Genetic Influences on Brain Aging: Analyzing Sex Differences in the UK Biobank using Structural MRI
Journal:
arXiv
Published Date:
May 25, 2025
Abstract
Brain aging trajectories differ between males and females, yet the genetic
factors underlying these differences remain underexplored. Using structural MRI
and genotyping data from 40,940 UK Biobank participants (aged 45-83), we
computed Brain Age Gap Estimates (BrainAGE) for total brain, hippocampal, and
ventricular volumes. We conducted sex-stratified genome-wide association
studies (GWAS) and Post-GWAS analyses to identify genetic variants associated
with accelerated brain aging. Distinct gene sets emerged by sex: in females,
neurotransmitter transport and mitochondrial stress response genes were
implicated; in males, immune and inflammation-related genes dominated. Shared
genes, including GMNC and OSTN, were consistently linked to brain volumes
across sexes, suggesting core roles in neurostructural maintenance. Tissue
expression analyses revealed sex-specific enrichment in pathways tied to
neurodegeneration. These findings highlight the importance of sex-stratified
approaches in aging research and suggest genetic targets for personalized
interventions against age-related cognitive decline.
