Genome-Wide Association Study of Cognitive Function in Population-Based Cohorts in Japan: The Tohoku Medical Megabank...

Heritability of cognitive function is estimated to be 50%-80%. Genome-wide association studies (GWASs) have identified multiple cognitive function-associated loci, primarily in the European population. However, those in Asian populations, particularly in individuals of Japanese ancestry, remain limited. Hence, this GWAS aimed to identify cognitive function-associated genetic loci in elderly individuals of Japanese ancestry. Herein, 2571 elderly participants from the Tohoku Medical Megabank Brain Magnetic Resonance Imaging Study were included. Their cognitive function was assessed using the Japanese version of the Mini-Mental State Examination (MMSE), and both binary and continuous MMSE scores were analysed. Genotyping was performed using the Affymetrix Axiom Japonica Array v2, and imputation was conducted with 3.5KJPNv2 and 1KGP3. Statistical analyses were performed using FastGWA-GLMM and FastGWA for binary and continuous MMSE scores, respectively. Although no genome-wide significant loci were identified using binary MMSE values, the following two were detected using continuous MMSE values: rs77877360 (20p12.1) near BANF2 and SNX5 and rs9460729 (6p22.3) near PRL and HDGFL1. Additionally, functional annotation suggested the involvement of these loci in pathways related to cognitive function, including chromatin structure regulation, neuroinflammation, and iron metabolism. Notably, SNX5, identified through chromatin-interaction mapping, has been implicated in neurodegenerative processes, particularly in Parkinson's disease. The findings of this study provide preliminary genome-wide evidence suggesting a genetic predisposition to impaired cognitive function in elderly Japanese individuals.