Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies

The Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) study, The METASTROKE consortium, The Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, the Stroke Genetics Network (SiGN), and the International Stroke Genetics Consortium (ISGC)

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Background Genetic determinants of stroke, the leading neurological cause of death and disability, are poorly understood and have seldom been explored in the general population. Our aim was to identify additional loci for stroke by doing a meta-analysis of genome-wide association studies. Methods For the discovery sample, we did a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts comprising 84 961 participants, of whom 4348 had stroke. Stroke diagnosis was ascertained and validated by the study investigators. Mean age at stroke ranged from 45·8 years to 76·4 years, and data collection in the studies took place between 1948 and 2013. We did validation analyses for variants yielding a significant association (at p<5 × 10−6) with all-stroke, ischaemic stroke, cardioembolic ischaemic stroke, or non-cardioembolic ischaemic stroke in the largest available cross-sectional studies (70 804 participants, of whom 19 816 had stroke). Summary-level results of discovery and follow-up stages were combined using inverse-variance weighted fixed-effects meta-analysis, and in-silico lookups were done in stroke subtypes. For genome-wide significant findings (at p<5 × 10−8), we explored associations with additional cerebrovascular phenotypes and did functional experiments using conditional (inducible) deletion of the probable causal gene in mice. We also studied the expression of orthologs of this probable causal gene and its effects on cerebral vasculature in zebrafish mutants. Findings We replicated seven of eight known loci associated with risk for ischaemic stroke, and identified a novel locus at chromosome 6p25 (rs12204590, near FOXF2) associated with risk of all-stroke (odds ratio [OR] 1·08, 95% CI 1·05–1·12, p=1·48 × 10−8; minor allele frequency 21%). The rs12204590 stroke risk allele was also associated with increased MRI-defined burden of white matter hyperintensity—a marker of cerebral small vessel disease—in stroke-free adults (n=21 079; p=0·0025). Consistently, young patients (aged 2–32 years) with segmental deletions of FOXF2 showed an extensive burden of white matter hyperintensity. Deletion of Foxf2 in adult mice resulted in cerebral infarction, reactive gliosis, and microhaemorrhage. The orthologs of FOXF2 in zebrafish (foxf2b and foxf2a) are expressed in brain pericytes and mutant foxf2b−/− cerebral vessels show decreased smooth muscle cell and pericyte coverage. Interpretation We identified common variants near FOXF2 that are associated with increased stroke susceptibility. Epidemiological and experimental data suggest that FOXF2 mediates this association, potentially via differentiation defects of cerebral vascular mural cells. Further expression studies in appropriate human tissues, and further functional experiments with long follow-up periods are needed to fully understand the underlying mechanisms. Funding NIH, NINDS, NHMRC, CIHR, European national research institutions, Fondation Leducq.

Original languageEnglish (US)
Pages (from-to)695-707
Number of pages13
JournalThe Lancet Neurology
Volume15
Issue number7
DOIs
StatePublished - Jun 1 2016

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Genome-Wide Association Study
Meta-Analysis
Stroke
Pericytes
Zebrafish
National Institute of Neurological Disorders and Stroke
Genome
Gliosis
Cerebral Infarction
Gene Frequency

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

The Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) study, The METASTROKE consortium, & The Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, the Stroke Genetics Network (SiGN), and the International Stroke Genetics Consortium (ISGC) (2016). Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies. The Lancet Neurology, 15(7), 695-707. https://doi.org/10.1016/S1474-4422(16)00102-2

Identification of additional risk loci for stroke and small vessel disease : a meta-analysis of genome-wide association studies. / The Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) study; The METASTROKE consortium; The Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, the Stroke Genetics Network (SiGN), and the International Stroke Genetics Consortium (ISGC).

In: The Lancet Neurology, Vol. 15, No. 7, 01.06.2016, p. 695-707.

