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

Chauhan, Ganesh (författare)
Centre Hospitalier Universitaire de Bordeaux
Lindgren, Arne (författare)
Lund University,Lunds universitet,Neurologi, Lund,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Klinisk strokeforskning,Forskargrupper vid Lunds universitet,Neurology, Lund,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine,Clinical Stroke Research Group,Lund University Research Groups
Melander, Olle (författare)
Lund University,Lunds universitet,Kardiovaskulär forskning - hypertoni,Forskargrupper vid Lunds universitet,Cardiovascular Research - Hypertension,Lund University Research Groups
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Debette, Stéphanie (författare)
Centre Hospitalier Universitaire de Bordeaux
den Hoed, Marcel, 1980- (författare)
Uppsala universitet,Hematologi och immunologi,Science for Life Laboratory, SciLifeLab,Medicinsk genetik och genomik,Uppsala University,den Hoed
Arnold, Corey R (författare)
Chu, Audrey Y (författare)
Fornage, Myriam (författare)
Bis, Joshua C (författare)
Havulinna, Aki S (författare)
Nik, Ali Moussavi (författare)
Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology
Lehmann, Ordan J (författare)
Launer, Lenore J (författare)
Ikram, M Arfan (författare)
Carlsson, Peter, 1959 (författare)
Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology
Chasman, Daniel I (författare)
Childs, Sarah J (författare)
Longstreth, William T (författare)
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Engelska 13 s.
Ingår i: The Lancet Neurology. - 1474-4465 .- 1474-4422. ; 15:7, s. 695-707
  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
  • 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. © 2016 Elsevier Ltd


MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Neurologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Neurology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medical Genetics (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Kardiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)


transcription factor
transcription factor FOXF2
unclassified drug
forkhead transcription factor
FOXF2 protein, human
brain hemorrhage
brain ischemia
brain pericyte
cardioembolic stroke
cerebrovascular accident
cerebrovascular disease
computer model
enhancer region
follow up
gene deletion
gene frequency
gene linkage disequilibrium
gene locus
gene replication
genetic association
genetic identification
genetic risk
genetic variability
genome-wide association study
nuclear magnetic resonance imaging
priority journal
risk assessment
single nucleotide polymorphism
stroke patient
white matter
zebra fish
meta analysis
middle aged
preschool child
very elderly
young adult
Aged, 80 and over
Cerebral Small Vessel Diseases
Child, Preschool
Forkhead Transcription Factors
Genetic Loci
Genome-Wide Association Study
Middle Aged
Young Adult

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