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GWAS Points to Possible Differences in Genetic Architecture Between Stroke Subtypes

NEW YORK (GenomeWeb) – A genome-wide association study in Nature Genetics online yesterday has uncovered a new genetic variant contributing to a form of stroke known as large vessel ischemic stroke, highlighting the genetic diversity that seems to exist from one stroke subtype to the next.

Members of the International Stroke Genetics Consortium and the Wellcome Trust Case Control Consortium 2 did a GWAS involving thousands of individuals of European descent with or without a history of stroke. Consistent with past studies, the team found loci linked to a stroke subtype known as cardioembolic stroke near genes called PITX2 and ZFHX3 and a chromosome 9 site associated with the large vessel stroke subtype.

But the search also led them to a site in the genome not implicated in stroke previously: a large vessel stroke-associated variant in the histone deacetylase 9 coding gene HDAC9 on chromosome 7.

"All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype," University of Oxford researchers Peter Donnelly and Hugh Markus, co-directors of the new study, and colleagues wrote. "This suggests distinct genetic architectures for different stroke subtypes."

Stroke is not a single condition but a collection of related cardiovascular diseases, the team explained. For instance, within the group of ischemic stroke, which involve blocked arteries in the brain, there are at least three main sub-types, classified as large vessel stroke, small vessel stroke, and cardioembolic stroke.

Together, ischemic stroke represents roughly 80 percent of stroke cases, they added, with risk for certain sub-types appearing more heritable than others.

To look for new stroke risk factors and their relationship to specific stroke sub-types, researchers used Illumina arrays to genotype 3,548 individuals from the UK and Germany who had experienced one of the ischemic stroke subtypes. They compared their genetic patterns with those found in samples from 5,972 unaffected controls from the same populations.

After narrowing in on the most suspicious sites in the genome in this discovery group, the team attempted to verify 45 candidate loci — including seven loci implicated previously in stroke and 38 suspicious new sites — through a two-stage replication study involving another 5,859 stroke-affected individuals and 6,281 controls from Europe and the US.

The search led to four loci: two known cardioembolic stroke-associated loci near the PITX2 and ZFHX3 genes, a locus on chromosome 9 that was previously found to affect large vessel stroke risk, and a new large vessel stroke risk locus on chromosome 7. The team further verified the association between large vessel stroke and the chromosome 7 SNP, which falls in an intron of HDAC9, by testing another 735 stroke cases and almost 28,600 controls.

In contrast, when investigators looked for associations between the HDAC9 SNP and cardioembolic stroke or small vessel strokes subtypes, they did not see significant ties to these other forms of ischemic stroke. Moreover, their statistical analyses suggested that the lack of shared association amongst the variants detected reflects genetic heterogeneity within the ischemic stroke subtypes.

"[A]ll the known loci exhibit genetic heterogeneity across the stroke subtypes, with at least some and possibly all affecting only a single subtype," researchers wrote. "This supports the possibility that distinct subtypes of the disease have differing genetic architecture."

"This genetic heterogeneity seems likely to reflect heterogeneity in the underlying pathogenic mechanisms," they concluded, "and reinforces the need for the consideration of stroke subtypes separately in research and clinical contexts."

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