Research output: Contribution to journalArticle

The Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) study, The METASTROKE consortium & The Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, the Stroke Genetics Network (SiGN), and the International Stroke Genetics Consortium (ISGC) 2016, 'Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies', The Lancet Neurology, vol. 15, no. 7, pp. 695-707. https://doi.org/10.1016/S1474-4422(16)00102-2
The Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) study, The METASTROKE consortium, The Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, the Stroke Genetics Network (SiGN), and the International Stroke Genetics Consortium (ISGC). Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies. The Lancet Neurology. 2016 Jun 1;15(7):695-707. https://doi.org/10.1016/S1474-4422(16)00102-2
The Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) study ; The METASTROKE consortium ; The Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, the Stroke Genetics Network (SiGN), and the International Stroke Genetics Consortium (ISGC). / Identification of additional risk loci for stroke and small vessel disease : a meta-analysis of genome-wide association studies. In: The Lancet Neurology. 2016 ; Vol. 15, No. 7. pp. 695-707.
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abstract = "Background Genetic determinants of stroke, the leading neurological cause of death and disability, are poorly understood and have seldom been explored in the general population. Our aim was to identify additional loci for stroke by doing a meta-analysis of genome-wide association studies. Methods For the discovery sample, we did a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts comprising 84{\^a}€ˆ961 participants, of whom 4348 had stroke. Stroke diagnosis was ascertained and validated by the study investigators. Mean age at stroke ranged from 45{\^A}·8 years to 76{\^A}·4 years, and data collection in the studies took place between 1948 and 2013. We did validation analyses for variants yielding a significant association (at p<5{\^a}€ˆ{\~A}—{\^a}€ˆ10{\^a}ˆ’6) with all-stroke, ischaemic stroke, cardioembolic ischaemic stroke, or non-cardioembolic ischaemic stroke in the largest available cross-sectional studies (70{\^a}€ˆ804 participants, of whom 19{\^a}€ˆ816 had stroke). Summary-level results of discovery and follow-up stages were combined using inverse-variance weighted fixed-effects meta-analysis, and in-silico lookups were done in stroke subtypes. For genome-wide significant findings (at p<5{\^a}€ˆ{\~A}—{\^a}€ˆ10{\^a}ˆ’8), we explored associations with additional cerebrovascular phenotypes and did functional experiments using conditional (inducible) deletion of the probable causal gene in mice. We also studied the expression of orthologs of this probable causal gene and its effects on cerebral vasculature in zebrafish mutants. Findings We replicated seven of eight known loci associated with risk for ischaemic stroke, and identified a novel locus at chromosome 6p25 (rs12204590, near FOXF2) associated with risk of all-stroke (odds ratio [OR] 1{\^A}·08, 95{\%} CI 1{\^A}·05{\^a}€“1{\^A}·12, p=1{\^A}·48{\^a}€ˆ{\~A}—{\^a}€ˆ10{\^a}ˆ’8; minor allele frequency 21{\%}). The rs12204590 stroke risk allele was also associated with increased MRI-defined burden of white matter hyperintensity{\^a}€”a marker of cerebral small vessel disease{\^a}€”in stroke-free adults (n=21{\^a}€ˆ079; p=0{\^A}·0025). Consistently, young patients (aged 2{\^a}€“32 years) with segmental deletions of FOXF2 showed an extensive burden of white matter hyperintensity. Deletion of Foxf2 in adult mice resulted in cerebral infarction, reactive gliosis, and microhaemorrhage. The orthologs of FOXF2 in zebrafish (foxf2b and foxf2a) are expressed in brain pericytes and mutant foxf2b{\^a}ˆ’/{\^a}ˆ’ cerebral vessels show decreased smooth muscle cell and pericyte coverage. Interpretation We identified common variants near FOXF2 that are associated with increased stroke susceptibility. Epidemiological and experimental data suggest that FOXF2 mediates this association, potentially via differentiation defects of cerebral vascular mural cells. Further expression studies in appropriate human tissues, and further functional experiments with long follow-up periods are needed to fully understand the underlying mechanisms. Funding NIH, NINDS, NHMRC, CIHR, European national research institutions, Fondation Leducq.",
author = "{The Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) study} and {The METASTROKE consortium} and {The Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, the Stroke Genetics Network (SiGN), and the International Stroke Genetics Consortium (ISGC)} and Ganesh Chauhan and Arnold, {Corey R.} and Chu, {Audrey Y.} and Myriam Fornage and Azadeh Reyahi and Bis, {Joshua C.} and Havulinna, {Aki S.} and Muralidharan Sargurupremraj and Smith, {Albert Vernon} and Adams, {Hieab H.H.} and Choi, {Seung Hoan} and Pulit, {Sara L.} and Stella Trompet and Garcia, {Melissa E.} and Ani Manichaikul and Alexander Teumer and Stefan Gustafsson and Bartz, {Traci M.} and C{\'e}line Bellenguez and Vidal, {Jean Sebastien} and Xueqiu Jian and Olafur Kjartansson and Wiggins, {Kerri L.} and Satizabal, {Claudia L.} and Flora Xue and Samuli Ripatti and Yongmei Liu and Joris Deelen and {Den Hoed}, Marcel and Steve Bevan and Hopewell, {Jemma C.} and Rainer Malik and Heckbert, {Susan R.} and Kenneth Rice and Smith, {Nicholas L.} and Christopher Levi and Pankaj Sharma and Sudlow, {Cathie L.M.} and Nik, {Ali Moussavi} and Cole, {John W.} and Reinhold Schmidt and James Meschia and Vincent Thijs and Arne Lindgren and Olle Melander and Grewal, {Raji P.} and Sacco, {Ralph L} and Tatjana Rundek and Rothwell, {Peter M.} and Arnett, {Donna K.}",
year = "2016",
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doi = "10.1016/S1474-4422(16)00102-2",
language = "English (US)",
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pages = "695--707",
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TY - JOUR

