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

Introduction: 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: 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. Results: A genome‐wide association study revealed one variant in RP11-552D8.1 (rs75615271; 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). Discussion and Conclusion: 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.