/C 0.455 0.99 (0.92‐1.06) 8.34E‐01 1.27E‐03

rs359297 10 17333680 SI ‐0.28 5.10E‐05 A/G 0.213 1.03 (0.95‐1.12) 8.39E‐01 6.51E‐03

rs12256421 10 17614097 SI ‐0.20 9.07E‐05 A/G 0.387 1.00 (0.94‐1.08) 5.42E‐01 1.95E‐02

rs1223629 10 95906315 PLCE1 SI ‐0.74 4.72E‐06 A/G 0.038 0.98 (0.83‐1.16) 4.29E‐01 7.44E‐03

rs10870301 10 134186772 LRRC27 SI ‐0.12 7.93E‐05 C/T 0.435 0.98 (0.92‐1.05) 4.49E‐01 2.41E‐02

rs4443996 10 134191005 LRRC27 SI ‐0.11 9.70E‐05 C/A 0.441 0.97 (0.91‐1.04) 3.22E‐01 3.98E‐02

rs10870302 10 134191738 LRRC27 SI ‐0.13 9.64E‐05 T/G 0.436 0.98 (0.92‐1.05) 4.06E‐01 3.01E‐02

rs10870303 10 134191811 LRRC27 SI ‐0.13 6.94E‐05 G/A 0.436 0.99 (0.92‐1.06) 8.09E‐01 8.24E‐03

rs4568920 10 134324451 SI ‐0.29 7.13E‐05 T/C 0.077 0.98 (0.86‐1.11) 2.63E‐01 4.36E‐02

rs7117567 11 7715079 OVCH2 SI ‐0.21 8.87E‐05 G/A 0.356 1.02 (0.93‐1.11) 7.59E‐01 2.80E‐03

rs121704 11 17904634 SERGEF SI 0.15 5.97E‐05 G/A 0.474 1.06 (0.98‐1.13) 5.16E‐02 1.44E‐01

rs10160242 11 108498885 SI 0.41 4.33E‐06 C/T 0.060 1.11 (0.93‐1.33) 7.79E‐01 2.29E‐03

rs2368785 12 260682 IQSEC3 SI 0.19 4.51E‐05 C/T 0.150 1.03 (0.93‐1.13) 9.50E‐02 8.83E‐02

71 Diabetes Page 108 of 127

rs1947234 12 39450491 SI 0.13 7.83E‐05 A/C 0.197 1.02 (0.93‐1.11) 8.21E‐01 8.47E‐03 rs10785139 12 75089475 SI 0.19 5.31E‐05 C/T 0.307 1.04 (0.96‐1.12) 6.92E‐01 9.95E‐03 rs9554019 13 27951711 SI ‐0.36 2.76E‐05 A/G 0.061 1.02 (0.80‐1.30) 7.86E‐01 5.56E‐03 rs17376318 13 108013050 FAM155A SI ‐0.41 4.00E‐05 C/T 0.119 0.98 (0.87‐1.11) 7.08E‐01 8.30E‐03 rs9559508 13 109805793 MYO16 SI ‐0.17 9.54E‐05 T/C 0.240 0.95 (0.88‐1.03) 5.34E‐01 2.04E‐02 rs10129961 14 34767305 SI 0.33 2.25E‐05 A/G 0.146 1.07 (0.97‐1.18) 2.02E‐01 3.62E‐02 rs17123946 14 51929722 SI ‐0.29 9.17E‐05 G/A 0.251 1.09 (1.00‐1.18) 1.50E‐01 1.54E‐04 rs10498430 14 51942961 SI ‐0.30 4.05E‐05 T/C 0.243 1.11 (1.02‐1.20) 7.37E‐02 3.08E‐05 rs17123969 14 51946458 SI ‐0.30 5.36E‐05 G/A 0.245 1.11 (1.02‐1.21) 2.37E‐01 2.22E‐04 rs4901281 14 52980190 TXNDC16 SI ‐0.29 5.98E‐05 A/C 0.148 1.03 (0.94‐1.14) 4.55E‐01 7.63E‐04 rs11631474 15 67934167 MAP2K5 SI ‐0.24 3.36E‐05 G/A 0.272 0.98 (0.91‐1.06) 8.76E‐01 4.77E‐03 rs896598 15 74036629 C15orf59 SI 0.37 5.83E‐07 A/G 0.119 1.07 (0.96‐1.19) 9.72E‐02 1.83E‐02 rs4887140 15 74046663 SI 0.31 6.91E‐08 G/T 0.143 0.97 (0.88‐1.07) 2.93E‐01 2.14E‐03 rs2415230 15 74059081 SI 0.26 7.20E‐06 A/G 0.171 1.07 (0.98‐1.17) 2.01E‐01 2.33E‐02 rs27230 16 3434699 ZNF434 SI ‐0.23 5.85E‐05 G/A 0.107 0.94 (0.84‐1.04) 6.25E‐01 1.26E‐02 rs16530 17 37357034 RPL19 SI ‐0.33 2.97E‐05 T/C 0.102 0.97 (0.86‐1.10) 7.24E‐01 1.36E‐03 rs691336 17 76518426 DNAH17 SI ‐0.27 2.91E‐05 T/C 0.261 0.98 (0.91‐1.06) 6.97E‐01 7.36E‐03 rs6139479 20 4566415 SI 0.23 9.73E‐05 A/G 0.308 0.94 (0.87‐1.02) 3.82E‐01 7.41E‐04 rs6100794 20 58799036 AX747739 SI ‐0.63 4.80E‐06 T/C 0.012 1.10 (0.60‐2.02) 8.27E‐01 7.02E‐04 rs2235438 1 4849384 BC037321 M 15.45 3.95E‐05 T/C 0.357 1.09 (1.01‐1.18) 7.53E‐02 9.92E‐02 rs2744761 1 26040514 MAN1C1 M ‐21.75 5.54E‐05 G/T 0.229 1.06 (0.97‐1.16) 8.04E‐01 7.47E‐03 rs11209072 1 67908644 M ‐22.54 7.60E‐05 G/A 0.393 1.05 (0.98‐1.12) 2.03E‐01 2.18E‐04 rs12135476 1 69649328 M ‐31.54 3.75E‐06 A/G 0.118 0.99 (0.89‐1.10) 9.13E‐01 1.41E‐03 rs10493454 1 69659840 M ‐29.41 6.08E‐06 G/A 0.136 1.00 (0.91‐1.09) 7.50E‐01 6.16E‐04 rs4650135 1 69684997 M ‐29.56 2.31E‐06 C/T 0.157 1.01 (0.92‐1.11) 8.17E‐01 4.57E‐04 rs1886644 1 85350658 LPAR3 M ‐22.90 6.28E‐06 C/A 0.295 0.93 (0.86‐1.00) 5.01E‐02 7.05E‐02 rs6665426 1 200148319 M ‐19.74 8.31E‐05 A/G 0.309 0.94 (0.87‐1.03) 3.54E‐01 3.34E‐02 rs17047682 1 218523025 TGFB2 M ‐31.01 1.19E‐05 G/A 0.078 1.09 (0.90‐1.31) 1.11E‐01 2.39E‐05 rs10926618 1 242251696 PLD5 M ‐23.32 8.79E‐05 T/C 0.386 1.02 (0.95‐1.10) 8.50E‐01 3.65E‐03 rs7558483 2 11537452 M ‐19.51 7.39E‐05 T/C 0.244 0.98 (0.91‐1.07) 9.67E‐01 4.63E‐03 rs17031893 2 44283172 M 27.41 9.83E‐05 G/A 0.101 0.93 (0.84‐1.03) 3.59E‐01 6.67E‐04 rs7595513 2 46687867 M ‐22.09 6.66E‐05 G/A 0.198 0.94 (0.86‐1.02) 4.35E‐01 2.33E‐02

72 Page 109 of 127 Diabetes

rs2138397 2 86974049 RMND5A M ‐24.39 3.71E‐05 A/G 0.442 1.00 (0.93‐1.07) 9.03E‐01 4.64E‐03 rs2889323 2 105039687 M ‐14.31 3.60E‐04 C/A 0.436 1.01 (0.94‐1.09) 7.85E‐01 6.61E‐03 rs10179986 2 134864344 M ‐17.78 7.95E‐06 G/A 0.467 1.00 (0.93‐1.07) 8.77E‐01 2.30E‐03 rs1996589 2 134865196 M ‐21.95 3.97E‐05 C/T 0.230 0.95 (0.88‐1.03) 7.90E‐01 6.58E‐03 rs4953902 2 134876049 M ‐25.81 1.41E‐05 C/A 0.140 0.95 (0.86‐1.05) 7.10E‐01 4.99E‐03 rs1111961 2 134880830 M ‐25.37 1.40E‐05 G/A 0.158 0.96 (0.87‐1.05) 6.47E‐01 5.99E‐03 rs13030335 2 142231898 LRP1B M ‐33.45 4.13E‐05 A/G 0.382 0.89 (0.83‐0.96) 9.78E‐04 5.70E‐01 rs10178963 2 142349495 LRP1B M 24.53 9.64E‐05 C/A 0.446 1.12 (1.04‐1.20) 6.83E‐03 3.98E‐01 rs1546676 2 154509239 M 23.62 8.00E‐06 A/G 0.325 1.02 (0.95‐1.10) 5.20E‐01 6.88E‐03 rs1429411 2 198144002 ANKRD44 M 21.71 4.09E‐04 G/A 0.436 1.07 (1.00‐1.14) 1.19E‐01 1.62E‐01 rs2178704 2 227579207 M 25.31 8.83E‐05 G/A 0.244 0.94 (0.87‐1.03) 1.39E‐01 1.34E‐04 rs11683087 2 227586606 M 20.54 7.42E‐07 G/A 0.412 1.02 (0.94‐1.11) 8.38E‐01 7.92E‐04 rs2251692 2 227589780 M 17.31 1.98E‐05 A/G 0.483 1.04 (0.97‐1.11) 6.73E‐01 6.56E‐03 rs10205233 2 227614005 IRS1 M 23.19 2.35E‐05 T/C 0.185 0.97 (0.89‐1.06) 2.18E‐01 1.13E‐04 rs2596937 3 9480906 SETD5 M ‐17.41 9.76E‐05 C/T 0.238 1.00 (0.93‐1.08) 2.32E‐01 5.60E‐02 rs2279440 3 9518511 SETD5 M ‐21.57 3.31E‐06 T/C 0.203 1.04 (0.96‐1.13) 9.13E‐01 1.32E‐03 rs17050395 3 9533974 M ‐17.84 8.31E‐05 G/A 0.235 0.96 (0.89‐1.03) 5.60E‐02 1.52E‐01 rs3806667 3 9860880 ARPC4‐TTLL3 M ‐20.45 2.79E‐05 G/T 0.272 1.03 (0.95‐1.11) 3.99E‐01 3.71E‐04 rs13106 3 12624580 MKRN2 M 126.46 3.41E‐05 A/G 0.028 0.90 (0.50‐1.62) 3.16E‐01 2.74E‐04 rs635787 3 32466487 CMTM7 M ‐22.82 1.24E‐05 A/G 0.453 0.98 (0.91‐1.06) 2.10E‐01 2.75E‐02 rs9682976 3 60118879 FHIT M ‐24.49 5.93E‐05 T/C 0.152 1.02 (0.93‐1.13) 7.28E‐01 2.03E‐03 rs17062321 3 60122156 FHIT M ‐24.84 2.39E‐05 T/C 0.163 1.03 (0.94‐1.14) 6.51E‐01 9.42E‐04 rs9854367 3 102259425 M 27.76 3.04E‐04 C/T 0.092 0.94 (0.84‐1.05) 6.85E‐01 4.50E‐03 rs12493716 3 106777359 LOC100302640 M ‐16.30 9.21E‐05 G/A 0.253 0.96 (0.88‐1.04) 3.71E‐01 3.30E‐02 rs12487584 3 132300293 ACAD11 M 19.13 2.87E‐05 T/C 0.284 1.06 (0.98‐1.15) 2.27E‐01 3.53E‐02 rs13094259 3 142444625 TRPC1 M ‐29.40 9.10E‐05 T/G 0.091 1.05 (0.94‐1.17) 5.03E‐02 3.31E‐05 rs9824464 3 167635899 LOC646168 M 27.97 8.41E‐05 T/C 0.468 0.98 (0.91‐1.04) 9.28E‐01 4.45E‐03 rs1426260 3 188260703 LPP M 27.98 4.25E‐06 T/C 0.501 1.01 (0.94‐1.08) 7.67E‐01 2.35E‐03 rs10937355 3 188289697 LPP M ‐23.26 4.12E‐05 T/C 0.306 0.97 (0.90‐1.05) 9.71E‐01 4.05E‐03 rs12511127 4 5142212 STK32B M ‐16.49 6.59E‐05 G/A 0.325 1.04 (0.97‐1.12) 6.18E‐01 1.50E‐03 rs6448852 4 12017993 M 15.04 5.55E‐05 C/T 0.468 0.95 (0.89‐1.02) 2.39E‐01 2.31E‐04 rs1025877 4 12074137 M ‐14.32 9.65E‐05 G/A 0.455 1.02 (0.96‐1.08) 9.44E‐01 5.00E‐03