T1 - Identification of additional risk loci for stroke and small vessel disease

T2 - a meta-analysis of genome-wide association studies

AU - The Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) study

AU - The METASTROKE consortium

AU - The Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, the Stroke Genetics Network (SiGN), and the International Stroke Genetics Consortium (ISGC)

AU - Chauhan, Ganesh

AU - Arnold, Corey R.

AU - Chu, Audrey Y.

AU - Fornage, Myriam

AU - Reyahi, Azadeh

AU - Bis, Joshua C.

AU - Havulinna, Aki S.

AU - Sargurupremraj, Muralidharan

AU - Smith, Albert Vernon

AU - Adams, Hieab H.H.

AU - Choi, Seung Hoan

AU - Pulit, Sara L.

AU - Trompet, Stella

AU - Garcia, Melissa E.

AU - Manichaikul, Ani

AU - Teumer, Alexander

AU - Gustafsson, Stefan

AU - Bartz, Traci M.

AU - Bellenguez, Céline

AU - Vidal, Jean Sebastien

AU - Jian, Xueqiu

AU - Kjartansson, Olafur

AU - Wiggins, Kerri L.

AU - Satizabal, Claudia L.

AU - Xue, Flora

AU - Ripatti, Samuli

AU - Liu, Yongmei

AU - Deelen, Joris

AU - Den Hoed, Marcel

AU - Bevan, Steve

AU - Hopewell, Jemma C.

AU - Malik, Rainer

AU - Heckbert, Susan R.

AU - Rice, Kenneth

AU - Smith, Nicholas L.

AU - Levi, Christopher

AU - Sharma, Pankaj

AU - Sudlow, Cathie L.M.

AU - Nik, Ali Moussavi

AU - Cole, John W.

AU - Schmidt, Reinhold

AU - Meschia, James

AU - Thijs, Vincent

AU - Lindgren, Arne

AU - Melander, Olle

AU - Grewal, Raji P.

AU - Sacco, Ralph L

AU - Rundek, Tatjana

AU - Rothwell, Peter M.

AU - Arnett, Donna K.

