Rationale, Design, and Methodology of the Women’s Genome Health Study: A Genome-Wide Association Study of More Than 25 000 Initially Healthy American Women

Abstract

The primary aim of the Women's Genome Health Study (WGHS) is to create a comprehensive, fully searchable genome-wide database of Ͼ360 000 single nucleotide polymorphisms among at least 25 000 initially healthy American women participating in the ongoing NIHfunded Women's Health Study (WHS). These women have already been followed over a 12-year period for major incident health events including but not limited to myocardial infarction, stroke, cancer, diabetes, osteoporosis, venous-thromboembolism, cognitive decline, and common visual disorders such as age-related macular degeneration and cataracts. Investigations within the WGHS will seek to identify relevant patterns of genetic polymorphism that predict future disease states in otherwise healthy American women, and to evaluate patterns of genetic polymorphism that relate to multiple intermediate phenotypes including blood-based determinants of disease that were measured at baseline for each study participant. By linking genome-wide data to the existing epidemiologic databank of the parent WHS, which includes comprehensive dietary, behavioral, and traditional exposure data on each participant since cohort inception in 1992, the WGHS will also allow exploration of gene-environment and gene-gene interactions as they relate to incident disease states. Thus, with continued follow-up of the WHS, the WGHS provides a unique scientific resource-a full-cohort, prospective, genome-wide association study among initially healthy American women.

Genetic Determinants of Statin-Induced Low-Density Lipoprotein Cholesterol Reduction

“…7,22 The association of SNP rs10455872 at the LPA locus with LDL-C lowering is probably related to a contribution of the cholesterol in lipoprotein (Lp)(a) particles to LDL-C measurements, 23 even though this same SNP was not strongly associated with baseline LDL-C in JUPITER (Figure 2). In separate data available to us, 24 SNP effects on plasma Lp(a) particle concentration at the LPA locus are highly correlated with weaker effects on plasma LDL-C (Spearman ϭ0.9) that may be not be manifest in JUPITER as a result of the LDL-C Ͻ130 mg/dL enrollment criterion. In particular, rs10455872 is associated with both Lp(a) and LDL-C in those other data (data not shown).…”

Gene × Environment Interactions in Type 2 Diabetes

“…An advantage of this approach is that it does not require knowledge of the interacting variables, which distinguishes it from almost all other interaction analysis methods. The authors applied their method to data from the Women's Genome Health Study, a study of more than 25,000 US women [56], and identified interactions between variants at LEPR (rs12753193) and BMI on C-reactive protein levels, ICAM1 (rs1799969) and smoking on soluble intercellular adhesion molecule-1 (ICAM-1) levels, and PNPLA3 (rs738409) and BMI on soluble ICAM-1 levels [55••].…”

Genome-Wide Association Studies (Gwas) of Blood Pressure in Different Populations

“…In an independent sample of 23,294 women [22], the authors found one SD increase in the genetic risk score was associated with a 21 % increase in the odds of HTN (95 %CI19 %-28 %). Among subjects in the top decile of the risk score, the prevalence of HTN was 29 % compared with 16 % in the bottom decile (OR: 2.09, 95 %CI: 1.86-2.36).…”