73 Diabetes Page 110 of 127

rs4834882 4 12108239 M 18.23 2.08E‐05 T/C 0.314 1.00 (0.93‐1.08) 9.93E‐01 2.57E‐03 rs9997603 4 66438114 EPHA5 M ‐31.75 1.54E‐05 T/G 0.080 1.01 (0.90‐1.13) 9.81E‐01 2.36E‐03 rs4320186 4 66483593 EPHA5 M ‐30.58 2.41E‐05 A/G 0.079 1.08 (0.95‐1.23) 3.57E‐01 2.76E‐04 rs1023514 4 108239396 M 7.76 5.36E‐02 A/G 0.413 1.07 (1.00‐1.15) 1.22E‐01 7.86E‐01 rs11930824 4 161451545 M 29.13 7.46E‐05 A/G 0.445 0.99 (0.93‐1.06) 3.48E‐01 5.30E‐04 rs4627838 4 175602762 GLRA3 M 19.97 7.25E‐05 A/C 0.427 1.02 (0.95‐1.09) 5.38E‐01 1.78E‐02 rs4695784 4 175608905 GLRA3 M 19.97 7.25E‐05 T/C 0.426 1.01 (0.94‐1.07) 7.84E‐01 8.99E‐03 rs6877846 5 81160103 M 20.99 5.27E‐05 A/G 0.328 1.02 (0.95‐1.10) 3.16E‐01 3.16E‐02 rs4835696 5 137972584 M 35.18 1.74E‐05 A/G 0.383 0.95 (0.88‐1.02) 2.35E‐01 1.06E‐04 rs13361457 5 152797679 M 23.81 9.63E‐06 T/C 0.477 1.04 (0.97‐1.12) 1.18E‐01 4.31E‐02 rs1019507 5 152798614 M ‐18.01 2.10E‐05 C/A 0.409 0.99 (0.93‐1.07) 4.74E‐01 1.24E‐02 rs1465417 5 153790531 GALNT10 M ‐20.39 7.72E‐05 T/C 0.198 0.98 (0.90‐1.06) 4.60E‐01 2.30E‐02 rs322394 5 172157768 M ‐15.83 3.38E‐05 C/T 0.360 1.17 (1.09‐1.26) 7.87E‐04 1.12E‐07 rs241439 6 32797537 TAP2 M 18.67 9.23E‐05 G/T 0.426 0.94 (0.87‐1.00) 6.69E‐01 2.16E‐03 rs16884633 6 53902171 MLIP M ‐23.78 3.67E‐05 A/G 0.234 0.97 (0.89‐1.06) 6.21E‐01 1.08E‐03 rs987672 6 77410315 M ‐17.03 9.05E‐05 G/A 0.358 1.03 (0.96‐1.11) 7.05E‐01 1.24E‐02 rs665791 6 106674850 ATG5 M 18.17 8.39E‐06 G/A 0.328 0.88 (0.82‐0.94) 5.92E‐02 7.32E‐06 rs484621 6 106734408 ATG5 M 18.89 4.12E‐06 T/C 0.323 0.95 (0.88‐1.02) 3.23E‐01 7.64E‐05 rs490010 6 106740458 ATG5 M 18.72 5.91E‐06 A/G 0.316 0.88 (0.82‐0.94) 9.35E‐02 1.14E‐05 rs510432 6 106774030 M 16.93 2.61E‐05 T/C 0.341 0.94 (0.88‐1.01) 1.47E‐01 6.38E‐05 rs4134409 6 170279658 M 19.26 3.79E‐05 A/G 0.245 0.89 (0.80‐0.99) 3.50E‐01 3.51E‐04 rs10267935 7 34885503 AAA1 M ‐26.04 3.55E‐04 A/C 0.105 0.99 (0.90‐1.10) 7.77E‐01 2.01E‐02 rs11768415 7 52347667 M ‐17.74 2.80E‐05 A/G 0.519 1.00 (0.93‐1.06) 6.10E‐01 9.28E‐03 rs11764734 7 52356515 M ‐18.43 1.41E‐05 T/C 0.520 0.97 (0.91‐1.05) 3.22E‐01 1.78E‐02 rs296307 7 52432938 M ‐15.67 8.25E‐05 T/C 0.470 0.97 (0.91‐1.04) 4.34E‐01 2.57E‐02 rs296316 7 52439967 M ‐16.72 9.52E‐05 T/C 0.369 0.93 (0.86‐1.00) 2.59E‐02 2.37E‐01 rs2188256 7 88213062 M ‐21.95 6.79E‐05 C/T 0.179 0.97 (0.89‐1.06) 8.44E‐01 3.11E‐03 rs1588422 7 97329406 M 44.15 3.19E‐05 T/C 0.278 1.00 (0.93‐1.07) 9.93E‐01 3.20E‐03 rs2968865 7 124810399 AX746567 M 29.85 1.40E‐05 G/A 0.459 0.99 (0.93‐1.06) 8.79E‐01 3.04E‐03 rs441606 8 17903046 M 26.11 9.48E‐05 A/G 0.462 0.92 (0.86‐0.99) 8.73E‐02 7.21E‐05 rs17197236 8 25193338 DOCK5 M 54.29 7.13E‐06 G/A 0.034 0.89 (0.73‐1.08) 1.64E‐01 3.21E‐05 rs13267838 8 25196710 DOCK5 M 54.96 4.03E‐06 T/G 0.035 0.90 (0.75‐1.08) 1.45E‐01 1.78E‐05

74 Page 111 of 127 Diabetes

rs13252932 8 25198091 DOCK5 M 47.71 5.17E‐06 T/C 0.049 0.89 (0.75‐1.04) 6.61E‐02 6.11E‐06 rs11780263 8 27823832 SCARA5 M ‐16.34 6.64E‐05 A/G 0.210 0.92 (0.84‐1.00) 1.21E‐02 2.95E‐01 rs9650426 8 27827391 SCARA5 M 15.63 6.38E‐05 C/T 0.334 0.97 (0.90‐1.05) 2.58E‐01 2.87E‐04 rs1715350 8 50396852 M ‐19.15 7.31E‐05 T/G 0.258 1.08 (1.00‐1.17) 2.91E‐01 3.84E‐04 rs4737430 8 57303823 M 17.90 6.71E‐05 A/G 0.404 0.98 (0.91‐1.05) 7.97E‐01 2.69E‐03 rs633142 8 102466767 M ‐16.14 8.10E‐05 T/G 0.337 0.93 (0.87‐0.99) 3.99E‐02 1.82E‐01 rs618854 8 102467706 M ‐16.61 5.04E‐05 T/C 0.343 0.93 (0.87‐1.00) 4.21E‐02 1.53E‐01 rs4333664 9 6556948 GLDC M 16.94 1.15E‐05 T/C 0.432 0.99 (0.92‐1.06) 7.79E‐01 3.70E‐03 rs17781302 9 24142314 M 21.35 6.10E‐05 C/A 0.178 1.09 (0.93‐1.27) 3.36E‐01 3.12E‐02 rs17060946 9 77808519 M 37.86 2.56E‐06 G/A 0.068 0.87 (0.75‐1.01) 6.89E‐02 3.99E‐06 rs7030420 9 77809075 M 29.63 5.75E‐05 G/A 0.080 0.95 (0.83‐1.09) 5.25E‐01 9.87E‐04 rs1888221 9 117778355 M 19.08 2.52E‐06 A/G 0.310 0.97 (0.90‐1.05) 8.52E‐01 5.40E‐04 rs17099236 10 92484110 M 28.87 5.13E‐05 A/G 0.114 0.96 (0.86‐1.07) 6.47E‐01 1.44E‐03 rs4564313 11 6083952 M ‐13.19 1.49E‐03 A/G 0.489 0.94 (0.88‐1.00) 2.72E‐02 4.94E‐01 rs1488933 11 17267029 M 30.81 2.76E‐05 T/C 0.448 1.08 (1.01‐1.16) 8.21E‐02 8.27E‐02 rs10841497 12 20524202 PDE3A M 17.05 3.17E‐05 G/T 0.356 1.05 (0.91‐1.22) 9.35E‐02 7.90E‐02 rs7964191 12 20551038 PDE3A M 24.85 5.20E‐05 C/T 0.150 1.12 (1.02‐1.24) 3.05E‐02 1.83E‐01 rs10770655 12 20574060 PDE3A M 23.56 9.20E‐05 C/A 0.180 1.12 (1.02‐1.23) 2.71E‐02 2.29E‐01 rs7311799 12 84718394 M ‐27.14 9.33E‐05 A/C 0.469 1.00 (0.93‐1.07) 7.60E‐01 2.89E‐03 rs11059101 12 127874250 M ‐25.34 9.30E‐05 C/T 0.100 0.99 (0.75‐1.31) 8.71E‐01 8.07E‐03 rs4760067 12 130611682 M ‐23.40 2.54E‐05 T/C 0.432 0.94 (0.88‐1.01) 2.16E‐01 3.55E‐02 rs2874868 13 36356679 MAB21L1 M 16.78 6.40E‐05 G/T 0.233 0.94 (0.87‐1.02) 7.78E‐01 2.48E‐03 rs7329452 13 39000963 M ‐23.70 3.64E‐05 G/T 0.498 0.97 (0.92‐1.03) 8.55E‐01 2.30E‐03 rs4520736 13 59174647 M ‐21.75 2.56E‐05 C/T 0.415 0.99 (0.92‐1.07) 8.42E‐01 4.57E‐03 rs4885169 13 74900793 M ‐23.04 5.31E‐06 A/G 0.239 1.10 (1.01‐1.19) 6.90E‐01 4.64E‐04 rs1041515 13 74905950 M ‐21.78 5.14E‐07 C/T 0.243 1.08 (1.00‐1.18) 7.18E‐01 1.41E‐04 rs7992923 13 74907043 M ‐13.94 7.86E‐05 A/G 0.427 1.05 (0.99‐1.13) 6.37E‐01 1.78E‐03 rs1331765 13 74907933 M ‐15.35 2.15E‐05 G/A 0.372 1.06 (0.99‐1.14) 6.38E‐01 8.46E‐04 rs10492494 13 74920186 M ‐22.02 5.04E‐07 A/C 0.240 1.11 (1.02‐1.20) 4.22E‐01 3.77E‐05 rs2325622 13 74932425 M ‐21.66 5.61E‐07 A/C 0.247 1.07 (0.99‐1.16) 9.52E‐01 3.42E‐04 rs9554374 13 97580064 M 20.73 4.37E‐04 T/G 0.387 1.07 (0.99‐1.15) 8.82E‐01 1.72E‐02 rs2389751 13 97584304 M 15.52 2.13E‐04 A/G 0.411 1.02 (0.95‐1.09) 4.73E‐01 1.77E‐03

