title: Genomic risk profiling of ischemic stroke: results of an international genome-wide association meta-analysis.
abstract: BACKGROUND
  Familial aggregation of ischemic stroke derives from shared genetic and environmental factors. We present a meta-analysis of genome-wide association scans (GWAS) from 3 cohorts to identify the contribution of common variants to ischemic stroke risk.
  
  
  METHODS
  This study involved 1464 ischemic stroke cases and 1932 controls. Cases were genotyped using the Illumina 610 or 660 genotyping arrays; controls, with Illumina HumanHap 550Kv1 or 550Kv3 genotyping arrays. Imputation was performed with the 1000 Genomes European ancestry haplotypes (August 2010 release) as a reference. A total of 5,156,597 single-nucleotide polymorphisms (SNPs) were incorporated into the fixed effects meta-analysis. All SNPs associated with ischemic stroke (P<1×10(-5)) were incorporated into a multivariate risk profile model.
  
  
  RESULTS
  No SNP reached genome-wide significance for ischemic stroke (P<5×10(-8)). Secondary analysis identified a significant cumulative effect for age at onset of stroke (first versus fifth quintile of cumulative profiles based on SNPs associated with late onset, ß = 14.77 [10.85,18.68], P = 5.5×10(-12)), as well as a strong effect showing increased risk across samples with a high propensity for stroke among samples with enriched counts of suggestive risk alleles (P<5×10(-6)). Risk profile scores based only on genomic information offered little incremental prediction.
  
  
  CONCLUSIONS
  There is little evidence of a common genetic variant contributing to moderate risk of ischemic stroke. Quintiles based on genetic loading of alleles associated with a younger age at onset of ischemic stroke revealed a significant difference in age at onset between those in the upper and lower quintiles. Using common variants from GWAS and imputation, genomic profiling remains inferior to family history of stroke for defining risk. Inclusion of genomic (rare variant) information may be required to improve clinical risk profiling.
authors.affiliation: Department of Neurology, Mayo Clinic, Jacksonville, Florida, United States of America. meschia.james@mayo.edu
authors.forename: James F
authors.initials: JF
authors.lastname: Meschia
authors.forename: Andrew
authors.initials: A
authors.lastname: Singleton
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nalls
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.forename: Pankaj
authors.initials: P
authors.lastname: Sharma
authors.forename: Luigi
authors.initials: L
authors.lastname: Ferrucci
authors.forename: Mar
authors.initials: M
authors.lastname: Matarin
authors.forename: Dena G
authors.initials: DG
authors.lastname: Hernandez
authors.forename: Kerra
authors.initials: K
authors.lastname: Pearce
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Brott
authors.forename: Robert D
authors.initials: RD
authors.lastname: Brown
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Bradford B
authors.initials: BB
authors.lastname: Worrall
mesh_terms: D017668:Age of Onset; D000368:Aged; D002545:Brain Ischemia / Q000150:complications*; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D023281:Genomics; D006801:Humans; D038622:Internationality; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D020521:Stroke / Q000150:complications* / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*