Update on the Genetics of Stroke and Cerebrovascular Disease 2008

Abstract

2008 has brought us the first fruits from genomewide association studies (GWASs), an unbiased and comprehensive approach to identify common risk alleles for complex diseases of adulthood. By genotyping >310 000 single nucleotide polymorphisms (SNPs) in over 1700 intracranial aneurysm (IA) cases and 7400 controls from Finland and the Netherlands, a multinational team of investigators recently identified several common SNPs that showed significant association with IA.1 SNPs on chromosomes 2q, 8q and 9p were found to replicate in an independent sample from Japan with similar odds ratios (OR) in all 3 samples. Pooled OR were between 1.24 and 1.36, and analyses of the combined effects suggested a significant linear relationship with risk score in each cohort, with a more than 3-fold increase from the lowest to highest strata. Collectively, the 3 loci were calculated to account for 38% to 46% of the population–attributable fraction of IA, which is substantial. Although additional work in other ethnic groups is required, the consistency emphasizes the robustness of the findings. The critical genetic intervals on chromosomes 8q and 9p both harbor genes that are implicated in the regulation of stem (progenitor) cell populations and expressed in the adult vasculature. SOX17 , the main candidate gene on 8q, is required for both endothelial formation and maintenance—an interesting aspect when considering the predominant location of IA at arterial branch points and sites of endothelial shear stress. The association between common variants at 9p and IA had already been reported in another study earlier last year.2 The 9p21.3 region was originally identified as a major risk locus for coronary artery disease and myocardial infarction.3 Subsequent analyses revealed that the same chromosomal region is also implicated in the risk of IA and abdominal aortic aneurysms. The estimated risk for IA conferred by the main risk …