75 Diabetes Page 112 of 127

rs555647 13 98632349 IPO5 M 20.89 8.65E‐05 G/A 0.403 1.00 (0.93‐1.07) 4.15E‐01 8.00E‐04 rs6572117 14 42360633 LRFN5 M ‐29.20 9.45E‐05 T/C 0.374 0.98 (0.91‐1.05) 2.70E‐01 4.76E‐02 rs17120327 14 49073392 M ‐22.43 3.06E‐05 A/G 0.199 1.03 (0.95‐1.12) 8.15E‐01 1.85E‐03 rs7165441 15 27828539 M 22.79 6.52E‐05 G/A 0.408 1.01 (0.94‐1.08) 4.83E‐01 2.00E‐02 rs17818867 15 55175350 M 19.09 1.24E‐05 C/T 0.255 1.01 (0.93‐1.09) 5.38E‐01 7.94E‐03 rs11637842 15 55200927 M 20.78 1.43E‐05 A/G 0.225 1.01 (0.93‐1.09) 6.06E‐01 6.86E‐03 rs17238052 15 55259099 M 22.68 9.39E‐05 G/A 0.235 1.03 (0.95‐1.11) 1.65E‐01 7.52E‐02 rs3826347 17 64970002 CACNG4 M 25.26 4.44E‐05 G/A 0.424 1.00 (0.93‐1.07) 9.15E‐01 4.92E‐03 rs6501303 17 77430593 RBFOX3 M 33.30 4.32E‐05 A/G 0.046 0.95 (0.80‐1.12) 1.30E‐01 7.43E‐05 rs626410 18 65855591 M 16.55 2.88E‐05 A/C 0.398 0.96 (0.90‐1.03) 6.99E‐01 1.23E‐03 rs12961613 18 66309996 M ‐22.84 6.23E‐05 T/C 0.229 1.07 (0.94‐1.21) 1.26E‐01 9.10E‐05 rs10408924 19 9253139 ZNF317 M 22.59 9.94E‐05 G/T 0.370 0.97 (0.90‐1.04) 4.57E‐01 1.05E‐03 rs892024 19 33399344 CEP89 M ‐23.28 8.92E‐05 A/G 0.168 1.00 (0.92‐1.10) 8.53E‐01 3.71E‐03 rs913555 20 3090124 LOC100134015 M 21.80 6.92E‐05 A/G 0.295 1.01 (0.94‐1.09) 8.91E‐01 6.59E‐03 rs911112 20 3144664 ProSAPiP1 M 22.86 6.70E‐05 T/C 0.254 1.00 (0.93‐1.09) 7.46E‐01 2.31E‐03 rs11907984 20 20862068 M ‐16.12 9.28E‐05 T/C 0.370 0.99 (0.92‐1.07) 7.18E‐01 2.53E‐03 rs4813402 20 20889803 M ‐16.68 5.21E‐05 C/T 0.366 0.99 (0.92‐1.06) 8.26E‐01 2.56E‐03 rs6137217 20 20997702 M 24.96 9.01E‐06 T/C 0.349 0.96 (0.89‐1.03) 6.94E‐01 6.31E‐04 rs6047982 20 22246450 M 12.85 6.23E‐04 G/T 0.419 0.98 (0.92‐1.06) 4.66E‐01 3.34E‐03 rs6113604 20 22252275 M 22.01 1.22E‐04 T/C 0.369 1.03 (0.96‐1.10) 6.89E‐01 2.69E‐03 rs4815102 20 22255173 CR627206 M 21.95 1.39E‐04 T/G 0.371 0.99 (0.92‐1.06) 3.79E‐01 9.13E‐04 rs1028444 20 22267058 M 26.33 5.22E‐06 C/T 0.404 1.02 (0.96‐1.10) 8.62E‐01 8.26E‐04 rs4813452 20 22276813 M 24.54 2.16E‐05 G/T 0.382 1.03 (0.96‐1.11) 7.51E‐01 1.25E‐03 rs17192831 20 22281954 M 24.83 1.64E‐05 T/C 0.386 0.98 (0.91‐1.05) 2.33E‐01 9.99E‐05 rs6018406 20 45941326 ZMYND8 M 18.51 5.91E‐05 C/A 0.247 0.88 (0.79‐0.97) 1.06E‐01 6.84E‐05 rs155004 20 57870356 M ‐24.33 2.48E‐05 G/A 0.283 0.95 (0.87‐1.04) 2.50E‐01 3.01E‐02 rs1573708 22 36427484 M 14.69 2.25E‐03 T/C 0.488 0.95 (0.89‐1.03) 6.46E‐01 1.30E‐02 rs763040 22 44763606 M 22.54 6.91E‐05 A/G 0.205 1.04 (0.96‐1.13) 8.50E‐01 7.36E‐03 rs2784739 1 8497558 RERE AIRg ‐1.98 1.91E‐05 G/T 0.243 1.01 (0.93‐1.10) 2.97E‐01 2.23E‐02 rs11121182 1 8522553 RERE AIRg ‐1.92 5.01E‐05 A/C 0.270 0.87 (0.81‐0.94) 4.40E‐03 3.93E‐01 rs10492966 1 8598005 RERE AIRg ‐1.96 4.70E‐05 T/C 0.273 0.87 (0.81‐0.94) 3.27E‐03 4.25E‐01 rs11121203 1 8648240 RERE AIRg ‐1.86 4.42E‐05 C/T 0.286 0.96 (0.88‐1.03) 5.20E‐02 1.30E‐01

76 Page 113 of 127 Diabetes

rs12061717 1 55024928 ACOT11 AIRg ‐2.10 2.66E‐05 T/C 0.080 0.95 (0.84‐1.08) 1.96E‐01 3.97E‐02

rs13375344 1 73500168 AIRg 16.86 3.10E‐05 A/C 0.002 2.77 (0.48‐16.12) 2.69E‐01 3.04E‐02

rs7537721 1 88514479 AIRg 8.45 2.92E‐05 A/G 0.010 0.79 (0.33‐1.90) 1.72E‐01 8.85E‐05

rs11185362 1 104561488 AIRg ‐1.65 3.21E‐05 G/A 0.309 1.06 (0.98‐1.14) 4.67E‐01 5.50E‐04

rs17018659 2 4211781 AIRg 10.57 5.39E‐05 G/A 0.004 1.35 (0.45‐4.06) 4.11E‐01 2.30E‐02

rs2053797 2 46370892 PRKCE AIRg 1.89 5.02E‐05 A/G 0.162 0.91 (0.83‐1.00) 1.42E‐02 4.21E‐06

rs4953320 2 46374529 PRKCE AIRg 2.13 8.13E‐05 C/T 0.099 0.95 (0.84‐1.07) 1.71E‐01 1.74E‐04

rs1345516 2 64703286 AIRg 1.04 4.11E‐05 A/C 0.420 0.95 (0.88‐1.02) 2.04E‐01 1.46E‐04

rs6756027 2 64720254 AIRg 1.09 6.05E‐05 A/G 0.432 0.95 (0.88‐1.02) 3.87E‐01 5.65E‐04

rs13002043 2 64726449 AIRg 1.07 7.92E‐05 A/G 0.437 0.99 (0.93‐1.05) 9.29E‐01 4.32E‐03

rs9809000 3 154268934 AIRg 2.17 2.76E‐05 G/A 0.080 0.99 (0.89‐1.11) 6.97E‐01 1.20E‐03

rs6803803 3 180116563 AIRg 17.53 1.64E‐06 C/T 0.002 0.63 (0.25‐1.59) 4.23E‐01 7.64E‐05

rs17013808 4 89004957 AIRg ‐3.15 4.05E‐05 A/G 0.056 1.03 (0.88‐1.20) 6.78E‐01 1.39E‐03

rs3893856 5 111163 AIRg 2.09 7.21E‐05 A/G 0.096 0.95 (0.85‐1.05) 5.26E‐01 1.14E‐03

rs10041174 5 11710193 CTNND2 AIRg ‐2.59 2.36E‐05 G/A 0.080 1.07 (0.95‐1.21) 5.16E‐01 5.62E‐04

rs11750248 5 52153066 ITGA1 AIRg 2.43 2.88E‐05 T/C 0.068 1.22 (1.07‐1.39) 1.75E‐02 2.02E‐01

rs6887101 5 122109207 AIRg ‐1.70 1.24E‐05 A/G 0.270 0.98 (0.91‐1.05) 4.56E‐01 1.04E‐02

rs193541 5 122253304 SNX24 AIRg ‐1.71 7.64E‐06 C/T 0.253 0.98 (0.91‐1.06) 4.08E‐01 9.90E‐03

rs17149748 5 122267367 SNX24 AIRg ‐2.14 5.70E‐05 G/A 0.093 0.94 (0.84‐1.06) 3.63E‐01 2.76E‐02

rs6891052 5 122358015 AIRg ‐2.31 2.32E‐05 T/G 0.092 0.92 (0.82‐1.04) 2.39E‐01 3.08E‐02

rs10476419 5 162296335 AIRg 4.71 8.86E‐05 G/A 0.010 1.23 (0.61‐2.47) 3.66E‐01 3.29E‐02

rs10078423 5 162312823 AIRg 7.29 4.94E‐05 G/A 0.005 0.87 (0.38‐1.97) 7.94E‐01 7.26E‐03

