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SUPPLEMENTARY DATA Page Supplementary Text ………………………………………………………………………………… SUPPLEMENTARY DATA 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 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. ………………………………………………………………………... 87 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 ©2014 American Diabetes Association. Published online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db14-0732/-/DC1 SUPPLEMENTARY DATA 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). ©2014 American Diabetes Association. Published online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db14-0732/-/DC1 SUPPLEMENTARY DATA 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. ©2014 American Diabetes Association. Published online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db14-0732/-/DC1 SUPPLEMENTARY DATA 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
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