# Whole Exome Sequencing Study of Early-Onset Ischemic Stroke

> **NIH VA I01** · BALTIMORE VA MEDICAL CENTER · 2021 · —

## Abstract

Stroke and related diseases consume 5% of Veteran Health Administration (VHA)
patient care resources, and about 15,000 Veterans annually receive acute inpatient care for
stroke. Genetic association studies based on large samples of carefully phenotyped subjects
are potentially powerful tools for better understanding disease etiology as they can highlight
biological mechanisms underlying disease and point the way to improved prevention and
treatment. Large genome-wide association studies (GWAS) of ischemic stroke (IS) populations
in older adults have identified over 30 variants associated with this disorder. As with other
complex traits, the challenge now is to identify the genes that these variants tag and the
pathways through which they alter stroke susceptibility.
 To complement these efforts in older adults our group has pursued the strategy of
studying the genetic underpinnings of early-onset ischemic stroke, a strategy that has been
used successfully for many other complex diseases to identify large effect susceptibility
variants and to generate novel biologic insights into disease etiology. As with other complex
disorders, early-onset stroke has a higher heritability than older-onset disease, and
approaches focusing on age of onset or early-onset disease have uncovered new stroke-
associated variants that were less prominent in older-onset disease. For example, in contrast
to the importance of atherosclerotic mechanisms in older-onset stroke, prothrombotic
mechanisms are likely to be more important and discernable in studies of early-onset stroke.
 The scientific premise underlying our study is that early-onset stroke (in contrast to
later-onset stroke) is enriched for rare variants with high penetrance and large effect sizes and
that occur disproportionately in the exons (coding regions) of genes. To address this
hypothesis, we have assembled a Young Stroke Exome Sequencing Consortium with over
19,000 well-phenotyped early-onset stroke cases (stroke onset 18-59 years) - including
ischemic stroke subtype, and ancestry-matched controls. Our consortium includes populations
of European Caucasian, African, Hispanic and Asian ancestry. Through a separate agreement
(see letter of support), we are currently obtaining whole exome sequencing (WES) in these
cases and their controls. Thus, this application is to provide administrative and analysis
support for the WES analysis.
 To identify variants and genes associated with early-onset IS and IS subtypes, we will
utilize both single variant and burden testing approaches. The analysis plan includes state-of-
the-art analysis methods that our group is experienced in using through our participation in
other sequencing consortia. Exonic variants or genes identified in our young stroke
consortium will be tested for association with stroke-related phenotypes in the UK Biobank,
biomarkers related to stroke in the TOPMed Consortium, and older-onset IS from the UK
Biobank and TOPMed Consortium.
 Genomic medici...

## Key facts

- **NIH application ID:** 9889564
- **Project number:** 1I01BX004672-01A1
- **Recipient organization:** BALTIMORE VA MEDICAL CENTER
- **Principal Investigator:** STEVEN J KITTNER
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2020-10-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9889564

## Citation

> US National Institutes of Health, RePORTER application 9889564, Whole Exome Sequencing Study of Early-Onset Ischemic Stroke (1I01BX004672-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9889564. Licensed CC0.

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