PY - 2016/6/1

Y1 - 2016/6/1

N2 - Background Genetic determinants of stroke, the leading neurological cause of death and disability, are poorly understood and have seldom been explored in the general population. Our aim was to identify additional loci for stroke by doing a meta-analysis of genome-wide association studies. Methods For the discovery sample, we did a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts comprising 84 961 participants, of whom 4348 had stroke. Stroke diagnosis was ascertained and validated by the study investigators. Mean age at stroke ranged from 45·8 years to 76·4 years, and data collection in the studies took place between 1948 and 2013. We did validation analyses for variants yielding a significant association (at p<5 × 10−6) with all-stroke, ischaemic stroke, cardioembolic ischaemic stroke, or non-cardioembolic ischaemic stroke in the largest available cross-sectional studies (70 804 participants, of whom 19 816 had stroke). Summary-level results of discovery and follow-up stages were combined using inverse-variance weighted fixed-effects meta-analysis, and in-silico lookups were done in stroke subtypes. For genome-wide significant findings (at p<5 × 10−8), we explored associations with additional cerebrovascular phenotypes and did functional experiments using conditional (inducible) deletion of the probable causal gene in mice. We also studied the expression of orthologs of this probable causal gene and its effects on cerebral vasculature in zebrafish mutants. Findings We replicated seven of eight known loci associated with risk for ischaemic stroke, and identified a novel locus at chromosome 6p25 (rs12204590, near FOXF2) associated with risk of all-stroke (odds ratio [OR] 1·08, 95% CI 1·05–1·12, p=1·48 × 10−8; minor allele frequency 21%). The rs12204590 stroke risk allele was also associated with increased MRI-defined burden of white matter hyperintensity—a marker of cerebral small vessel disease—in stroke-free adults (n=21 079; p=0·0025). Consistently, young patients (aged 2–32 years) with segmental deletions of FOXF2 showed an extensive burden of white matter hyperintensity. Deletion of Foxf2 in adult mice resulted in cerebral infarction, reactive gliosis, and microhaemorrhage. The orthologs of FOXF2 in zebrafish (foxf2b and foxf2a) are expressed in brain pericytes and mutant foxf2b−/− cerebral vessels show decreased smooth muscle cell and pericyte coverage. Interpretation We identified common variants near FOXF2 that are associated with increased stroke susceptibility. Epidemiological and experimental data suggest that FOXF2 mediates this association, potentially via differentiation defects of cerebral vascular mural cells. Further expression studies in appropriate human tissues, and further functional experiments with long follow-up periods are needed to fully understand the underlying mechanisms. Funding NIH, NINDS, NHMRC, CIHR, European national research institutions, Fondation Leducq.

AB - Background Genetic determinants of stroke, the leading neurological cause of death and disability, are poorly understood and have seldom been explored in the general population. Our aim was to identify additional loci for stroke by doing a meta-analysis of genome-wide association studies. Methods For the discovery sample, we did a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts comprising 84 961 participants, of whom 4348 had stroke. Stroke diagnosis was ascertained and validated by the study investigators. Mean age at stroke ranged from 45·8 years to 76·4 years, and data collection in the studies took place between 1948 and 2013. We did validation analyses for variants yielding a significant association (at p<5 × 10−6) with all-stroke, ischaemic stroke, cardioembolic ischaemic stroke, or non-cardioembolic ischaemic stroke in the largest available cross-sectional studies (70 804 participants, of whom 19 816 had stroke). Summary-level results of discovery and follow-up stages were combined using inverse-variance weighted fixed-effects meta-analysis, and in-silico lookups were done in stroke subtypes. For genome-wide significant findings (at p<5 × 10−8), we explored associations with additional cerebrovascular phenotypes and did functional experiments using conditional (inducible) deletion of the probable causal gene in mice. We also studied the expression of orthologs of this probable causal gene and its effects on cerebral vasculature in zebrafish mutants. Findings We replicated seven of eight known loci associated with risk for ischaemic stroke, and identified a novel locus at chromosome 6p25 (rs12204590, near FOXF2) associated with risk of all-stroke (odds ratio [OR] 1·08, 95% CI 1·05–1·12, p=1·48 × 10−8; minor allele frequency 21%). The rs12204590 stroke risk allele was also associated with increased MRI-defined burden of white matter hyperintensity—a marker of cerebral small vessel disease—in stroke-free adults (n=21 079; p=0·0025). Consistently, young patients (aged 2–32 years) with segmental deletions of FOXF2 showed an extensive burden of white matter hyperintensity. Deletion of Foxf2 in adult mice resulted in cerebral infarction, reactive gliosis, and microhaemorrhage. The orthologs of FOXF2 in zebrafish (foxf2b and foxf2a) are expressed in brain pericytes and mutant foxf2b−/− cerebral vessels show decreased smooth muscle cell and pericyte coverage. Interpretation We identified common variants near FOXF2 that are associated with increased stroke susceptibility. Epidemiological and experimental data suggest that FOXF2 mediates this association, potentially via differentiation defects of cerebral vascular mural cells. Further expression studies in appropriate human tissues, and further functional experiments with long follow-up periods are needed to fully understand the underlying mechanisms. Funding NIH, NINDS, NHMRC, CIHR, European national research institutions, Fondation Leducq.

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