# Whole Genome Sequence Analysis of Ischemic Stroke in the Women's Health Initiative

> **NIH NIH R01** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2020 · $509,240

## Abstract

ABSTRACT
Stroke is among the understudied disorders despite its high burden to morbidity and mortality in the US.
Ischemic stroke, which is due to cerebral vessel occlusion, accounts for 80% of cases. Ischemic stroke is a
complex, multi-factorial disease, with heterogeneity by age, sex, and stroke subtype. A substantial proportion
of stroke risk remains unexplained. The relatively low yield of stroke genetic studies to date may reflect the
heterogeneous causes and clinical presentations of the various subtypes. Many of the studies participating in
stroke GWAS have included have had little or no data available on stroke-specific risk factors or other CVD
outcomes, which are key to understanding causal mechanisms and potential gene–environment interactions.
Next generation sequencing (NGS) and multi-omics integrative biology research offer new opportunities in the
way we research and understand stroke. Whole genome sequence (WGS) data, including both coding and
functional non-coding variants, are required to identify the full spectrum of contributions of uncommon variants
to stroke risk. Deep WGS data are currently being generated in over 11,000 WHI participants through the
NHLBI TOPMed project, including over 4,000 ischemic stroke cases. Here we propose to apply innovative
statistical approaches to perform a well-powered analysis to discover, replicate, and functionally characterize
new loci (particularly rare or low frequency coding and non-coding regulatory variants) for ischemic stroke (and
its subtypes) using WGS and imputation. Discovery will be performed in ~4,000 incident ischemic stroke cases
and over 5,000 controls from WHI with WGS through TOPMed. Single variant and gene-based tests will be
performed, prioritizing ~100 genomic regions based on prior GWAS and current epigenomic and proteomic
analyses. Replication will be performed through state-of-the art WGS-based exome and GWAS imputation in
up to ~77,000 additional ischemic stroke cases (and controls) obtained through UKBiobank, Million Veteran
Program, and the SiGN and METASTROKE stroke genomics consortia. To assess the biologic mechanism of
stroke-associated genetic loci, we will further test any newly identified stroke loci for association with: (1) a rich
set of CVD risk factors and ~40 plasma biomarkers related to atherosclerosis, thrombosis, inflammation, and
hormones available in WHI; (2) a new, commercial panel of 184 emerging biomarkers related to neurovascular
disease and CVD in 2000 WHI TOPMed samples selected on the basis of genotype. Using casual inference
methodology, we will perform mediation analyses to determine mechanistic relationships between genotype,
intermediate biomarker phenotype, and stroke outcome.

## Key facts

- **NIH application ID:** 9859225
- **Project number:** 5R01HL136574-04
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** Charles L Kooperberg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $509,240
- **Award type:** 5
- **Project period:** 2017-04-05 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9859225

## Citation

> US National Institutes of Health, RePORTER application 9859225, Whole Genome Sequence Analysis of Ischemic Stroke in the Women's Health Initiative (5R01HL136574-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9859225. Licensed CC0.

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