WHI GARNET

This substudy phs000315 WHI GARNET contains genotypes generated using Illumina array, produced as part of NHGRI's GARNET project. Summary level phenotypes for the WHI Cohort study participants can be viewed at the top-level study page phs000200 WHI Cohort. Individual level phenotype data and molecular data for all WHI top-level study and substudies are available by requesting Authorized Access to the WHI Cohort study phs000200.

GWAS of Hormone Treatment and CVD and Metabolic Outcomes in the WHI

This study is part of the Genomics and Randomized Trials Network (GARNET, http://www.garnetstudy.org) funded by the National Human Genome Research Institute (NHGRI). The overarching goal is to identify novel genetic factors that contribute to incidence of myocardial infarction, stroke, venous thrombosis, and diabetes through large-scale genome-wide association studies of treatment response in a randomized clinical trial of hormone therapy. Genotyping was performed at the Broad Institute of MIT and Harvard. Data cleaning and harmonization were performed at the GARNET Coordinating Center at the University of Washington.

Participants were selected as a nested case-control sample of coronary heart disease, stroke, venous thrombosis, and incident diabetes events from the parent WHI Hormone Trial.

WHI GARNET participants are women enrolled in the WHI Hormone Therapy (HT) Trial who meet eligibility requirements for this study and eligibility for submission to dbGaP, and who provided DNA samples. Of the approximately 27,000 women who participated in the HT trial, 4,894 were genotyped on the Illumina Omni-Quad as part of WHI GARNET, a genome-wide association study (GWAS) to identify genetic components involved in differential responses from the HT trial. Case selection of adjudicated phenotypes of interest included coronary heart disease, stroke, venous thrombosis, and incident diabetes cases that occurred during the active phase of the Hormone Trial (HT). Controls were participants in the HT trial free of all 4 case conditions by the end of the trials. HT participants with treated diabetes at baseline were excluded from the diabetes cases and controls pool, but were still considered for cases of other 3 conditions. Matching criteria for controls were age, race/ethnicity, hysterectomy status, and enrollment date. GARNET WHI participants belong to the following self-identified ethnic groups: white (87%), black (5%), Hispanic (3%), Asian/Pacific Islander (1.8%), and American Indian (0.7%). The ethnic group is unknown for 1.9% of participants.

• Study Weblinks:
  • Scientific Resources Website: Women's Health Initiative
  • NHLBI Women's Health Initiative
  • GARNET
• Study Design:
  • Case-Control
• Study Type:
  • Case-Control
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 4894
• Subject Sample Telemetry Report (SSTR)

• BioProject
• BioSample
• MeSH

Women's Health Initiative:

Women were eligible for WHI participation if they were between 50 and 79 years of age, postmenopausal, likely to live in the area for 3 years and have no condition predicting survival < 3 years. The WHI CT enrolled and randomized 68,132 women ages 50-79 into at least one of three clinical trials (hormone therapy; low fat dietary modification, calcium and vitamin D). The OS enrolled 93,676 women ages 50-79 into a parallel prospective cohort study. Population based enrollment occurred from 1993 to 1998 at 40 centers throughout the US. Exclusion criteria are listed in Table 1 of the Baseline Monograph paper (available at https://www.whi.org/about/Baseline%20Monograph/baseline_Recruitment.pdf#search=baseline%20recruitment).

GARNET:

All centrally confirmed cases of CHD (MI or coronary death), stroke, VTE and self-report treated diabetes in the WHI Hormone Therapy (HT) trial were selected as potential cases from the August 14th, 2009 database using the cutoff date of July 7, 2002 (for E+P trial) or February 29, 2004 (for E-alone trial). Controls are participants in the HT trials free of all 4 case conditions by the end of the trials. HT participants with treated diabetes at baseline were excluded from the diabetes cases and controls. In addition, cases and controls were subject to the following exclusion criteria: (1) did not have sufficient DNA volume (<2µg); (2) were successfully genotyped in the SHARe project; (3) did not have IRB approval for data submission into dbGaP (IRB approved all WHI participants for dbGAP except for those who (a) refused supplemental consent, (b) signed supplemental consent but later declined genetic testing, and (c) declined genetic testing without ever signing to Supplemental Consent). Matching criteria are Age (±5 years), Race/Ethnicity (±0), Hysterectomy status (±0), Enrollment date (±1.5 years), and Length of follow-up (±48 months). Controls were also prioritized on the basis of availability of plasma CVD biomarker availability (Glucose, HDL-C, LDL-C, Total cholesterol, Insulin, Triglycerides, CRP, Fibrinogen).

Of 4949 unique subjects submitted for genotyping, Omni 1 M high-quality genotype data was released on 99.2% of subjects (4909/4949) to the GARNET Data Coordinating Center with genotyping data on 981,877 SNPs (96.6% of the total Infinium array content). The raw data underwent additional cleaning and processing, including (a) genotyping batch quality, (b) sample quality, (c) sample identify, including gender discrepancies, relatedness and population structure, (d) case-control confounding analysis, (e) SNP quality, and (f) preliminary association analysis. Therefore, 4,894 subjects are available for analysis. These include 2,344 controls, 497 CHD cases, 1,043 incident diabetes cases, 342 stroke cases, 304 VTE cases, 167 cases of more than one type, and 197 QC samples (SHARe participants previously genotyped on Affy6.0). Based on principal component analysis, 13 discrepant samples with reported ethnicity were identified. These were retained in the data set, but flagged for discrepancy with self-reported ancestry. After additional exclusion of SNPs based on missingness (33,592) discordance (36 dropped) or HWE P<10^-4 (1,237 dropped), a total of 942,499 SNPs are available for analysis. Tests of SNP allele frequencies by treatment arm suggested no genome-wide differences.

• Primary Phenotype: Cardiovascular Diseases
• Myocardial Infarction
• Diabetes Mellitus, Type 2
• Stroke
• Venous Thromboembolism

• Principal Investigator
  • Alex Reiner. Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
• Funding Sources
  • U01HG005152. National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.