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; 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 ). 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.