rs10051450 5 162378040 AIRg 7.39 3.14E‐05 T/C 0.005 1.20 (0.50‐2.91) 5.10E‐01 1.32E‐02

rs4712523 6 20657564 CDKAL1 AIRg ‐1.17 1.60E‐05 G/A 0.315 1.03 (0.96‐1.11) 2.64E‐01 1.23E‐04

rs6456369 6 20660365 CDKAL1 AIRg ‐0.98 5.17E‐05 C/T 0.350 1.09 (1.01‐1.17) 2.97E‐02 1.09E‐05

rs7754840 6 20661250 CDKAL1 AIRg ‐1.26 3.83E‐06 C/G 0.310 1.10 (1.02‐1.18) 9.77E‐03 3.50E‐07

rs9368222 6 20686996 CDKAL1 AIRg ‐1.46 1.28E‐06 A/C 0.262 1.12 (1.00‐1.25) 3.31E‐03 3.78E‐08

rs2206734 6 20694884 CDKAL1 AIRg ‐2.05 1.02E‐06 T/C 0.194 1.19 (1.09‐1.30) 1.41E‐03 1.11E‐08

rs1040558 6 20713706 CDKAL1 AIRg ‐1.92 5.52E‐06 G/A 0.218 1.15 (1.05‐1.24) 5.05E‐03 2.04E‐07

rs6935599 6 20717095 CDKAL1 AIRg ‐1.73 5.83E‐05 G/A 0.245 1.03 (0.96‐1.11) 2.01E‐01 1.80E‐04

rs10946403 6 20717404 CDKAL1 AIRg ‐1.74 5.56E‐05 G/A 0.242 1.09 (1.01‐1.18) 5.25E‐03 1.41E‐06

rs9358357 6 20719145 CDKAL1 AIRg ‐1.77 3.60E‐05 G/A 0.247 1.16 (1.07‐1.26) 2.64E‐03 4.46E‐07

77 Diabetes Page 114 of 127

rs9356746 6 20720279 CDKAL1 AIRg ‐1.73 3.29E‐05 C/T 0.193 1.16 (1.06‐1.27) 8.95E‐03 1.71E‐06 rs3873380 6 31262438 HLA‐B AIRg 1.55 4.50E‐05 T/C 0.408 0.89 (0.70‐1.12) 3.21E‐01 3.35E‐04 rs35473403 6 43480822 YIPF3 AIRg 16.32 7.58E‐05 T/C 0.002 1.02 (0.32‐3.29) 9.73E‐01 5.53E‐03 rs7750450 6 55714563 BMP5 AIRg 1.40 6.21E‐05 C/T 0.322 0.92 (0.86‐0.99) 4.67E‐02 2.26E‐05 rs11963462 6 121021878 AIRg 1.60 6.06E‐05 C/T 0.232 1.09 (1.00‐1.19) 1.72E‐01 6.13E‐02 rs9321207 6 130397238 L3MBTL3 AIRg ‐0.97 7.43E‐05 A/G 0.365 0.97 (0.90‐1.04) 5.05E‐01 1.98E‐02 rs4897370 6 130466676 SAMD3 AIRg 1.43 3.80E‐05 G/A 0.346 0.97 (0.90‐1.04) 8.71E‐01 2.46E‐03 rs2038586 6 158091108 ZDHHC14 AIRg 1.97 1.49E‐05 T/C 0.184 0.92 (0.81‐1.05) 6.47E‐02 1.26E‐05 rs9295206 6 163326692 PACRG AIRg ‐1.18 4.78E‐05 G/A 0.400 1.00 (0.93‐1.07) 9.75E‐01 3.76E‐03 rs7779074 7 22986107 FAM126A AIRg 2.13 9.56E‐05 A/G 0.101 1.17 (1.05‐1.32) 2.90E‐02 2.24E‐01 rs10232215 7 92097166 AIRg 1.96 4.41E‐05 G/A 0.248 0.95 (0.88‐1.03) 7.07E‐01 1.61E‐03 rs2111200 7 92140397 PEX1 AIRg 1.96 3.21E‐05 T/C 0.251 0.96 (0.88‐1.05) 4.02E‐01 1.89E‐02 rs10237822 7 93760001 AIRg 3.94 3.53E‐05 G/T 0.025 1.03 (0.81‐1.31) 3.89E‐01 2.06E‐02 rs10242768 7 93784157 AIRg 3.94 6.87E‐05 C/T 0.022 1.10 (0.84‐1.46) 1.60E‐01 6.87E‐02 rs11779094 8 10666813 SOX7 AIRg ‐2.18 8.16E‐05 A/G 0.075 1.10 (0.94‐1.27) 7.19E‐01 2.36E‐03 rs7000560 8 16993943 AIRg 2.00 3.35E‐05 C/A 0.476 1.04 (0.97‐1.12) 8.77E‐01 4.74E‐03 rs4922265 8 16996435 AIRg 2.11 6.61E‐06 A/C 0.469 1.00 (0.93‐1.07) 8.54E‐01 9.11E‐04 rs6988635 8 95744466 DPY19L4 AIRg 1.18 7.73E‐05 G/A 0.444 0.96 (0.89‐1.03) 5.33E‐01 1.21E‐03 rs7018475 9 22137685 AIRg ‐1.64 4.90E‐06 G/T 0.323 1.09 (1.02‐1.17) 2.34E‐03 7.31E‐08 rs13301551 9 25683697 AIRg 2.39 8.39E‐05 T/C 0.075 0.97 (0.85‐1.11) 1.80E‐01 1.92E‐04 rs2295926 9 101593825 GALNT12 AIRg ‐1.61 2.21E‐05 C/T 0.348 0.92 (0.82‐1.04) 1.08E‐01 6.23E‐02 rs7341705 9 107651348 ABCA1 AIRg 13.32 1.77E‐05 C/T 0.003 1.02 (0.49‐2.10) 3.82E‐01 1.56E‐02 rs1602111 9 109277184 BC017988 AIRg ‐1.53 2.16E‐05 C/A 0.233 1.00 (0.93‐1.08) 9.49E‐01 3.09E‐03 rs2287005 9 113791313 LPAR1 AIRg 2.61 6.49E‐05 C/T 0.068 1.08 (0.92‐1.26) 7.63E‐01 9.03E‐03 rs7036846 9 119798885 ASTN2 AIRg 10.86 9.25E‐06 C/T 0.005 1.11 (0.57‐2.17) 6.67E‐01 5.82E‐04 rs10870202 9 139257411 DNLZ AIRg ‐1.04 5.37E‐05 T/C 0.430 1.12 (1.05‐1.20) 2.08E‐02 7.10E‐06 rs7919192 10 93660727 AIRg ‐1.45 5.00E‐05 C/T 0.216 0.92 (0.84‐1.01) 6.01E‐01 1.25E‐02 rs6584696 10 107578214 AIRg 4.14 2.66E‐05 C/T 0.026 0.82 (0.66‐1.02) 2.70E‐01 1.77E‐04 rs2129969 11 45586169 AIRg 1.14 2.10E‐05 G/A 0.477 0.91 (0.85‐0.98) 2.38E‐02 4.10E‐06 rs510398 11 66054823 YIF1A AIRg 12.63 4.37E‐06 C/T 0.003 1.89 (0.65‐5.53) 6.85E‐01 3.07E‐03 rs11227856 11 67377758 NDUFV1 AIRg 6.51 5.34E‐05 T/C 0.005 1.77 (0.88‐3.55) 4.86E‐01 1.81E‐02 rs10898909 11 72952496 AIRg 1.41 4.03E‐06 A/G 0.404 0.94 (0.86‐1.02) 9.27E‐02 8.64E‐06

78 Page 115 of 127 Diabetes

rs3847554 11 92668826 AIRg ‐1.64 1.08E‐06 T/C 0.343 1.07 (1.00‐1.15) 1.96E‐01 1.29E‐05

rs1387153 11 92673828 AIRg ‐2.55 2.21E‐09 T/C 0.220 1.07 (0.98‐1.16) 1.97E‐01 2.72E‐07

rs2166706 11 92691532 AIRg ‐1.70 1.24E‐06 C/T 0.308 1.07 (0.99‐1.15) 2.47E‐01 2.17E‐05

rs10830961 11 92694757 AIRg ‐1.59 1.91E‐06 G/A 0.331 1.07 (0.99‐1.15) 2.41E‐01 2.70E‐05

rs10830963 11 92708710 MTNR1B AIRg ‐2.76 5.23E‐12 G/C 0.220 1.08 (1.00‐1.18) 1.83E‐01 5.86E‐09

rs686413 11 117537710 DSCAML1 AIRg ‐1.19 5.67E‐05 A/G 0.327 0.94 (0.88‐1.00) 1.03E‐01 9.00E‐02

rs12292105 11 117983479 TMPRSS4 AIRg 3.77 3.77E‐05 G/T 0.024 0.92 (0.73‐1.16) 9.00E‐01 2.68E‐03

rs7927108 11 134038949 NCAPD3 AIRg 10.54 4.35E‐05 T/G 0.004 0.82 (0.35‐1.93) 5.25E‐01 8.36E‐04

rs7962050 12 1031454 RAD52 AIRg 1.20 7.67E‐05 G/A 0.323 0.96 (0.89‐1.03) 2.74E‐01 3.56E‐04

rs247352 12 14900457 AIRg 4.42 9.24E‐05 C/T 0.013 1.20 (0.94‐1.52) 5.40E‐01 1.98E‐02

rs12816878 12 23155705 AK094733 AIRg 1.31 9.69E‐05 T/C 0.283 0.98 (0.91‐1.05) 8.61E‐01 3.97E‐03

rs3847896 12 23159966 AK094733 AIRg 1.12 6.47E‐05 C/T 0.453 0.94 (0.88‐1.01) 1.16E‐01 8.32E‐05

rs1489076 12 29129874 AIRg ‐1.37 1.97E‐05 T/C 0.377 0.97 (0.91‐1.04) 4.26E‐01 1.41E‐02

rs11049971 12 29130200 AIRg ‐1.37 1.78E‐05 T/C 0.376 0.98 (0.91‐1.05) 3.78E‐01 1.59E‐02

rs1489078 12 29141413 AIRg ‐1.34 2.48E‐05 G/A 0.376 0.98 (0.92‐1.06) 6.42E‐01 7.97E‐03

rs11113214 12 107588082 AIRg ‐1.93 6.21E‐05 G/A 0.219 1.08 (0.99‐1.17) 6.07E‐01 1.40E‐03

rs3026485 12 110782027 ATP2A2 AIRg 15.24 6.78E‐06 C/T 0.002 2.54 (0.96‐6.73) 4.64E‐02 7.61E‐02

rs16940879 12 110928719 AIRg 11.03 6.21E‐05 G/A 0.003 1.51 (0.68‐3.37) 3.93E‐01 2.59E‐02

rs10774579 12 121405210 AIRg 1.59 7.01E‐05 C/T 0.252 0.97 (0.89‐1.06) 1.46E‐01 1.24E‐04

