M24 - WHI Sequencing Project (WHISP)

Investigator Names and Contact Information

Rebecca Jackson (Rebecca.Jackson@osumc.edu)

Introduction/Intent

The overarching goal of the Women’s Health Initiative Sequencing Project (WHISP) is to identify possible rare causal genetic variants directly responsible for cardiovascular disease-susceptibility. To fully examine the genetic architecture of CVD-related traits, we have prposed to perform CVD phenotype-based sequencing for the unbiased discovery of rare variants having large effects in a subset of participants selected from the tails of CVD related phenotypic distributions or in cases and controls in the Women’s Health Initiative (WHI) Clinical Trial and Observational Study. The principals below were utilized to guide our selection of the 2-3 phenotypes proposed for sequencing in the first round of WHISP:

• The trait must be of interest for both NHLBI and WHI.
• There must be evidence of heritability of the trait or disease outcome.
• For clinical events, the diagnosis should be specific, and ideally should be adjudicated. In addition, the cases should represent a clinically distinct subset of a more common clinical event.
• For quantitative traits, the more extreme the tails of the distribution are, the better the likelihood of success. In addition, those with direct clinical relevance are of greatest interest.
• Because the nucleotide diversity of African Americans is higher than other ethnic groups, it is important to consider ethnicity in these analyses.

Thus, considering these parameters, we propose that the initial round of analysis be focused on the following set of traits:

(1) Tails of the HDL quantitative trait [n = 192 (96 at each tail)]

(2) Tails of extreme obesity (BMI >45) in African Americans [n = 192 (96 at each tail)] which will help to develop analytic approaches for racial admixture

(3) Atrial fibrillation [n =192 (96 cases and 96 controls)] which utilizes a case-control design

Results/Findings

For a complete, up-to-date list of WHI papers related to this ancillary study, please use the searchable Papers section of this website.