Multi-population Genome-Wide Association Study Identifies Multiple Novel Loci associated with Asymptomatic Intracranial Large Artery Stenosis.

Background: 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.

Methods And Results: 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 (MRA). A genome-wide association study revealed one variant in (rs75615271; OR, 1.22 [1.11-1.33]; =4.85×10) associated with global ILAS at genome-wide significance (<5×10). Gene-based association analysis identified a gene-set enriched in chr1q32 region, including , , , , and , in global ILAS (=1.34 ×10) and anterior ILAS (=1.77 ×10).

Conclusion: This study reveals one variant rs75615271 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.