Meta-Analysis

. 2020 Aug;51(8):2454-2463.

doi: 10.1161/STROKEAHA.120.029123. Epub 2020 Jul 22.

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

Keith L Keene^#¹, Hyacinth I Hyacinth^#², Joshua C Bis³, Steven J Kittner⁴, Braxton D Mitchell⁴, Yu-Ching Cheng⁴, Guillaume Pare⁵, Michael Chong⁵, Martin O'Donnell⁶, James F Meschia⁷, Wei-Min Chen⁸, Michèle M Sale⁸, Stephen S Rich⁸, Mike A Nalls^{9

10}, Alan B Zonderman¹¹, Michele K Evans¹¹, James G Wilson¹², Adolfo Correa¹², Hugh S Markus¹³, Matthew Traylor¹⁴, Cathryn M Lewis¹⁵, Cara L Carty¹⁶, Alexander Reiner¹⁷, Jeff Haessler¹⁷, Carl D Langefeld¹⁸, Rebecca Gottesman¹⁹, Thomas H Mosley¹², Daniel Woo²⁰, Kristine Yaffe²¹, YongMei Liu¹⁸, William T Longstreth³, Bruce M Psaty^{22

23}, Charles Kooperberg¹⁷, Leslie A Lange²⁴, Ralph Sacco²⁵, Tatjana Rundek²⁵, Jin-Moo Lee²⁶, Carlos Cruchaga²⁶, Karen L Furie²⁷, Donna K Arnett²⁸, Oscar R Benavente²⁹, Raji P Grewal³⁰, Leema Reddy Peddareddygari³⁰, Martin Dichgans^{31

32}, Rainer Malik³¹, Bradford B Worrall³³, Myriam Fornage³⁴; COMPASS, SiGN, and METASTROKE Consortia

Affiliations

¹ Department of Biology; Brody School of Medicine Center for Health Disparities, East Carolina University, Greenville, NC (K.L.K.).
² Aflac Cancer and Blood Disorder Center of Emory University and Children's Healthcare of Atlanta University, GA (H.I.H.).
³ University of Washington, Seattle, WA (J.C.B., W.T.L.).
⁴ Baltimore Veterans Administration Medical Center and University of Maryland School of Medicine, Baltimore, MD (S.J.K., B.D.M., Y.-C.C.).
⁵ McMaster University and Population Health Research Institute, Hamilton Ontario (G.P., M.C.).
⁶ National University of Ireland Galway, Ireland (M.O.).
⁷ Mayo Clinic Florida, Jacksonville (J.F.M.).
⁸ Center for Public Health Genomics, University of Virginia, Charlottesville (W.-M.C., M.M.S., S.S.R.).
⁹ Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD (M.A.N.).
¹⁰ Data Tecnica International, Glen Echo, MD (M.A.N.).
¹¹ Laboratory of Epidemiology and Population Science, National Institute on Aging, Baltimore, MD (A.B.Z., M.K.E.).
¹² University of Mississippi Medical Center, Jackson (J.G.W., A.C., T.H.M.).
¹³ University of Cambridge, England, United Kingdom (H.S.M.).
¹⁴ William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (M.T.).
¹⁵ Social, Genetic and Developmental Psychiatry Centre, King's College London, United Kingdom (C.M.L.).
¹⁶ Initiative for Research and Education to Advance Community Health, Washington State University, Seattle (C.L.C.).
¹⁷ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (A.R., J.H., C.K.).
¹⁸ Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC (C.D.L., C.L.).
¹⁹ Johns Hopkins University School of Medicine, Baltimore, MD (R.G.).
²⁰ Department of Neurology, University of Cincinnati, OH (D.W.).
²¹ University of California, San Francisco (K.Y.).
²² Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle (B.M.P.).
²³ Kaiser Permanente Washington Health Research Institute, Seattle, WA (B.M.P.).
²⁴ University of Colorado Anschutz Medical Campus, Denver (L.A.L.).
²⁵ University of Miami, Miller School of Medicine, FL (R.S., T.R.).
²⁶ Washington University School of Medicine, St. Louis, MO (J.-M.L., C.C.).
²⁷ Brown University Warren Alpert Medical School, Providence, RI (K.L.F.).
²⁸ University of Kentucky, College of Public Health, Lexington (D.K.A.).
²⁹ University of British Columbia, Vancouver, (O.R.B.).
³⁰ Neuroscience Institute, Saint Francis Medical Center, Trenton, NJ (R.P.G., L.R.P.).
³¹ Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Germany (M.D., R.M.).
³² Munich Cluster for Systems Neurology (SyNergy), Germany (M.D.).
³³ Department of Neurology, University of Virginia, Charlottesville (B.B.W.).
³⁴ Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston (M.F.).

