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

TitleIdentification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies.
Publication TypeJournal Article
Year of Publication2016
Corporate AuthorsNeurology 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)
JournalLancet Neurol
Date Published2016 06
KeywordsAdolescent, Adult, Aged, Aged, 80 and over, Animals, Cerebral Small Vessel Diseases, Child, Child, Preschool, Female, Forkhead Transcription Factors, Genetic Loci, Genome-Wide Association Study, Humans, Male, Mice, Middle Aged, Stroke, Young Adult

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

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.

Alternate JournalLancet Neurol
PubMed ID27068588
PubMed Central IDPMC4943223
Grant ListR01 NS017950 / NS / NINDS NIH HHS / United States
095626 / WT_ / Wellcome Trust / United Kingdom
UL1 TR000124 / TR / NCATS NIH HHS / United States
MR/K026992/1 / MRC_ / Medical Research Council / United Kingdom
R01 HL105756 / HL / NHLBI NIH HHS / United States
R01 AG033193 / AG / NIA NIH HHS / United States
U01 AG049505 / AG / NIA NIH HHS / United States
R01 AG054076 / AG / NIA NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
R01 AG008122 / AG / NIA NIH HHS / United States
P30 AG010129 / AG / NIA NIH HHS / United States
R01 HL088521 / HL / NHLBI NIH HHS / United States