title: Genetic heritability of ischemic stroke and the contribution of previously reported candidate gene and genomewide associations.
abstract: OBJECTIVE
  The contribution of genetics to stroke risk, and whether this differs for different stroke subtypes, remainsuncertain. Genomewide complex trait analysis allows heritability to be assessed from genomewide association study (GWAS) data. Previous candidate gene studies have identified many associations with stoke but whether these are important requires replication in large independent data sets. GWAS data sets provide a powerful resource to perform replication studies.
  
  
  METHODS
  We applied genomewide complex trait analysis to a GWAS data set of 3752 ischemic strokes and 5972 controls and determined heritability for all ischemic stroke and the most common subtypes: large-vessel disease, small-vessel disease, and cardioembolic stroke. By systematic review we identified previous candidate gene and GWAS associations with stroke and previous GWAS associations with related cardiovascular phenotypes (myocardial infarction, atrial fibrillation, and carotid intima-media thickness). Fifty associations were identified.
  
  
  RESULTS
  For all ischemic stroke, heritability was 37.9%. Heritability varied markedly by stroke subtype being 40.3% for large-vessel disease and 32.6% for cardioembolic but lower for small-vessel disease (16.1%). No previously reported candidate gene was significant after rigorous correction for multiple testing. In contrast, 3 loci from related cardiovascular GWAS studies were significant: PHACTR1 in large-vessel disease (P=2.63e(-6)), PITX2 in cardioembolic stroke (P=4.78e(-8)), and ZFHX3 in cardioembolic stroke (P=5.50e(-7)).
  
  
  CONCLUSIONS
  There is substantial heritability for ischemic stroke, but this varies for different stroke subtypes. Previous candidate gene associations contribute little to this heritability, but GWAS studies in related cardiovascular phenotypes are identifying robust associations. The heritability data, and data from GWAS, suggest detecting additional associations will depend on careful stroke subtyping.
authors.affiliation: Stroke and Dementia Research Group, St Georges, University of London, Cranmer Terrace, Tooting, London, SW17 0RE, UK. sbevan@sgul.ac.uk
authors.forename: Steve
authors.initials: S
authors.lastname: Bevan
authors.forename: Matthew
authors.initials: M
authors.lastname: Traylor
authors.forename: Poneh
authors.initials: P
authors.lastname: Adib-Samii
authors.forename: Rainer
authors.initials: R
authors.lastname: Malik
authors.forename: Nicola L M
authors.initials: NL
authors.lastname: Paul
authors.forename: Caroline
authors.initials: C
authors.lastname: Jackson
authors.forename: Martin
authors.initials: M
authors.lastname: Farrall
authors.forename: Peter M
authors.initials: PM
authors.lastname: Rothwell
authors.forename: Cathie
authors.initials: C
authors.lastname: Sudlow
authors.forename: Martin
authors.initials: M
authors.lastname: Dichgans
authors.forename: Hugh S
authors.initials: HS
authors.lastname: Markus
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001281:Atrial Fibrillation / Q000453:epidemiology; D002545:Brain Ischemia / Q000453:epidemiology / Q000235:genetics*; D059168:Carotid Intima-Media Thickness / Q000706:statistics & numerical data; D016208:Databases, Factual / Q000706:statistics & numerical data; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D055106:Genome-Wide Association Study / Q000706:statistics & numerical data*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D008875:Middle Aged; D009203:Myocardial Infarction / Q000453:epidemiology; D010641:Phenotype; D012307:Risk Factors; D020521:Stroke / Q000453:epidemiology / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D044465:White People / Q000235:genetics / Q000706:statistics & numerical data; D000097577:Homeobox Protein PITX2
chemical_list: D018398:Homeodomain Proteins; D008840:Microfilament Proteins; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C570134:PHACTR1 protein, human; C071660:ZFHX3 protein, human