Genome-Wide Association Study Meta-Analysis of Stroke in 22 000 Individuals of African Descent Identifies Novel Associations with Stroke

Keith L. Keene, Hyacinth I. Hyacinth, Joshua C. Bis, Steven J. Kittner, Braxton D. Mitchell, Yu Ching Cheng, Guillaume Pare, Michael Chong, Martin O'Donnell, James F. Meschia, Wei Min Chen, Michèle M. Sale, Stephen S. Rich, Mike A. Nalls, Alan B. Zonderman, Michele K. Evans, James G. Wilson, Adolfo Correa, Hugh S. Markus, Matthew TraylorCathryn M. Lewis, Cara L. Carty, Alexander Reiner, Jeff Haessler, Carl D. Langefeld, Rebecca Gottesman, Thomas H. Mosley, Daniel Woo, Kristine Yaffe, Yong Mei Liu, William T. Longstreth, Bruce M. Psaty, Charles Kooperberg, Leslie A. Lange, Ralph Sacco, Tatjana Rundek, Jin Moo Lee, Carlos Cruchaga, Karen L. Furie, Donna K. Arnett, Oscar R. Benavente, Raji P. Grewal, Leema Reddy Peddareddygari, Martin Dichgans, Rainer Malik, Bradford B. Worrall, Myriam Fornage

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


Background and Purpose: Stroke is a complex disease with multiple genetic and environmental risk factors. Blacks endure a nearly 2-fold greater risk of stroke and are 2× to 3× more likely to die from stroke than European Americans. Methods: The COMPASS (Consortium of Minority Population Genome-Wide Association Studies of Stroke) has conducted a genome-wide association meta-analysis of stroke in >22 000 individuals of African ancestry (3734 cases, 18 317 controls) from 13 cohorts. Results: In meta-analyses, we identified one single nucleotide polymorphism (rs55931441) near the HNF1A gene that reached genome-wide significance (P=4.62×10-8) and an additional 29 variants with suggestive evidence of association (P<1×10-6), representing 24 unique loci. For validation, a look-up analysis for a 100 kb region flanking the COMPASS single nucleotide polymorphism was performed in SiGN (Stroke Genetics Network) Europeans, SiGN Hispanics, and METASTROKE (Europeans). Using a stringent Bonferroni correction P value of 2.08×10-3 (0.05/24 unique loci), we were able to validate associations at the HNF1A locus in both SiGN (P=8.18×10-4) and METASTROKE (P=1.72×10-3) European populations. Overall, 16 of 24 loci showed evidence for validation across multiple populations. Previous studies have reported associations between variants in the HNF1A gene and lipids, C-reactive protein, and risk of coronary artery disease and stroke. Suggestive associations with variants in the SFXN4 and TMEM108 genes represent potential novel ischemic stroke loci. Conclusions: These findings represent the most thorough investigation of genetic determinants of stroke in individuals of African descent, to date.

Original languageEnglish
Pages (from-to)2454-2463
Number of pages10
Issue number8
StatePublished - Aug 1 2020

Bibliographical note

Funding Information:
schia), respectively. Both studies received additional support, in part, from the Intramural Research Program of the National Institute of Aging (Z01 AG000954-06; PI Singleton), and used samples and clinical data from the NIH-NINDS Human Genetics Resource Center DNA and Cell Line Repository (http://ccr.cori-ell. org/ninds), human subjects protocol numbers 2003–081 and 2004–147. WHI (Women’s Health Initiative): supported by the NHLBI, NIH, and the US Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. The funders had no role in study design, data collection and analysis, decision to publish, or manuscript preparation. Dr Hyacinth is supported by NIH/NHLBI grants U01HL117721, R01HL138423, and R56HL136210. HANDLS (Healthy Aging in Neighborhoods of Diversity Across the Life Span): supported by the Intramural Research Program of the NIH, National Institute of Aging (project no. Z01-AG000513 and human subjects protocol no. 09AGN248).

Funding Information:
SLESS (South London Ethnicity and Stroke Study). Recruitment to SLESS was supported by a program grant from the Stroke Association. This study represents independent research part-funded by the National Institute for Health Research Biomedical Research Centre at South London and Maudsley National Health Service (NHS) Foundation Trust and King’s College London, and the National Institute for Health Research Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. Hugh Markus is supported by a National Institute for Health Research (NIHR) Senior Investigator Award, and his work is supported by NIHR Comprehensive Biomedical Research Unit funding awarded to Cambridge University Hospitals Trust. ISGS (Ischemic Stroke Genetics Study) and SWISS (Siblings with Ischemic Stroke Study): ISGS and SWISS were supported by the National Institute of Neurological Disorders and Stroke grants (R01 NS42733; Dr Meschia) and (R01NS39987; Dr Me-

Funding Information:
NINDS-SiGN Groups 4: The SiGN study was funded by a cooperative agreement grant from the NINDS U01 NS069208. Genotyping services were provided by the Johns Hopkins University CIDR, which is fully funded through a federal contract from the NIH to the Johns Hopkins University (contract No.HHSN268200782096C). The Biostatistics Department Genetics Coordinating Center at the University of Washington (Seattle) provided more extensive quality control of the genotype data through a subcontract with CIDR. Additional support to the Administrative Core of SiGN was provided by the Dean’s Office, University of Maryland School of Medicine.

Funding Information:
Dr Nall’s participation is supported by a consulting contract between Data Tecnica International and the National Institute on Aging, National Institutes of Health (NIH). Dr Nall consults for the Michael J. Fox Foundation, Vivid Genomics, Lysosomal Therapies, Inc, Illumina, Inc, and SK Therapeutics. Dr Furie is a Deputy Editor for Stroke journal. Dr Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Dr Cruchaga receives research support from Biogen, EISAI, Alector, and Parabon. Dr Cruchaga is a member of the advisory board of Vivid genetics, Halia Therapeutics, and ADx Healthcare. Dr Worrall serves as Deputy Editor for the journal Neurology. H.S. Markus has received personal fees from BIBA. Dr Gottesman is a former Associate Editor for the journal Neurology. Dr Lee consults for Regenera. The other authors report no conflicts.

Publisher Copyright:
© 2020 The Authors.


  • brain ischemia
  • coronary artery disease
  • genome-wide association study
  • meta-analysis
  • phenotype
  • risk factors

ASJC Scopus subject areas

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialized Nursing


Dive into the research topics of 'Genome-Wide Association Study Meta-Analysis of Stroke in 22 000 Individuals of African Descent Identifies Novel Associations with Stroke'. Together they form a unique fingerprint.

Cite this