RNF213 variation, a broader role in neurovascular disease in Caucasian and Japanese populations

Moyamoya disease (MMD) is a chronic, occlusive cerebrovascular disease that predominantly affects East Asian populations. The major genetic mutation associated with MMD in Asian populations is the p.R4810K substitution in Ring Finger Protein 213 (RNF213). Interestingly, variants in the gene have also been implicated in intracranial aneurysms (IA) in French-Canadian population, suggesting that variation in this gene may play a broader role in cerebrovascular phenotypes. In a recent genome-wide association study (GWAS) in a Caucasian population, variants rs6565653 and rs12601526 in the () gene, which is less than 10kb away from , showed a suggestive association with young onset ischemic stroke. We propose that the signal could be tagging an association with common variation in the gene. We analyzed the linkage disequilibrium (LD) pattern in the gene region and we observed a high LD between variants in this region based on D’ values. We show that rs6565653 variant tags rs12944088, a missense variant that is more common among subjects with IA than in healthy individuals. Given the fact that rs6565653 tags several variants, it is highly likely that some of these tagged variants modify the risk of suffering stroke. The LD analyses suggest that the signal from the young onset ischemic stroke GWAS performed in a Caucasian population is also tagging variation at the loci, supporting the hypothesis that variation may result in a variety of neurovascular disorders including an increased risk and/or worse prognosis following ischemic stroke in Caucasian population.