Multi-population genome-wide association study identifies multiple novel loci associated with asymptomatic...

Intracranial large artery stenosis (ILAS) is one of the most common causes of stroke worldwide and is associated with the risk for future vascular events. Asymptomatic ILAS is a frequent finding on neuroimaging and shares many risk factors with atherosclerotic vascular disease. Whether asymptomatic ILAS is driven by genetic variants is not well-understood.

This study included 4960 participants from seven geographically diverse population-based cohorts (34% Whites, 16% African Americans, 22% Hispanics, 24% Asians, 5% native Ecuadorians). We defined asymptomatic ILAS as luminal stenosis >50% in any large brain artery using time-of-flight magnetic resonance angiography.

A genome-wide association study revealed one variant in RP11-552D8.1 (rs75615271; odds ratio (OR), 1.22 (1.11-1.33); p = 4.85×10^-8) associated with global ILAS at genome-wide significance (p < 5×10^-8). Gene-based association analysis identified a gene-set enriched in chr1q32 region, including NEK2, LPGAT1, INTS7, DTL, and TMEM206, in global ILAS (p = 1.34 ×10^-7) and anterior ILAS (p = 1.77 ×10^-8).

This study reveals one variant rs75615271 and a gene-set enriched in chr1q32 region associated with asymptomatic ILAS in a multi-population. Further functional studies may help elucidate the role that this variant plays in the pathophysiology of asymptomatic ILAS.