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

• Type of Material: Article
• Authors: Keith L Keene, East Carolina University; Hyacinth Hyacinth, Emory University; Joshua C Bis, University of Washington; Steven J Kittner, Baltimore Veterans Administration Medical Center; Braxton D Mitchell, Baltimore Veterans Administration Medical Center; Yu-Ching Cheng, Baltimore Veterans Administration Medical Center; Guillaume Pare, McMaster University; Michael Chong, McMaster University; Martin O'Donnell, National University of Ireland Galway; James F Meschia, Mayo Clinic Florida; Wei-Min Chen, University of Virginia; Michele M Sale, University of Virginia; Stephen S Rich, University of Virginia; Mike A Nalls, National Institute on Aging, Bethesda; Alan B Zonderman, National Institute on Aging, Bethesda; Michele K Evans, National Institute on Aging, Bethesda; James G Wilson, University of Mississippi; Adolfo Correa, Emory University; Hugh S Markus, University of Cambridge; Matthew Traylor, Queen Mary University London; Cathryn M Lewis, Kings Coll London; Cara L Carty, Washington State University; Alexander Reiner, Fred Hutchinson Cancer Research Center; Jeff Haessler, Fred Hutchinson Cancer Research Center; Carl D Langefeld, Wake Forest School of Medicine; Rebecca Gottesman, Johns Hopkins University; Thomas H Mosley, University of Mississippi; Daniel Woo, University of Cincinnati; Kristine Yaffe, University of California San Francisco; YongMei Liu, Wake Forest School of Medicine; WT Longstreth, University of Washington; Bruce M Psaty, University of Washington; Charles Kooperberg, Fred Hutchinson Canc Res Ctr; Leslie A Lange, University of Colorado Anschutz Medical Campus; Ralph Sacco, University of Miami; Tatjana Rundek, University of Miami; Jin-Moo Lee, Washington University in St. Louis; Carlos Cruchaga, Washington University in St. Louis; Karen L Furie, Brown University; Donna K Arnett, University of Kentucky; Oscar R Benavente, Univ British Columbia; Raji P Grewal, Saint Francis Medical Center; Leema Reddy Peddareddygari, Saint Francis Medical Center; Martin Dichgans, University Hospital, LMU Munich; Rainer Malik, University Hospital, LMU Munich; Bradford B Worrall, University of Virginia; Myriam Fornage, University of Texas Health Science Center at Houston
• Language: English
• Date: 2020-08-01
• Publisher: LIPPINCOTT WILLIAMS & WILKINS
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2020 The Authors. Stroke is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1161/STROKEAHA.120.029123
• Title of Journal or Parent Work: STROKE
• Volume: 51
• Issue: 8
• Start Page: 2454
• End Page: 2463
• Grant/Funding Information: See publication for funding information related to each individual study.
• Keywords: CANDIDATE GENE; Science & Technology; Clinical Neurology; SUBTYPES; CORONARY-ARTERY-DISEASE; RISK-FACTORS; Peripheral Vascular Disease; brain ischemia; Neurosciences & Neurology; RATIONALE; Life Sciences & Biomedicine; Cardiovascular System & Cardiology; ISCHEMIC-STROKE; SHARED GENETIC SUSCEPTIBILITY; phenotype; DESIGN; ATHEROSCLEROSIS; COMMON VARIANTS; genome-wide association study; risk factors; coronary artery disease; meta-analysis

Abstract

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.