Multi-population Genome-Wide Association Study Identifies Multiple Novel Loci associated with Asymptomatic...

Area of Science:

• Genetics
• Neurology
• Epidemiology

Background:

• Intracranial large artery stenosis (ILAS) is a significant global cause of stroke and a predictor of future vascular events.
• Asymptomatic ILAS is frequently observed in neuroimaging and shares risk factors with broader atherosclerotic vascular disease.
• The genetic underpinnings of asymptomatic ILAS remain largely unexplored.

Purpose of the Study:

• To investigate the association between genetic variants and asymptomatic intracranial large artery stenosis (ILAS).
• To identify specific genetic markers contributing to the risk of developing ILAS.

Main Methods:

• A genome-wide association study (GWAS) was conducted on 4960 participants from seven diverse population-based cohorts.
• Asymptomatic ILAS was defined as >50% stenosis in large brain arteries, assessed via time-of-flight magnetic resonance angiography (MRA).
• Gene-based association analyses were performed to identify enriched gene sets in specific chromosomal regions.

Main Results:

• A genome-wide significant variant, rs75615271 in RP11-552D8.1, was associated with global ILAS (OR, 1.22; P=4.85×10⁻⁸).
• Gene-set analysis identified enrichment in the chr1q32 region, including genes like NEK2 and LPGAT1, associated with global and anterior ILAS.
• The identified variant rs75615271 showed a statistically significant association with asymptomatic ILAS across multiple ethnic groups.

Conclusions:

• This study identifies a novel genetic variant, rs75615271, associated with asymptomatic intracranial large artery stenosis (ILAS) in a multi-population setting.
• The findings suggest a genetic contribution to the pathophysiology of asymptomatic ILAS.
• Further functional studies are warranted to elucidate the precise role of rs75615271 in ILAS development.