rs10744163 12 124383950 DNAH10 AIRg 1.75 2.66E‐05 T/C 0.200 0.97 (0.89‐1.06) 2.32E‐01 1.36E‐04

rs9553849 13 27082326 AIRg 1.57 6.70E‐05 A/G 0.199 0.86 (0.79‐0.94) 1.29E‐02 4.70E‐06

rs9670049 13 31692454 AIRg 1.81 9.20E‐05 C/T 0.176 1.02 (0.94‐1.10) 3.81E‐01 3.19E‐02

rs9585660 13 101962642 NALCN AIRg 8.29 2.60E‐05 A/G 0.006 1.55 (0.82‐2.94) 6.36E‐02 9.64E‐02

rs7158254 14 37264674 SLC25A21 AIRg 7.18 3.91E‐05 C/T 0.007 1.22 (0.74‐2.01) 5.50E‐01 1.29E‐02

rs1690356 15 55301874 AIRg 13.41 1.47E‐05 A/C 0.003 0.95 (0.29‐3.07) 9.94E‐01 2.14E‐03

rs2570133 15 87604296 AIRg ‐1.00 6.64E‐05 C/T 0.416 1.03 (0.95‐1.10) 6.31E‐01 1.58E‐03

rs9935964 16 66216144 AIRg 28.14 9.57E‐08 A/G 0.001 2.15 (0.21‐22.37) 5.63E‐01 7.71E‐04

rs7192071 16 78953857 WWOX AIRg 4.34 7.30E‐05 G/A 0.024 0.94 (0.77‐1.15) 6.35E‐01 1.69E‐03

rs16953087 17 420033 VPS53 AIRg ‐1.81 3.26E‐05 C/T 0.130 1.02 (0.93‐1.13) 9.47E‐01 3.84E‐03

rs1006703 17 3865399 ATP2A3 AIRg 2.13 2.65E‐06 T/C 0.087 0.92 (0.81‐1.05) 8.38E‐01 5.30E‐04

rs2619996 17 71703758 AIRg 3.15 7.69E‐05 T/C 0.042 0.97 (0.81‐1.17) 8.86E‐01 7.06E‐03

rs899596 17 71735485 AIRg 2.20 2.64E‐06 G/A 0.230 0.98 (0.90‐1.06) 5.32E‐01 1.67E‐04

79 Diabetes Page 116 of 127

rs9955097 18 7965469 PTPRM AIRg 11.62 3.10E‐05 C/A 0.004 0.64 (0.19‐2.10) 4.54E‐01 5.11E‐04 rs9950590 18 8043661 PTPRM AIRg 11.99 5.19E‐06 T/C 0.005 0.48 (0.19‐1.19) 1.47E‐01 2.15E‐05 rs2068732 18 26236729 AIRg 2.42 6.85E‐05 C/A 0.120 1.08 (0.97‐1.19) 9.87E‐02 9.94E‐02 rs12608167 18 71893294 AIRg 1.36 2.48E‐05 G/A 0.264 1.01 (0.93‐1.09) 8.70E‐01 1.95E‐03 rs33845 19 34014316 AIRg 1.00 7.03E‐05 A/G 0.361 1.03 (0.96‐1.11) 7.03E‐01 1.11E‐02 rs6030572 20 41598995 PTPRT AIRg ‐1.96 8.83E‐05 C/A 0.175 0.96 (0.88‐1.05) 4.28E‐01 2.70E‐02 rs17646111 21 34954782 DONSON AIRg ‐1.57 3.16E‐05 A/G 0.237 1.07 (0.99‐1.16) 7.21E‐01 1.40E‐03 rs1892700 21 35016137 DONSON AIRg ‐1.52 5.02E‐05 A/G 0.236 1.01 (0.93‐1.09) 2.99E‐01 3.29E‐02 rs5752933 22 29902192 AIRg 2.11 1.36E‐05 C/A 0.230 1.00 (0.91‐1.10) 9.23E‐01 1.66E‐03 rs2985125 1 17004186 DI 3.11 3.02E‐05 G/A 0.052 1.01 (0.70‐1.45) 9.82E‐01 3.02E‐03 rs16866049 1 35836440 ZMYM4 DI 21.17 3.08E‐05 G/A 0.002 1.18 (0.38‐3.65) 7.18E‐01 7.10E‐03 rs513553 1 182494063 RGSL1 DI ‐1.83 8.14E‐05 G/A 0.262 1.08 (1.00‐1.17) 7.92E‐02 5.64E‐05 rs185580 1 182519861 RGSL1 DI ‐1.47 9.30E‐05 A/G 0.227 1.04 (0.95‐1.13) 3.41E‐01 5.89E‐04 rs266549 1 182528269 RGSL1 DI ‐1.59 6.29E‐05 T/C 0.229 0.99 (0.91‐1.08) 4.60E‐01 8.02E‐04 rs474939 1 182538615 DI ‐1.69 3.59E‐05 A/G 0.239 1.06 (0.97‐1.15) 2.15E‐01 1.45E‐04 rs10919851 1 200187504 DI ‐1.16 5.29E‐05 C/T 0.442 0.98 (0.91‐1.05) 7.31E‐01 1.92E‐03 rs6427807 1 200189305 DI 1.15 6.79E‐05 A/C 0.462 1.05 (0.98‐1.12) 6.41E‐01 1.29E‐02 rs7603311 2 49041322 DI 1.44 2.30E‐05 C/T 0.441 1.04 (0.97‐1.12) 2.94E‐01 2.44E‐02 rs4482537 2 49052255 DI 1.38 5.52E‐05 T/C 0.404 1.05 (0.98‐1.12) 2.62E‐01 3.95E‐02 rs17492567 2 50212116 NRXN1 DI 2.54 4.51E‐05 C/T 0.089 0.99 (0.89‐1.10) 3.21E‐01 2.90E‐02 rs12986646 2 52372389 DI 2.64 8.76E‐05 A/G 0.044 0.90 (0.75‐1.08) 8.01E‐01 9.44E‐03 rs881952 2 60888202 DI ‐2.30 4.59E‐06 C/T 0.477 0.94 (0.88‐1.01) 1.17E‐01 3.30E‐02 rs6753918 2 137214258 DI 6.77 2.54E‐05 C/T 0.012 0.96 (0.77‐1.19) 8.94E‐01 3.93E‐03 rs7560169 2 142148511 LRP1B DI 1.57 8.79E‐05 T/C 0.388 1.02 (0.95‐1.10) 6.30E‐01 1.50E‐02 rs684428 2 220505265 SLC4A3 DI 1.61 8.27E‐05 T/C 0.170 0.97 (0.88‐1.06) 9.15E‐01 6.76E‐03 rs7559293 2 236422975 AGAP1 DI 1.95 6.75E‐05 A/G 0.408 1.03 (0.96‐1.11) 2.65E‐01 4.25E‐02 rs28415051 3 66008918 MAGI1 DI 15.79 5.80E‐05 G/A 0.003 0.79 (0.44‐1.40) 7.93E‐01 2.46E‐03 rs9832209 3 96825782 EPHA6 DI 2.00 5.13E‐05 A/G 0.356 1.07 (1.00‐1.15) 5.20E‐02 1.36E‐01 rs602149 3 185244569 LIPH DI ‐2.95 4.20E‐05 T/G 0.059 1.10 (0.95‐1.28) 6.29E‐01 1.20E‐03 rs612304 3 185251001 LIPH DI ‐3.25 3.31E‐05 C/T 0.059 1.07 (0.92‐1.25) 9.49E‐01 3.85E‐03 rs1520323 4 125146503 DI ‐3.68 6.82E‐05 T/C 0.021 0.99 (0.78‐1.25) 9.94E‐01 4.95E‐03 rs467650 5 97969453 DI 1.94 3.33E‐05 C/T 0.271 1.01 (0.93‐1.09) 8.86E‐01 4.61E‐03

80 Page 117 of 127 Diabetes

rs6902991 6 78060981 DI ‐0.52 1.58E‐01 T/C 0.534 1.03 (0.96‐1.10) 1.47E‐01 4.30E‐02 rs13193467 6 85211681 DI ‐2.10 4.66E‐05 T/C 0.132 1.02 (0.92‐1.13) 5.99E‐01 1.15E‐03 rs1510292 6 124371914 NKAIN2 DI ‐3.05 5.10E‐05 A/G 0.060 0.90 (0.78‐1.03) 1.69E‐01 5.85E‐02 rs17086954 6 156337304 DI 2.02 2.71E‐05 G/A 0.220 0.92 (0.85‐1.00) 1.77E‐01 8.74E‐05 rs10225719 7 12691988 SCIN DI ‐2.17 3.17E‐05 T/C 0.418 1.01 (0.94‐1.08) 5.45E‐01 7.52E‐04 rs10267836 7 30755583 INMT DI 3.20 6.27E‐06 T/C 0.041 0.95 (0.81‐1.12) 9.93E‐01 1.37E‐03 rs1346111 7 49742459 DI ‐2.04 2.28E‐05 C/T 0.226 1.00 (0.92‐1.08) 1.49E‐01 4.83E‐02 rs10278107 7 125278195 DI ‐1.90 5.14E‐05 C/T 0.477 1.05 (0.99‐1.11) 2.10E‐01 1.76E‐04 rs12539028 7 154812950 DI ‐1.74 8.46E‐05 A/G 0.435 1.03 (0.96‐1.11) 5.08E‐01 1.16E‐03 rs1077489 8 6635669 DI ‐2.37 9.47E‐05 T/C 0.072 1.06 (0.91‐1.23) 5.84E‐01 1.76E‐02 rs12546336 8 39620015 ADAM2 DI 1.65 9.24E‐05 A/G 0.333 1.06 (0.99‐1.14) 2.26E‐01 5.63E‐02 rs2891781 8 124608162 DI ‐1.38 4.34E‐03 T/C 0.537 0.97 (0.90‐1.04) 1.06E‐01 3.82E‐01 rs13253406 8 143200557 DI ‐1.77 6.65E‐05 G/T 0.390 1.01 (0.95‐1.07) 9.75E‐01 5.14E‐03 rs2382470 9 14387817 NFIB DI ‐1.59 2.02E‐05 A/G 0.255 0.95 (0.88‐1.02) 7.38E‐01 5.48E‐03 rs2020927 9 107553185 ABCA1 DI ‐1.74 5.74E‐05 G/A 0.161 0.95 (0.87‐1.03) 4.55E‐01 2.05E‐02 rs10121901 9 107553524 ABCA1 DI ‐1.74 5.63E‐05 G/A 0.161 0.96 (0.87‐1.05) 6.85E‐01 1.04E‐02 rs2066720 9 107554069 ABCA1 DI ‐1.74 5.74E‐05 T/C 0.161 0.95 (0.87‐1.04) 5.79E‐01 1.42E‐02 rs11145750 9 139259249 CARD9 DI ‐1.69 2.71E‐05 A/G 0.474 1.11 (1.04‐1.18) 2.77E‐02 6.06E‐06 rs10781499 9 139266405 CARD9 DI ‐0.97 4.13E‐02 G/A 0.491 1.07 (1.01‐1.15) 1.53E‐01 1.42E‐02 rs4077515 9 139266496 CARD9 DI ‐0.89 5.71E‐02 C/T 0.491 1.08 (1.01‐1.15) 1.48E‐01 1.79E‐02 rs3812560 9 139269905 DI ‐1.83 6.16E‐06 T/C 0.465 1.09 (1.02‐1.16) 1.89E‐01 3.71E‐05 rs3812570 9 139275204 SNAPC4 DI ‐1.87 1.72E‐06 A/C 0.461 1.07 (0.99‐1.14) 4.93E‐02 1.81E‐06 rs4266763 9 139289825 SNAPC4 DI ‐2.00 3.46E‐06 A/G 0.489 1.10 (1.03‐1.18) 1.23E‐02 4.34E‐07 rs8413 9 139323311 INPP5E DI ‐1.77 2.83E‐05 T/C 0.470 1.07 (1.00‐1.15) 3.83E‐02 9.62E‐06 rs10870194 9 139327034 INPP5E DI ‐1.58 5.86E‐05 A/G 0.446 1.07 (1.01‐1.14) 3.40E‐01 4.38E‐04 rs10781542 9 139327439 INPP5E DI ‐1.59 5.77E‐05 A/G 0.446 1.06 (0.99‐1.14) 7.76E‐02 4.28E‐05 rs1148233 10 31461599 DI 8.86 9.09E‐06 T/C 0.008 1.29 (0.70‐2.38) 8.19E‐01 2.92E‐03 rs1414894 10 89785190 DI 1.67 4.62E‐05 C/T 0.286 1.02 (0.95‐1.10) 9.05E‐01 5.17E‐03 rs2488069 10 94505421 DI ‐18.48 5.73E‐05 G/T 0.002 2.34 (0.90‐6.07) 2.63E‐01 2.76E‐04 rs7081634 10 94685886 EXOC6 DI ‐22.06 2.62E‐05 G/A 0.002 2.24 (0.87‐5.80) 1.40E‐01 5.87E‐05 rs7068036 10 95315193 DI 1.94 6.79E‐05 T/C 0.156 0.99 (0.88‐1.11) 9.89E‐01 5.01E‐03 rs2237896 11 2858440 KCNQ1 DI 1.64 1.57E‐05 A/G 0.247 0.75 (0.69‐0.82) 2.90E‐13 2.13E‐16

