Loci associated with ischaemic stroke and its subtypes (SiGN): A genome-wide association study
2016
Summary Background The discovery of disease-associated loci through genome-wide association studies (GWAS) is the leading genetic approach to the identification of novel
biological pathwaysunderlying diseases in humans. Until recently, GWAS in ischaemic
strokehave been limited by small sample sizes and have yielded few loci associated with ischaemic
stroke. We did a large-scale GWAS to identify additional susceptibility genes for
strokeand its subtypes. Methods To identify genetic loci associated with ischaemic
stroke, we did a two-stage GWAS. In the first stage, we included 16 851 cases with state-of-the-art phenotyping data and 32 473
stroke-free controls. Cases were aged 16 to 104 years, recruited between 1989 and 2012, and subtypes of ischaemic
strokewere recorded by centrally trained and certified investigators who used the web-based protocol, Causative Classification of
Stroke(CCS). We constructed case-control strata by identifying samples that were genotyped on nearly identical arrays and were of similar genetic ancestral background. We cleaned and imputed data by use of dense imputation reference panels generated from whole-genome sequence data. We did genome-wide testing to identify
stroke-associated loci within each stratum for each available phenotype, and we combined summary-level results using
inverse variance-weightedfixed-effects meta-analysis. In the second stage, we did in-silico lookups of 1372 single nucleotide polymorphisms identified from the first stage GWAS in 20 941 cases and 364 736 unique
stroke-free controls. The ischaemic
strokesubtypes of these cases had previously been established with the Trial of Org 10 172 in Acute
StrokeTreatment (TOAST) classification system, in accordance with local standards. Results from the two stages were then jointly analysed in a final meta-analysis. Findings We identified a novel locus (G allele at rs12122341) at 1p13.2 near
TSPAN2that was associated with large artery atherosclerosis-related
stroke(first stage odds ratio [OR] 1·21, 95% CI 1·13–1·30, p=4·50 × 10 −8 ; joint OR 1·19, 1·12–1·26, p=1·30 × 10 −9 ). Our results also supported robust associations with ischaemic
strokefor four other loci that have been reported in previous studies, including
PITX2(first stage OR 1·39, 1·29–1·49, p=3·26 × 10 −19 ; joint OR 1·37, 1·30–1·45, p=2·79 × 10 −32 ) and ZFHX3 (first stage OR 1·19, 1·11–1·27, p=2·93 × 10 −7 ; joint OR 1·17, 1·11–1·23, p=2·29 × 10 −10 ) for cardioembolic
stroke, and
HDAC9(first stage OR 1·29, 1·18–1·42, p=3·50 × 10 −8 ; joint OR 1·24, 1·15–1·33, p=4·52 × 10 −9 ) for large artery atherosclerosis
stroke. The 12q24 locus near
ALDH2, which has previously been associated with all ischaemic
strokebut not with any specific subtype, exceeded genome-wide significance in the meta-analysis of small artery
stroke(first stage OR 1·20, 1·12–1·28, p=6·82 × 10 −8 ; joint OR 1·17, 1·11–1·23, p=2·92 × 10 −9 ). Other loci associated with
strokein previous studies, including NINJ2 , were not confirmed. Interpretation Our results suggest that all ischaemic
stroke-related loci previously implicated by GWAS are subtype specific. We identified a novel gene associated with large artery atherosclerosis
strokesusceptibility. Follow-up studies will be necessary to establish whether the locus near
TSPAN2can be a target for a novel therapeutic approach to
strokeprevention. In view of the subtype-specificity of the associations detected, the rich phenotyping data available in the
StrokeGenetics Network (SiGN) are likely to be crucial for further genetic discoveries related to ischaemic
stroke. Funding US National Institute of Neurological Disorders and
Stroke, National Institutes of Health.
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