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 Traylor; Cathryn 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

doi:10.1161/STROKEAHA.120.029123

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

Neurology

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	2454-2463
Number of pages	10
Journal	Stroke
Volume	51
Issue number	8
DOIs	https://doi.org/10.1161/STROKEAHA.120.029123
State	Published - Aug 1 2020

Keywords

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

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10.1161/STROKEAHA.120.029123

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Keene, K. L., Hyacinth, H. I., Bis, J. C., Kittner, S. J., Mitchell, B. D., Cheng, Y. C., Pare, G., Chong, M., O'Donnell, M., Meschia, J. F., Chen, W. M., Sale, M. M., Rich, S. S., Nalls, M. A., Zonderman, A. B., Evans, M. K., Wilson, J. G., Correa, A., Markus, H. S., ... Fornage, M. (2020). Genome-Wide Association Study Meta-Analysis of Stroke in 22 000 Individuals of African Descent Identifies Novel Associations with Stroke. Stroke, 51(8), 2454-2463. https://doi.org/10.1161/STROKEAHA.120.029123

Keene, KL, Hyacinth, HI, Bis, JC, Kittner, SJ, Mitchell, BD, Cheng, YC, Pare, G, Chong, M, O'Donnell, M, Meschia, JF, Chen, WM, Sale, MM, Rich, SS, Nalls, MA, Zonderman, AB, Evans, MK, Wilson, JG, Correa, A, Markus, HS, Traylor, M, Lewis, CM, Carty, CL, Reiner, A, Haessler, J, Langefeld, CD, Gottesman, R, Mosley, TH, Woo, D, Yaffe, K, Liu, YM, Longstreth, WT, Psaty, BM, Kooperberg, C, Lange, LA, Sacco, R, Rundek, T, Lee, JM, Cruchaga, C, Furie, KL, Arnett, DK, Benavente, OR, Grewal, RP, Peddareddygari, LR, Dichgans, M, Malik, R, Worrall, BB & Fornage, M 2020, 'Genome-Wide Association Study Meta-Analysis of Stroke in 22 000 Individuals of African Descent Identifies Novel Associations with Stroke', Stroke, vol. 51, no. 8, pp. 2454-2463. https://doi.org/10.1161/STROKEAHA.120.029123

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

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",

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

note = "Publisher Copyright: {\textcopyright} 2020 The Authors.",

year = "2020",

month = aug,

day = "1",

doi = "10.1161/STROKEAHA.120.029123",

language = "English (US)",

volume = "51",

pages = "2454--2463",

journal = "Stroke",

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TY - JOUR

T1 - Genome-Wide Association Study Meta-Analysis of Stroke in 22 000 Individuals of African Descent Identifies Novel Associations with Stroke

AU - Keene, Keith L.

AU - Hyacinth, Hyacinth I.

AU - Bis, Joshua C.

AU - Kittner, Steven J.

AU - Mitchell, Braxton D.

AU - Cheng, Yu Ching

AU - Pare, Guillaume

AU - Chong, Michael

AU - O'Donnell, Martin

AU - Meschia, James F.

AU - Chen, Wei Min

AU - Sale, Michèle M.

AU - Rich, Stephen S.

AU - Nalls, Mike A.

AU - Zonderman, Alan B.

AU - Evans, Michele K.

AU - Wilson, James G.

AU - Correa, Adolfo

AU - Markus, Hugh S.

AU - Traylor, Matthew

AU - Lewis, Cathryn M.

AU - Carty, Cara L.

AU - Reiner, Alexander

AU - Haessler, Jeff

AU - Langefeld, Carl D.

AU - Gottesman, Rebecca

AU - Mosley, Thomas H.

AU - Woo, Daniel

AU - Yaffe, Kristine

AU - Liu, Yong Mei

AU - Longstreth, William T.

AU - Psaty, Bruce M.

AU - Kooperberg, Charles

AU - Lange, Leslie A.

AU - Sacco, Ralph

AU - Rundek, Tatjana

AU - Lee, Jin Moo

AU - Cruchaga, Carlos

AU - Furie, Karen L.

AU - Arnett, Donna K.

AU - Benavente, Oscar R.

AU - Grewal, Raji P.

AU - Peddareddygari, Leema Reddy

AU - Dichgans, Martin

AU - Malik, Rainer

AU - Worrall, Bradford B.

AU - Fornage, Myriam

PY - 2020/8/1

Y1 - 2020/8/1

N2 - 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.

AB - 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.

KW - brain ischemia

KW - coronary artery disease

KW - genome-wide association study

KW - meta-analysis

KW - phenotype

KW - risk factors

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

Abstract

Keywords

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