81 Diabetes Page 118 of 127

rs2237897 11 2858546 KCNQ1 DI 1.75 7.04E‐06 T/C 0.251 0.73 (0.68‐0.79) 1.89E‐19 1.24E‐21 rs5241 11 14990543 CALCA DI 5.81 9.58E‐05 T/G 0.016 1.22 (0.74‐2.01) 3.22E‐01 3.97E‐02 rs4756016 11 45699134 DI 1.50 4.61E‐05 G/A 0.416 1.00 (0.94‐1.07) 8.85E‐01 2.85E‐03 rs744434 11 65847982 PACS1 DI 15.07 5.45E‐05 G/T 0.003 0.82 (0.38‐1.77) 8.63E‐01 2.93E‐03 rs1351571 11 98408860 DI ‐1.31 4.20E‐05 T/C 0.472 1.02 (0.95‐1.09) 7.58E‐01 1.84E‐03 rs17108749 11 108796817 DDX10 DI ‐9.79 7.57E‐05 G/T 0.009 2.10 (0.91‐4.88) 1.31E‐01 1.11E‐04 rs7971324 12 3098924 TEAD4 DI 3.44 5.00E‐05 C/A 0.056 0.81 (0.70‐0.94) 6.09E‐02 2.75E‐05 rs17107718 12 70488764 DI 2.52 6.92E‐05 T/C 0.054 1.05 (0.92‐1.21) 9.50E‐01 5.61E‐03 rs7304911 12 129705400 TMEM132D DI ‐1.40 2.69E‐05 T/C 0.223 1.04 (0.96‐1.14) 4.63E‐01 4.88E‐04 rs1537435 13 27909319 DI 1.61 5.12E‐05 T/C 0.316 0.97 (0.91‐1.04) 4.77E‐01 7.61E‐04 rs17085484 13 27930039 DI 1.52 8.64E‐05 C/T 0.318 0.97 (0.90‐1.04) 5.01E‐01 1.15E‐03 rs870767 13 27938560 DI 1.53 5.87E‐05 G/A 0.233 1.02 (0.90‐1.15) 6.17E‐01 1.40E‐03 rs2764026 13 36291051 MAB21L1 DI ‐1.77 6.43E‐05 G/A 0.282 0.93 (0.86‐1.00) 3.26E‐01 3.31E‐02 rs9575437 13 36731208 DI 2.02 2.08E‐05 G/A 0.296 1.08 (1.00‐1.16) 1.46E‐01 4.76E‐02 rs9575445 13 36731586 DI 1.88 1.48E‐05 A/G 0.285 1.01 (0.93‐1.10) 2.58E‐01 2.36E‐02 rs1328641 13 36745029 SOHLH2 DI 1.96 1.96E‐05 T/C 0.227 1.10 (1.02‐1.20) 5.84E‐02 9.28E‐02 rs2149423 13 36772381 SOHLH2 DI 2.18 3.67E‐07 G/A 0.315 1.01 (0.94‐1.09) 2.95E‐01 4.30E‐03 rs2054715 15 59607007 MYO1E DI ‐1.35 6.02E‐05 C/T 0.172 1.06 (0.96‐1.16) 6.85E‐01 1.79E‐03 rs11073891 15 90363995 DI 1.37 9.68E‐05 C/A 0.274 1.03 (0.94‐1.13) 4.94E‐01 1.19E‐03 rs4238710 16 84546021 DI ‐2.08 3.68E‐05 A/G 0.310 0.98 (0.91‐1.06) 8.69E‐01 2.41E‐03 rs2326274 16 84546108 DI ‐2.10 3.97E‐05 T/G 0.308 1.03 (0.96‐1.11) 5.31E‐01 8.11E‐04 rs9891963 17 2875114 RAP1GAP2 DI ‐3.23 8.32E‐05 T/C 0.038 0.99 (0.84‐1.15) 5.55E‐01 1.80E‐02 rs654136 18 48464204 ME2 DI ‐1.43 9.26E‐05 T/C 0.359 0.95 (0.88‐1.02) 9.87E‐02 1.10E‐01 rs4073064 18 59532727 RNF152 DI ‐10.09 7.42E‐05 C/T 0.010 1.18 (0.37‐3.73) 9.68E‐01 5.55E‐03 rs2541872 18 63632952 DI ‐1.93 9.90E‐05 A/G 0.385 0.97 (0.91‐1.05) 9.18E‐01 7.37E‐03 rs2587374 18 63638807 DI ‐2.07 5.93E‐05 A/G 0.250 0.95 (0.88‐1.04) 6.46E‐01 1.19E‐02 rs4802566 19 49632309 PPFIA3 DI 1.77 2.84E‐05 T/C 0.392 0.95 (0.88‐1.03) 2.25E‐01 1.34E‐04 rs219628 21 27865420 CYYR1 DI 1.40 5.01E‐05 C/T 0.255 0.98 (0.91‐1.06) 5.33E‐01 9.37E‐04 rs2833555 21 33285149 HUNK DI ‐2.93 6.09E‐05 T/C 0.079 1.02 (0.90‐1.14) 1.18E‐01 8.16E‐05 rs133937 22 33395851 SYN3 DI 1.65 6.74E‐05 C/A 0.335 0.94 (0.87‐1.01) 7.94E‐01 2.67E‐03 rs1674879 1 4497217 SG 0.19 5.99E‐05 T/C 0.079 1.00 (0.88‐1.14) 9.07E‐01 5.86E‐03 rs1572823 1 19889959 SG ‐0.14 6.36E‐05 T/C 0.125 1.07 (0.97‐1.18) 5.69E‐01 1.23E‐03

82 Page 119 of 127 Diabetes

rs11805807 1 155064844 SG 1.14 2.89E‐05 T/C 0.004 0.55 (0.16‐1.91) 3.20E‐01 2.52E‐04

rs563988 1 182474160 RGSL1 SG ‐0.11 9.29E‐05 C/T 0.268 1.07 (0.99‐1.16) 6.42E‐02 4.65E‐05

rs471910 1 182474704 RGSL1 SG ‐0.11 5.55E‐05 C/T 0.269 1.05 (0.98‐1.14) 2.59E‐01 2.63E‐04

rs7570259 2 23202248 SG 1.59 5.51E‐06 A/C 0.002 0.79 (0.29‐2.17) 8.19E‐01 2.28E‐03

rs11684134 2 27558252 GTF3C2 SG 0.10 5.99E‐05 A/G 0.436 0.93 (0.87‐1.00) 1.05E‐01 6.77E‐05

rs4665969 2 27574953 GTF3C2 SG 0.11 1.44E‐05 T/C 0.468 0.96 (0.89‐1.02) 2.08E‐01 7.58E‐05

rs6716894 2 27583273 SG 0.11 3.40E‐05 A/G 0.468 0.96 (0.91‐1.02) 1.99E‐01 1.23E‐04

rs7586601 2 27584666 SG 0.11 3.20E‐05 A/G 0.425 0.94 (0.88‐1.01) 5.98E‐02 1.94E‐05

rs11695549 2 27586155 SG ‐0.11 3.21E‐05 C/A 0.479 1.04 (0.97‐1.11) 2.41E‐01 1.63E‐04

rs7602534 2 27592423 EIF2B4 SG 0.11 5.06E‐05 C/T 0.465 0.97 (0.91‐1.04) 3.37E‐01 3.93E‐04

rs13472 2 27600239 ZNF513 SG 0.11 4.28E‐05 G/A 0.469 0.97 (0.91‐1.04) 2.44E‐01 2.01E‐04

rs4803 2 27667297 KRTCAP3 SG 0.11 8.09E‐05 A/G 0.459 0.98 (0.91‐1.05) 3.46E‐01 5.54E‐04

rs11126999 2 27670307 IFT172 SG 0.11 3.09E‐05 G/A 0.474 0.98 (0.92‐1.05) 3.41E‐01 2.95E‐04

rs704795 2 27716494 FNDC4 SG 0.11 7.12E‐05 G/A 0.460 0.98 (0.91‐1.05) 3.23E‐01 4.51E‐04

rs1260320 2 27722416 GCKR SG 0.11 9.73E‐05 G/A 0.467 0.98 (0.92‐1.05) 3.80E‐01 7.32E‐04

rs2293571 2 27729480 GCKR SG 0.12 1.98E‐05 G/A 0.476 0.94 (0.86‐1.02) 1.61E‐01 6.09E‐05

rs1260326 2 27730940 GCKR SG 0.13 4.04E‐06 T/C 0.335 0.96 (0.89‐1.03) 5.58E‐02 3.99E‐06

rs780093 2 27742603 GCKR SG 0.14 1.12E‐06 T/C 0.341 0.96 (0.90‐1.03) 2.07E‐01 1.46E‐05

rs11681351 2 27743423 GCKR SG 0.11 3.35E‐05 G/A 0.479 0.96 (0.90‐1.03) 2.83E‐01 2.22E‐04

rs4852424 2 70283210 PCBP1‐AS1 SG ‐0.15 5.50E‐05 G/A 0.382 1.00 (0.93‐1.07) 7.39E‐01 2.02E‐03

rs3755388 2 70310878 PCBP1‐AS1 SG ‐0.15 6.51E‐05 G/A 0.388 1.07 (1.00‐1.15) 2.45E‐01 2.67E‐04

rs6743318 2 70373677 SG ‐0.15 4.91E‐05 G/T 0.392 1.01 (0.93‐1.10) 5.35E‐01 9.33E‐04

