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Original Investigation
July 2015

Rare and Coding Region Genetic Variants Associated With Risk of Ischemic Stroke: The NHLBI Exome Sequence Project

Author Affiliations
  • 1Joseph J. Zilber School of Public Health, University of Wisconsin, Milwaukee
  • 2Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
  • 3Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland
  • 4Department of Neurology, Mayo Clinic, Jacksonville, Florida
  • 5Department of Neurology, University of Virginia, Charlottesville
  • 6Department of Neurology, University of Washington, Seattle
  • 7Department of Neurology, Boston University School of Medicine, Boston, Massachusetts
  • 8Department of Neurology, George Washington University Hospital, Washington, DC
  • 9Center for Public Health Genomics, University of Virginia, Charlottesville
  • 10Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts
  • 11Institute for Molecular Medicine, University of Texas Health Science Center, Houston
  • 12Department of Neuroscience, Reta Lila Weston Institute, University College London, London, England
  • 13Department of Internal Medicine, The Ohio State University, Columbus
  • 14Department of Medicine, University of Washington, Seattle
  • 15Department of Genome Sciences, University of Washington, Seattle
  • 16Department of Neurology, University of Minnesota, Minneapolis
  • 17Department of Genetics, University of North Carolina, Chapel Hill
  • 18Department of Biostatistics, University of Washington, Seattle
JAMA Neurol. 2015;72(7):781-788. doi:10.1001/jamaneurol.2015.0582

Importance  Stroke is the second leading cause of death and the third leading cause of years of life lost. Genetic factors contribute to stroke prevalence, and candidate gene and genome-wide association studies (GWAS) have identified variants associated with ischemic stroke risk. These variants often have small effects without obvious biological significance. Exome sequencing may discover predicted protein-altering variants with a potentially large effect on ischemic stroke risk.

Objective  To investigate the contribution of rare and common genetic variants to ischemic stroke risk by targeting the protein-coding regions of the human genome.

Design, Setting, and Participants  The National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP) analyzed approximately 6000 participants from numerous cohorts of European and African ancestry. For discovery, 365 cases of ischemic stroke (small-vessel and large-vessel subtypes) and 809 European ancestry controls were sequenced; for replication, 47 affected sibpairs concordant for stroke subtype and an African American case-control series were sequenced, with 1672 cases and 4509 European ancestry controls genotyped. The ESP’s exome sequencing and genotyping started on January 1, 2010, and continued through June 30, 2012. Analyses were conducted on the full data set between July 12, 2012, and July 13, 2013.

Main Outcomes and Measures  Discovery of new variants or genes contributing to ischemic stroke risk and subtype (primary analysis) and determination of support for protein-coding variants contributing to risk in previously published candidate genes (secondary analysis).

Results  We identified 2 novel genes associated with an increased risk of ischemic stroke: a protein-coding variant in PDE4DIP (rs1778155; odds ratio, 2.15; P = 2.63 × 10−8) with an intracellular signal transduction mechanism and in ACOT4 (rs35724886; odds ratio, 2.04; P = 1.24 × 10−7) with a fatty acid metabolism; confirmation of PDE4DIP was observed in affected sibpair families with large-vessel stroke subtype and in African Americans. Replication of protein-coding variants in candidate genes was observed for 2 previously reported GWAS associations: ZFHX3 (cardioembolic stroke) and ABCA1 (large-vessel stroke).

Conclusions and Relevance  Exome sequencing discovered 2 novel genes and mechanisms, PDE4DIP and ACOT4, associated with increased risk for ischemic stroke. In addition, ZFHX3 and ABCA1 were discovered to have protein-coding variants associated with ischemic stroke. These results suggest that genetic variation in novel pathways contributes to ischemic stroke risk and serves as a target for prediction, prevention, and therapy.