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Identification of a...
Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies
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- Chauhan, Ganesh (författare)
- Centre Hospitalier Universitaire de Bordeaux
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- 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
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- 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
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- den Hoed, Marcel, 1980- (författare)
- Uppsala universitet,Hematologi och immunologi,Science for Life Laboratory, SciLifeLab,Medicinsk genetik och genomik,Uppsala University,den Hoed
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Arnold, Corey R (författare)
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Chu, Audrey Y (författare)
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Fornage, Myriam (författare)
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Bis, Joshua C (författare)
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Havulinna, Aki S (författare)
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- Nik, Ali Moussavi (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology
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Lehmann, Ordan J (författare)
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Launer, Lenore J (författare)
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Ikram, M Arfan (författare)
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- Carlsson, Peter, 1959 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology
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Chasman, Daniel I (författare)
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Childs, Sarah J (författare)
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Longstreth, William T (författare)
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(creator_code:org_t)
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- 2016
- 2016
- Engelska 13 s.
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Ingår i: The Lancet Neurology. - 1474-4465 .- 1474-4422. ; 15:7, s. 695-707
- Relaterad länk:
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http://dx.doi.org/10...
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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https://urn.kb.se/re...
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https://gup.ub.gu.se...
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Abstract
Ämnesord
Stäng
- 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
Ämnesord
- 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)
Nyckelord
- DNA
- transcription factor
- transcription factor FOXF2
- unclassified drug
- forkhead transcription factor
- FOXF2 protein, human
- Article
- 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
- genotype
- human
- neuroimaging
- nonhuman
- nuclear magnetic resonance imaging
- orthology
- phenotype
- priority journal
- risk assessment
- single nucleotide polymorphism
- stroke patient
- white matter
- zebra fish
- adolescent
- adult
- aged
- animal
- child
- female
- genetics
- male
- meta analysis
- middle aged
- mouse
- preschool child
- very elderly
- young adult
- Adolescent
- 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
Publikations- och innehållstyp
- art (ämneskategori)
- ref (ämneskategori)
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Till lärosätets databas
- Av författaren/redakt...
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Chauhan, Ganesh
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Lindgren, Arne
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Melander, Olle
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Debette, Stéphan ...
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den Hoed, Marcel ...
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Arnold, Corey R
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visa fler...
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Chu, Audrey Y
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Fornage, Myriam
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Bis, Joshua C
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Havulinna, Aki S
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Nik, Ali Moussav ...
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Lehmann, Ordan J
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Launer, Lenore J
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Ikram, M Arfan
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Carlsson, Peter, ...
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Chasman, Daniel ...
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Childs, Sarah J
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Longstreth, Will ...
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Neurologi
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Medicinska och f ...
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och Medicinsk geneti ...
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Kardiologi
- Artiklar i publikationen
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The Lancet Neuro ...
- Av lärosätet
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Lunds universitet
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Uppsala universitet
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Göteborgs universitet