rs14234 2 70524142 FAM136A SG 0.10 2.34E‐05 A/G 0.412 0.98 (0.91‐1.05) 5.66E‐01 6.84E‐04

rs9816690 3 82046207 BC031255 SG 0.23 7.44E‐05 A/G 0.055 1.09 (0.94‐1.26) 8.23E‐01 8.22E‐03

rs11927192 3 183730657 ABCC5 SG 0.77 5.32E‐05 A/G 0.004 1.03 (0.39‐2.78) 4.88E‐01 1.79E‐02

rs523079 3 187615862 SG 0.25 1.53E‐07 T/C 0.069 0.92 (0.81‐1.05) 3.39E‐01 1.14E‐05

rs13059988 3 187624906 SG 0.22 3.40E‐07 T/G 0.063 1.01 (0.86‐1.17) 6.78E‐01 9.62E‐05

rs10000105 4 53623677 SG 1.32 7.67E‐05 A/G 0.002 0.95 (0.12‐7.74) 3.83E‐01 6.41E‐04

rs3775781 4 70595637 SULT1B1 SG ‐0.38 3.26E‐05 T/C 0.027 0.88 (0.71‐1.08) 1.58E‐01 5.25E‐02

rs1011631 4 82440730 SG 0.09 9.08E‐05 T/C 0.328 1.06 (0.99‐1.14) 3.84E‐01 3.14E‐02

rs6871313 5 2397617 SG 0.10 4.12E‐05 G/A 0.372 1.12 (1.05‐1.21) 3.04E‐02 1.71E‐01

rs6885718 5 31657655 PDZD2 SG 0.22 4.62E‐05 G/A 0.081 1.06 (0.90‐1.26) 2.68E‐01 3.60E‐02

83 Diabetes Page 120 of 127

rs17165293 5 126183502 SG 0.28 8.94E‐05 A/G 0.041 1.01 (0.82‐1.24) 6.68E‐01 1.36E‐02 rs7708035 5 161834699 SG 1.71 1.99E‐05 A/G 0.003 1.71 (0.64‐4.56) 1.98E‐01 3.52E‐02 rs28011 5 179407229 RNF130 SG ‐0.08 8.59E‐05 C/T 0.325 1.05 (0.97‐1.13) 5.41E‐01 1.33E‐03 rs4700708 5 179529895 RASGEF1C SG ‐0.08 6.82E‐05 A/G 0.419 1.03 (0.96‐1.10) 5.13E‐01 1.04E‐03 rs2064197 6 8998811 SG ‐0.19 7.23E‐06 G/A 0.164 1.18 (1.08‐1.30) 7.01E‐04 2.56E‐08 rs367274 6 90622187 SG 0.12 2.51E‐05 T/C 0.418 1.07 (1.00‐1.15) 4.86E‐02 1.13E‐01 rs7744034 6 135143748 SG 0.13 5.45E‐05 A/G 0.253 0.95 (0.88‐1.03) 2.32E‐01 2.17E‐04 rs11752655 6 135160309 SG 0.19 1.12E‐05 G/A 0.081 0.91 (0.81‐1.02) 6.90E‐02 1.13E‐05 rs16876733 7 10945193 SG ‐0.17 5.24E‐05 C/A 0.129 1.02 (0.92‐1.13) 9.52E‐01 3.71E‐03 rs539518 7 73753250 CLIP2 SG 0.09 9.40E‐05 T/C 0.366 0.99 (0.93‐1.07) 7.40E‐01 2.73E‐03 rs1421221 8 97004203 SG ‐0.11 9.91E‐05 C/T 0.385 1.00 (0.94‐1.07) 6.75E‐01 1.41E‐02 rs883952 9 71514651 PIP5K1B SG 0.10 5.56E‐05 G/A 0.478 1.02 (0.95‐1.09) 7.38E‐01 8.95E‐03 rs12313180 12 30308868 SG 0.14 5.88E‐06 T/C 0.336 0.98 (0.91‐1.07) 7.41E‐01 2.98E‐03 rs4931283 12 30334071 SG 0.16 1.34E‐05 G/A 0.322 1.02 (0.95‐1.09) 9.22E‐01 2.61E‐03 rs909013 12 30334754 SG 0.16 1.75E‐05 G/A 0.317 1.02 (0.95‐1.09) 9.82E‐01 2.26E‐03 rs17518256 12 30339648 SG 0.17 1.32E‐05 C/A 0.295 0.99 (0.92‐1.07) 6.30E‐01 6.14E‐03 rs10843647 12 30341934 SG 0.17 4.13E‐06 T/G 0.331 1.00 (0.93‐1.07) 6.81E‐01 3.03E‐03 rs11837387 12 73467487 SG 2.02 2.22E‐05 C/T 0.001 2.96 (1.26‐6.92) 5.74E‐02 9.78E‐02 rs11104268 12 76627445 SG 0.33 6.74E‐06 G/A 0.042 1.04 (0.87‐1.25) 8.66E‐01 9.58E‐04 rs7296900 12 104177668 NT5DC3 SG 0.12 4.05E‐05 T/C 0.453 0.97 (0.91‐1.04) 9.58E‐02 4.50E‐05 rs11113179 12 107452785 CRY1 SG ‐0.12 1.28E‐05 T/C 0.286 0.99 (0.91‐1.07) 5.74E‐01 7.19E‐03 rs7319628 13 34502705 RFC3 SG 0.95 2.21E‐05 A/G 0.006 1.35 (0.56‐3.25) 3.94E‐01 1.66E‐02 rs17081477 13 35134265 SG 0.44 3.83E‐05 C/T 0.013 1.23 (0.81‐1.85) 2.62E‐01 3.42E‐02 rs1748124 13 52455098 SG ‐0.11 8.53E‐05 C/T 0.480 0.96 (0.90‐1.03) 3.35E‐01 3.60E‐02 rs9550193 13 113324324 C13orf35 SG ‐0.12 3.19E‐05 T/G 0.351 1.07 (0.99‐1.17) 1.16E‐01 5.03E‐05 rs2145516 14 26129412 SG 0.09 8.88E‐05 A/G 0.457 0.94 (0.87‐1.01) 2.91E‐02 1.60E‐05 rs12432901 14 26494469 SG ‐0.18 4.44E‐05 A/G 0.105 0.97 (0.87‐1.09) 5.37E‐01 1.43E‐02 rs7140895 14 49724328 SG 0.17 9.31E‐05 C/T 0.123 0.98 (0.89‐1.08) 5.29E‐01 1.33E‐03 rs1429751 15 34116858 RYR3 SG 0.14 9.22E‐05 C/T 0.253 1.03 (0.95‐1.11) 7.11E‐01 1.23E‐02 rs1115936 16 7171923 RBFOX1 SG ‐0.13 5.22E‐05 G/A 0.363 1.02 (0.95‐1.10) 7.93E‐01 7.47E‐03 rs4783122 16 82535037 SG ‐0.16 3.56E‐05 G/A 0.243 1.01 (0.93‐1.09) 9.90E‐01 3.37E‐03 rs7202949 16 82593560 SG ‐0.09 9.47E‐05 G/A 0.474 1.01 (0.95‐1.09) 5.97E‐01 1.72E‐03

84 Page 121 of 127 Diabetes

rs4299147 16 82883338 CDH13 SG 0.10 8.86E‐05 T/C 0.410 0.96 (0.89‐1.03) 2.05E‐01 2.44E‐04

rs1559310 16 82918371 CDH13 SG ‐0.11 4.08E‐05 G/T 0.437 1.04 (0.97‐1.11) 3.11E‐01 2.98E‐04

rs11150514 16 82923464 CDH13 SG 0.10 4.41E‐05 G/T 0.414 0.94 (0.88‐1.01) 4.40E‐01 5.93E‐04

rs12933472 16 82924685 CDH13 SG ‐0.12 8.16E‐06 A/G 0.435 1.06 (0.99‐1.14) 9.55E‐02 1.47E‐05

rs11150519 16 82934307 CDH13 SG ‐0.11 4.32E‐05 G/A 0.441 1.05 (0.98‐1.12) 1.37E‐01 7.99E‐05

rs1559438 16 83308559 CDH13 SG 0.09 6.67E‐05 C/T 0.476 1.04 (0.95‐1.13) 8.39E‐01 3.04E‐03

rs16947417 17 13143819 SG 0.26 2.24E‐05 G/T 0.053 1.07 (0.90‐1.27) 9.35E‐02 7.00E‐02

rs9896748 17 64939574 SG 0.27 2.37E‐05 T/G 0.070 0.91 (0.80‐1.03) 1.60E‐01 6.82E‐05

rs94312 18 7806492 PTPRM SG ‐0.27 8.39E‐05 G/A 0.049 0.97 (0.82‐1.16) 3.68E‐01 3.20E‐02

rs2048132 18 73694904 SG 0.16 2.16E‐05 T/G 0.225 1.01 (0.93‐1.11) 9.16E‐01 3.40E‐03

rs6566045 18 75650801 SG 0.14 4.52E‐05 C/T 0.289 0.96 (0.89‐1.04) 2.42E‐01 2.05E‐04

rs2291004 19 37997952 ZNF793 SG 0.16 3.82E‐05 A/C 0.153 0.89 (0.82‐0.97) 9.88E‐03 2.18E‐06

rs788338 19 50778543 MYH14 SG ‐0.17 1.66E‐06 C/T 0.287 0.97 (0.89‐1.05) 7.42E‐01 1.61E‐03

rs788332 19 50782462 MYH14 SG ‐0.16 1.77E‐05 A/C 0.264 0.98 (0.86‐1.13) 8.03E‐01 4.26E‐03

rs2004423 19 50939867 MYBPC2 SG 0.12 4.51E‐05 A/G 0.325 0.97 (0.89‐1.05) 2.63E‐01 2.36E‐04

rs4802723 19 51172786 SHANK1 SG ‐0.16 1.90E‐05 G/A 0.150 1.03 (0.94‐1.14) 9.26E‐01 2.00E‐03

rs4802724 19 51173218 SHANK1 SG ‐0.16 1.81E‐05 C/A 0.151 1.01 (0.89‐1.13) 8.80E‐01 3.44E‐03

rs2825882 21 21283010 SG ‐0.10 9.16E‐05 C/T 0.474 1.06 (0.99‐1.14) 9.78E‐01 5.34E‐03

rs9984764 21 27497497 APP SG 0.81 2.06E‐05 A/G 0.997 0.82 (0.29‐2.28) 5.58E‐01 6.13E‐04

rs9974077 21 43835771 UBASH3A SG 0.13 3.44E‐05 T/G 0.259 1.02 (0.94‐1.10) 9.59E‐01 3.02E‐03

85 Diabetes Page 122 of 127

Supplementary Table 7. Top regions from GWAS of T2D-related quantitative traits with translation to T2D in Mexican-origin cohorts ordered by trait from the Discovery stage.

