Genetic Influences on Brain Aging: Analyzing Sex Differences in the UK Biobank using Structural MRI

TL;DR

This study investigates genetic factors influencing brain aging differences between sexes using structural MRI and GWAS in a large UK Biobank cohort, revealing sex-specific genetic associations and pathways involved in neurodegeneration.

Contribution

It is the first large-scale study to identify sex-specific genetic variants associated with brain aging, emphasizing the need for sex-stratified analyses in neurogenetics.

Findings

Distinct sex-specific gene sets linked to brain aging

Shared genes like GMNC and OSTN associated with brain volumes

Sex-specific pathways related to neurodegeneration identified

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.