^# Contributed equally.

PMID: 32693751
PMCID: PMC7387190
DOI: 10.1161/STROKEAHA.120.029123

Meta-Analysis

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

Keith L Keene et al. Stroke. 2020 Aug.

. 2020 Aug;51(8):2454-2463.

doi: 10.1161/STROKEAHA.120.029123. Epub 2020 Jul 22.

Authors

Affiliations

¹ Department of Biology; Brody School of Medicine Center for Health Disparities, East Carolina University, Greenville, NC (K.L.K.).
² Aflac Cancer and Blood Disorder Center of Emory University and Children's Healthcare of Atlanta University, GA (H.I.H.).
³ University of Washington, Seattle, WA (J.C.B., W.T.L.).
⁴ Baltimore Veterans Administration Medical Center and University of Maryland School of Medicine, Baltimore, MD (S.J.K., B.D.M., Y.-C.C.).
⁵ McMaster University and Population Health Research Institute, Hamilton Ontario (G.P., M.C.).
⁶ National University of Ireland Galway, Ireland (M.O.).
⁷ Mayo Clinic Florida, Jacksonville (J.F.M.).
⁸ Center for Public Health Genomics, University of Virginia, Charlottesville (W.-M.C., M.M.S., S.S.R.).
⁹ Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD (M.A.N.).
¹⁰ Data Tecnica International, Glen Echo, MD (M.A.N.).
¹¹ Laboratory of Epidemiology and Population Science, National Institute on Aging, Baltimore, MD (A.B.Z., M.K.E.).
¹² University of Mississippi Medical Center, Jackson (J.G.W., A.C., T.H.M.).
¹³ University of Cambridge, England, United Kingdom (H.S.M.).
¹⁴ William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (M.T.).
¹⁵ Social, Genetic and Developmental Psychiatry Centre, King's College London, United Kingdom (C.M.L.).
¹⁶ Initiative for Research and Education to Advance Community Health, Washington State University, Seattle (C.L.C.).
¹⁷ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (A.R., J.H., C.K.).
¹⁸ Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC (C.D.L., C.L.).
¹⁹ Johns Hopkins University School of Medicine, Baltimore, MD (R.G.).
²⁰ Department of Neurology, University of Cincinnati, OH (D.W.).
²¹ University of California, San Francisco (K.Y.).
²² Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle (B.M.P.).
²³ Kaiser Permanente Washington Health Research Institute, Seattle, WA (B.M.P.).
²⁴ University of Colorado Anschutz Medical Campus, Denver (L.A.L.).
²⁵ University of Miami, Miller School of Medicine, FL (R.S., T.R.).
²⁶ Washington University School of Medicine, St. Louis, MO (J.-M.L., C.C.).
²⁷ Brown University Warren Alpert Medical School, Providence, RI (K.L.F.).
²⁸ University of Kentucky, College of Public Health, Lexington (D.K.A.).
²⁹ University of British Columbia, Vancouver, (O.R.B.).
³⁰ Neuroscience Institute, Saint Francis Medical Center, Trenton, NJ (R.P.G., L.R.P.).
³¹ Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Germany (M.D., R.M.).
³² Munich Cluster for Systems Neurology (SyNergy), Germany (M.D.).
³³ Department of Neurology, University of Virginia, Charlottesville (B.B.W.).
³⁴ Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston (M.F.).

^# Contributed equally.

PMID: 32693751
PMCID: PMC7387190
DOI: 10.1161/STROKEAHA.120.029123

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.

Keywords: brain ischemia; coronary artery disease; genome-wide association study; meta-analysis; phenotype; risk factors.

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Figures

**Figure 1.**
LocusZoom plots, with linkage disequilibrium based on hg19/1000 Genomes Nov 2014 AFR, depicting the top (P= 10⁻⁸) three associations with ischemic stroke in COMPASS individuals of African descent. **A.)** *HNF1A* (rs55931441) chromosome 12 locus; **B.)** *TMEM108* (rs113509723) chromosome 3 locus; **C.)** Chromosome 2 (rs142655108) locus nearest *NPM1P48*.

See this image and copyright information in PMC

Comment in

Advances in the genetics of stroke risk and recovery.
Majumder SN, Hrastelj J, Robertson NP. Majumder SN, et al. J Neurol. 2023 Jan;270(1):590-591. doi: 10.1007/s00415-022-11525-w. Epub 2022 Dec 22. J Neurol. 2023. PMID: 36547717 Free PMC article. No abstract available.

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

Affiliations

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

Authors

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Abstract

Figures

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LinkOut - more resources

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Medical

Research Materials