§ || ‡ Model 1 Model 2 Marker Chr Position* Gene RA† RAF Trait Beta P-value Beta P-value rs7219451 17 38957002 KRT28 / KRT10 SI +M C 0.38 -6.8 3.92E-06 -5.86 1.43E-04 rs6815953 4 183109012 TENM3 SI +M T 0.431 4.10 3.14E-05 3.59 3.53E-04 rs7581057 2 115958079 DPP10 SI +M G 0.056 -5.47 1.74E-04 -4.52 9.35E-03 rs322394 5 172157768 NEURL1B / DUSP1 M C 0.36 -15.8 3.38E-05 -13.94 8.64E-05 rs17060946 9 77808519 OSTF1 / PCSK5 M G 0.068 37.86 2.56E-06 31.94 2.94E-05 rs13252932 8 25198091 DOCK5 M T 0.049 47.71 5.17E-06 39.14 5.93E-05 ¶ rs10830963 11 92708710 MTNR1B AIRg G 0.22 -2.76 5.23E-12 -2.81 3.22E-13 # rs2206734 6 20694884 CDKAL1 AIRg T 0.194 -2.05 1.02E-06 -1.90 5.03E-06 ** rs7018475 9 22137685 CDKN2B-AS1 / DMRTA1 AIRg G 0.323 -1.64 4.90E-06 -1.60 8.24E-06 †† rs1387153 11 92673828 MTNR1B AIRg T 0.22 -2.55 2.21E-09 -2.62 2.16E-10 rs2129969 11 45586169 PRDN11 / CHST1 AIRg G 0.477 1.14 2.10E-05 1.21 4.56E-06 rs2053797 2 46370892 PRKCE AIRg A 0.162 1.89 5.02E-05 1.81 6.75E-05 rs9553849 13 27082326 CDK8 / WASF3 AIRg A 0.199 1.57 6.70E-05 1.54 6.07E-05 rs10870202 9 139257411 DNLZ AIRg T 0.43 -1.04 5.37E-05 -1.06 2.09E-05 rs10898909 11 72952496 P2RY2 AIRg A 0.404 1.41 4.03E-06 1.31 7.78E-06 rs2237897 11 2858546 KCNQ1‡‡ DI A 0.251 1.75 7.04E-06 1.82 1.59E-06 rs4266763 9 139289825 SNAPC4 DI A 0.489 -2.00 3.46E-06 -1.93 3.35E-06 rs2064197 6 8998811 SLC35B3 / TFAP2A SG G 0.164 -0.19 7.23E-06 -0.19 7.31E-06 rs2291004 19 37997952 ZNF793 SG A 0.153 0.16 3.82E-05 0.15 1.97E-05 §§ rs1260326 2 27730940 GCKR SG T 0.335 0.13 4.04E-06 0.13 1.43E-05 SNPs with evidence of association with the nearest annotated RefSeq gene(s) listed. *Build hg19, †Reference Allele, ‡Reference Allele Frequency, §Model 1 covariates included age, gender, study site (in multi-center recruitment studies), and admixture proportions, ||Model 2 covariates included age, gender, study site (in multi-center recruitment studies), admixture proportions, and BMI, ¶Previously identified T2D locus (MTNR1B rs1387153, r2=0.69), #Previously identified T2D locus (CDKAL1 rs7754840, r2=0.42), **Previously identified T2D locus (CDKN2B rs7018475), ††Previously identified T2D locus (MTNR1B rs1387153), ‡‡Previously identified T2D locus (KCNQ1 rs2237892, r2=0.90; and KCNQ1 rs231362, r2=0.038), §§Previously identified T2D locus (GCKR rs780094, r2=0.91).

86 Page 123 of 127 Diabetes

Supplementary Table 8. Top regions from GWAS of T2D-related quantitative traits with translation to T2D in Mexican-origin cohorts ordered by trait from the Discovery stage with conditional analyses performed at loci with multiple signals of association or in close proximity to previously identified T2D loci. Discovery Cohorts Translation Cohorts Discovery and Conditional Analysis Translation Marker Chr:Position* Gene OR Trait RAF‡ Beta P-value P-value Meta-Analysis SNP r2|| P-value (95% CI)§ P-value 1.08 rs7219451 17:38957002 KRT28 / KRT10 S +M 0.380 (C) -6.80 3.92E-06 1.06E-02 3.97E-07 I (1.00‐1.16) 0.92 rs6815953 4:183109012 TENM3 S +M 0.431 (T) 4.10 3.14E-05 1.25E-02 2.47E-06 I (0.86‐0.99) 1.29 rs7581057 2:115958079 DPP10 S +M 0.056 (G) -5.47 1.74E-04 6.67E-03 4.82E-06 I (1.10‐1.50) 1.17 rs322394 5:172157768 NEURL1B / DUSP1 M 0.360 (C) -15.83 3.38E-05 7.87E-04 1.12E-07 (1.09‐1.26) 0.87 rs17060946 9:77808519 OSTF1 / PCSK5 M 0.068 (G) 37.86 2.56E-06 6.89E-02 3.99E-06 (0.75‐1.01) 0.89 rs13252932 8:25198091 DOCK5 M 0.049 (T) 47.71 5.17E-06 6.61E-02 6.11E-06 (0.75‐1.04) 1.08 rs10830963 11:92708710 MTNR1B AIR 0.220 (G) -2.76 5.23E-12 rs1387153¶ 0.69 8.67E-05 1.83E-01 5.86E-09 g (1.00‐1.18) 1.19 rs2206734 6:20694884 CDKAL1 AIR 0.194 (T) -2.05 1.02E-06 rs7754840¶ 0.42 9.37E-03 1.41E-03 1.11E-08 g (1.09‐1.30) CDKN2B-AS1 / 1.09 rs7018475 9:22137685 AIR 0.323 (G) -1.64 4.90E-06 2.34E-03 7.31E-08 DMRTA1 g (1.02‐1.17) 1.07 rs1387153 11:92673828 MTNR1B AIR 0.220 (T) -2.55 2.21E-09 1.97E-01 2.72E-07 g (0.98‐1.16) 0.91 rs2129969 11:45586169 PRDN11 / CHST1 AIR 0.477 (G) 1.14 2.10E-05 2.38E-02 4.10E-06 g (0.85‐0.98) 0.91 rs2053797 2:46370892 PRKCE AIR 0.162 (A) 1.89 5.02E-05 1.42E-02 4.21E-06 g (0.83‐1.00) 0.86 rs9553849 13:27082326 CDK8 / WASF3 AIR 0.199 (A) 1.57 6.70E-05 1.29E-02 4.70E-06 g (0.79‐0.94) 1.12 rs10870202 9:139257411 DNLZ AIR 0.430 (T) -1.04 5.37E-05 2.08E-02 7.10E-06 g (1.05‐1.20) 0.94 rs10898909 11:72952496 P2RY2 AIR 0.404 (A) 1.41 4.03E-06 9.27E-02 8.64E-06 g (0.86‐1.02) rs2237892¶ 0.90 1.57E-04 0.73 rs2237897 11:2858546 KCNQ1†† DI 0.251 (A) 1.75 7.04E-06 1.89E-19 1.24E-21 rs231362¶ 0.038 1.06E-05 (0.68‐0.79) 1.10 rs4266763 9:139289825 SNAPC4 DI 0.489 (A) -2.00 3.46E-06 1.23E-02 4.34E-07 (1.03‐1.18) 0.94 rs2064197 6:8998811 SLC35B3 / TFAP2A S 0.164 (G) -0.19 7.23E-06 7.01E-04 2.56E-08 G (0.87‐1.01) 0.89 rs2291004 19:37997952 ZNF793 S 0.153 (A) 0.16 3.82E-05 9.88E-03 2.18E-06 G (0.82‐0.97) 0.96 rs1260326 2:27730940 GCKR S 0.335 (T) 0.13 4.04E-06 rs780094¶ 0.91 9.62E-01 5.58E-02 3.99E-06 G (0.89‐1.03)

87 Diabetes Page 124 of 127

SNPs with evidence of association with the nearest annotated RefSeq gene(s) listed. *Build hg19, †Reference Allele, ‡Reference Allele Frequency, §Odds Ratio (OR) and 95% Confidence Interval (95% CI), ||Correlation from the largest set of unrelated individuals from BetaGene ¶Previously identified T2D locus

88 Page 125 of 127 Diabetes

Supplementary Figure 1. Power to detect association with T2D (n=6,463 T2D cases and 9,232 controls) with an α of 5.00x10-8 at minor allele frequencies (MAF) ranging from 0.05-0.45.

89 Diabetes Page 126 of 127

90 Page 127 of 127 Diabetes

Supplementary Figure 2. Regional plots of loci with evidence of association (P<2.00x10-6) in the Discovery meta-analysis. A) GNA15 rs2302063 with MCRI/T2D, B) MFSD8 rs1602084 with

SI+M/T2D, C) MYT1L/TSSC1 rs896232 with SI+M/T2D, D) HAAO/SFP36L2/THADA rs1978648 with SI/T2D, E) C15orf59 rs4887140 with SI/T2D, F) HMGN3/LCA5 rs196701 with SI/T2D, G) KLF12/LINC00347 rs10492494 with M/T2D, H) LOC646736/IRS1 rs11683087 with M/T2D, I) MTNR1B rs10830963 with AIRg/T2D, J) CDKAL1 rs2206734 with AIRg/T2D, K) PEX5L/TTC14 rs6803803 with AIRg/T2D, L) SOHLH2 rs2149423 with DI/T2D, M) SNAPC4 rs3812570 with DI/T2D, N) BCL6/LPP rs523079 with SG/T2D, O) GCKR rs780093 with SG/T2D, and P) MYH14 rs788338 with SG. Genotyped SNPs passing quality control measures across all Discovery cohorts are plotted with their Discovery meta-analysis p-values (as -log10 values) as a function of genomic position (hg19). In each panel, the index variant is represented by a diamond, with the discovery results denoted in red and the discovery and translational meta- analysis denoted in purple. Estimated recombination rates (taken from HapMap) are plotted to reflect the local LD structure. Color of additional variants indicates correlation with the index SNP (red, r2≥0.80; orange, 0.60≤r2<0.80; green, 0.40≤r2<0.60; blue, 0.20≤r2<0.40; white, r2<0.20; gray no r2 value available) based on pairwise r2 values from HapMap. Gene annotations were taken from the University of California Santa Cruz genome browser.

91 Diabetes Page 128 of 127

A) B) C)

D) E) F)

G) H) I)

J) K) L)

92 Page 129 of 127 Diabetes

M) N) O)