Abstract
Introduction:
Larger brain arterial diameters, which may be a consequence of connective tissue disorders or hypertension, are associated with mortality, cognitive decline and risk of dementia. Whether there may be genetic determinants of large brain arterial diameters is unknown, but identifying such traits may shed light into possible mechanistic links between large brain arterial diameters and the observed outcomes.
Methods:
We studied 3654 participants from four ethnically diverse population-based cohorts: The Atherosclerosis Risk in Communities study (n=1565: 74.3% white, 25.7% black), The Northern Manhattan Study (n=1092: 13.8% white, 16.6% black, 69.6% Hispanic), Epidemiology of Dementia in Singapore (n=647: 31.7% Chinese, 35.7% Malay, 32.6% Indian), and Memory Clinic Cohort in Singapore (n=350: 84.9% Chinese, 7.8% Malay, 7.3% Indian). We measured brain arterial diameters for 13 segments and normalized the averaged diameter per participant to obtain global brain arterial diameter as dependent variable. Genome-wide association studies (GWAS) was performed in each study using linear regression, adjusted for sex, age, head size, number of missing arteries and population substructure. Meta-analysis of association statistics was performed using the METAL to generate combined trait-specific effect estimates. We also performed trans-ethnic meta-regression by MR-MEGA to account for the heterogeneity in allelic effect that is correlated with ancestry.
Results:
Genome-wide significant (P<5x10
-8
) associations were observed for global brain arterial diameter with three SNPs: rs7921574(P=1.2x10
-8
) mapping to an intron of CNNM2; rs2075858(P=2.47x10
-8
) and rs2075857 (P=2.37x10
-8
) mapping to introns of MUC5B. MR-MEGA analysis showed suggestive evidence of association (P=5.05x10
-8
) for rs7921574. These loci comprise genes involved in response to magnesium transport, neuronal transmission, hypertension, mucociliary clearance and host defense.
Conclusion:
Our study reveals two novel risk loci for large brain arterial diameters. We have begun to replicate these associations and to identify functional causal variants in independent studies. Identifying these loci may help us to elucidate underlying disease mechanisms.