Journal
GENETIC EPIDEMIOLOGY
Volume 37, Issue 5, Pages 495-503Publisher
WILEY
DOI: 10.1002/gepi.21729
Keywords
genome-wide association study; heterogeneity; ischaemic stroke; age at onset
Funding
- Wellcome Trust, as part of the Wellcome Trust Case Control Consortium 2 project [085475/B/08/Z, 085475/Z/08/Z, WT084724MA]
- Medical Research Council
- Stroke Association
- Dunhill Medical Trust
- National Institute of Health Research (NIHR)
- NIHR Biomedical Research Centre, Oxford
- Wellcome Trust
- Binks Trust
- Scottish Funding Council
- Chief Scientist Office
- National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London
- Maudsley NHS Foundation Trust
- King's College London
- Medical Research Council [G9817803B] Funding Source: researchfish
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Genome-wide association studies (GWAS) have been successful in identifying common variants related to complex disorders. However, some disorders have proved resistant to this strategy with few associations confirmed, despite evidence from twin and family studies of a genetic component. Sophisticated strategies that account for phenotypic heterogeneity may be required to uncover these genetic contributions. Age at onset is an example of a potential source of this heterogeneity in ischaemic stroke. We explore the contribution of age at onset in the Wellcome Trust Case-Control Consortium 2 ischaemic stroke study. We first examine four established stroke loci in younger onset cases. We extend this to all single-nucleotide polymorphisms (SNPs) genome-wide, testing for stronger association signals in younger subsets of cases. Finally, we estimate the pseudoheritability accounted for by common SNPs present on genome-wide genotyping arrays for cases stratified by age at onset. We find evidence for stronger associations in younger onset cases for the four established stroke loci. Genome-wide, in cardioembolic and small vessel stroke subphenotypes, a significant number of SNPs show stronger association P-values when the oldest cases are removed. Finally, we show that the pseudoheritability estimated by common SNPs in cardioembolic stroke increased from 16.5% for older onset cases to 28.5% for younger onset cases. Our results indicate that age at onset is a valuable measure for case ascertainment and in analysis of GWAS in ischaemic stroke: focussing on younger cases who may have a stronger genetic predisposition increases power to detect associations.
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