Rizwan Kalani, MD

Foroud T, Lai D, Koller D, van’t Hof F, Kurki MI, Anderson CS, et al. Genome-Wide Association Study of Intracranial Aneurysm Identifies a New Association on Chromosome 7. Stroke. 2014

Aneurysmal subarachnoid hemorrhage (SAH) carries up to 45% 30-day mortality. Research aimed towards improving those outcomes is critically needed. Prior studies have raised the possibility of a genetic contribution to this condition and genome-wide association studies (GWAS) have identified distinct susceptibility loci for intracranial aneurysms.

In this study, Foroud et al seeked to identify additional loci associated with intracranial aneurysms (IA). This was systematically done in two main steps:

1. A large cohort of European ancestry with 2617 Caucasian patients with IA and 2548 Caucasian controls was evaluated. After genotyping, standard quality review methods were applied prior to analysis. The genotyped single nucleotide polymorphisms (SNPs) were then tested for association with IA susceptibility.
2. Two independent cohorts of patients with IA’s (ruptured and unruptured) were separately evaluated for a SNP found from above (1) to determine whether results could be replicated. One was a 786 Dutch patient group with 3110 controls; the other a Finnish cohort of 851 patients with 3217 controls. Finally, a meta-analysis was done in the identified SNP region with all patients included.
When evaluating the initial large cohort, a novel SNP was identified on chromosome 7, located in an intergenic region of the TWISTNB, MIR3146, and TMEM196 genes (p<1×10-7). SNPs near this one have been previously associated with ischemic stroke and large vessel disease (LVD) subtype. Additional SNPs associated with IAs were found in CDKN2BAS on chromosome 9 (p<1×10-11, OR 1.34) as well as on chromosomes 4 and 8 (demonstrated in prior reports).
            
When the novel SNP on chromosome 7 was analyzed in the two pre-identified, independent patient cohorts, the Dutch sample population replicated the initial findings (p=0.01), whereas the other group did not. The meta-analysis of results with inclusion of all cohorts did re-demonstrate significant association (p<1×10-9) between this SNP and IA.
This study addressed some of the key issues that can limit GWAS interpretation – a large patient sample was used, standard quality control metrics employed, and the novel finding was replicated in an independent cohort. The fact that the same region on chromosome 7 was previously associated with ischemic stroke and LVD phenotypes supports the biological plausibility of the new result (given shared epidemiologic risk factors with IA). A corollary of this is that genetics and pathophysiology of IA and LVD-associated stroke may be shared. Furthermore, SNP’s consistently identified from the chromosome 9 region associated with IA have also been linked to LVD, myocardial infarction, and aortic aneurysm.
           
After confirmation of these findings in other large European ancestry populations, the next step will be evaluation of how individual genotypes (and combinations thereof) interact with traditional risk factors and environment (diet/lifestyle) to lead to stroke syndromes and other
vascular pathologies. Implications of such work may allow us to improve targeted prevention efforts for different individuals as well develop novel therapeutics that have a rational basis on the functions of implicated genetic regions.