Advances in Stroke Advances in Stroke 2009

2009 will be remembered as the year that genome-wide association studies (GWAS) revealed both their promise and limitations as an approach to understand the genetic architecture of stroke. The promise of GWAS lies in their extraordinary power to detect novel biologic loci that, if replicated, can serve as markers for novel genes, proteins, and ultimately mechanisms of disease. In this regard, since our previously yearly review,1 new GWAS from 2009 suggested that loci on chromosomes 4q25 (PITX2 gene, encoding a -catenin–regulated transcription factor associated with atrial fibrillation),2 16q22 (ZFHX3 gene, encoding a homeodomain zinc-finger protein that has also been associated with atrial fibrillation),3 and 12p13 (NINJ2 gene, encoding a protein that is upregulated by nerve injury)4 could be added to the list of stroke-associated loci identified from earlier studies. The mechanistic basis for the associations with genetic markers across the spectrum of stroke-associated loci can now be explored. However, the limitations of stroke GWAS have also become apparent. These include the fact that so far, no locus has been replicated in 2 independent study samples. Indeed, targeted experiments in independent samples that have studied positive hits from earlier stroke GWAS have generally not replicated the initial positive findings.5 This could indicate that the “ischemic stroke” phenotype is very heterogeneous between study sample populations and as such needs to be narrowed or made more specific. Perhaps future experiments might more fruitfully evaluate specific subphenotypes or account for genetic determinants of risk factors for stroke, such as lipids6,7 or blood pressure.8,9 Stroke GWAS can also be performed with presymptomatic phenotypes. For instance, several new loci were associated with carotid intima-media thickness (IMT) as measured by ultrasound.10 It might also be informative to evaluate the genetic basis of stroke and its related phenotypes in different ethnic groups. Importantly, the effect sizes identified in the positive GWAS of stroke were modest, a general feature of GWAS that has raised concerns that the results may not have clinical relevance.11 Finding other loci will require even larger sample sizes to detect even smaller effect sizes, and these in turn might be even less likely to have clinical relevance. However, there is general consensus that at least some of the loci identified in GWAS will be shown to have revealed a new aspect of previously unappreciated stroke biology.12 GWAS of stroke and related traits will thus continue to populate the literature for the foreseeable future.