Delta age is a biomarker of brain aging that captures differences between the actual age and the predicted age from brain MRI. This study investigates an explainable and causal basis of high delta age by analyzing UK Biobank data in three steps. A visual saliency map of brain regions showed that lower volumes in the fornix and the lower part of the thalamus are key predictors of high delta age. Genetic association analysis on both the single variants and the gene regions identified that genes related to carcinogenesis, immune response, and neuron survival are associated with high delta age. Mendelian randomization (MR) for all metabolomic biomarkers and blood-related phenotypes showed that immune-related phenotypes have a causal impact on increasing delta age. Taken together, these observations revealed regions in the brain that are susceptible to the aging process and provided evidence of the causal and genetic connection between immune responses and brain aging.

Genome-wide association studies (GWAS) on diverse ancestry groups are lacking, resulting in deficits of genetic discoveries and polygenic scores. We conducted GWAS for 76 phenotypes in Korean biobank data, namely Korean Genome and Epidemiology Study (KoGES, n=72,298). Our analysis discovered 2,237 associated loci, including 117 novel associations, many of which replicated in Biobank Japan (BBJ) GWAS. We also applied several up-to-date methods for genetic association tests to increase the power, discovering additional associations that are not identified in simple case-control GWAS. We evaluated genetic pleiotropy to investigate genes associated with multiple traits. Following meta-analysis of 32 phenotypes between KoGES and Biobank Japan (BBJ), we further identified 379 novel associations and demonstrated the improved predictive performance of polygenic risk scores by using the meta-analysis results. The summary statistics of 76 KoGES GWAS phenotypes are publicly available, contributing to a better comprehension of the genetic architecture of the East Asian population.