AS753 - TOPMed X01 – Omics resources for Women's Health Initiative African American women cardiovascular health research

Investigator Names and Contact Information

Charles Kooperberg (clk@fredhutch.org) Alex Reiner (apreiner@uw.edu) Nora Franceschini (noraf@unc.edu)

Introduction/Intent

The NHLBI's TransOmics for Precision Medicine (TOPMed) program seeks to apply whole genome sequencing (WGS) and other -omics technologies to various heart, lung, and blood (HLB) disorders -- generating large volumes of omics data and making those datasets accessible to the broad research community to stimulate discovery research. While samples funded through prior TOPMed X01s have largely supported the production of omics data related to heart, lung, and blood diseases and their risk factors, there has been relatively little multi-omics data generated in RNA-seq, DNA methylation, metabolite and protein profiling from under-represented minority samples such as African Americans (AAs). In addition, there is a gap in understanding the molecular basis of chronic conditions understudied among women and/or that disproportionately affect populations of women, such as heart failure with preserved ejection fraction (HFpEF). The current X01 proposal addresses these gaps by expanding the TOPMed multi-omic resource to address HLB conditions, germline genetic variants, and phenotypes which disproportionately impact AA and women, thereby allowing mechanistic follow-up of implicated genetic variants and to determine their full phenomic or clinical spectrum. We propose to measure omics data (WGS, RNA-seq, DNA methylation, metabolite and protein profiling) in additional WHI AA participants, which, together with the clinical, phenotypic, and environmental data already available in the same WHI AAs, can be used to inform the molecular pathobiology of additional HLBS conditions such as heart failure, stroke, VTE, and sickle cell that disproportionately affect AAs. We propose to apply innovative statistical approaches and to collaborate with other TOPMed investigators with additional AA participants and disease phenotypes. The ultimate goal is to transform genomic science from simple genetic locus-trait associations to comprehensive understanding of complex disease pathobiology at a multi-omics, systems level. SPECIFIC AIMS The main goal of this TOPMed X01 is to enhance omics resources for WHI AA women to facilitate mechanistic and risk prediction genomics studies of Heart and Blood outcomes in understudied AA women. We propose the following aims: Aim 1: Greatly expand the pool of available omics in WHI AA women with WGS in approximately 8,700 participants at baseline. Aim 2: Generate/fill in baseline multi-omics (DNA methylation, proteins, metabolites) in all new + old TOPMed AA Aim 3: Additionally generate longitudinal multi-omics (DNA methylation, proteins, metabolites, RNA-seq) in available WHI AA women who have samples at LLS-1.