The Genetic Heterogeneity of Multimodal Human Brain Age.

The complex biological mechanisms underlying human brain aging remain incompletely understood, involving multiple body organs and chronic diseases. In this study, we used multimodal magnetic resonance imaging and artificial intelligence to examine the genetic heterogeneity of the brain age gap (BAG) derived from gray matter volume (GM-BAG), white matter microstructure (WM-BAG), and functional connectivity (FC-BAG). We identified sixteen significant genomic loci, with GM-BAG loci showing abundant associations with neurodegenerative and neuropsychiatric traits, WM-BAG loci implicated in cancer and Alzheimer's disease (AD), and FC-BAG in insomnia. A gene-drug-disease network highlighted genes linked to GM-BAG for treating neurodegenerative and neuropsychiatric disorders and WM-BAG genes for cancer therapy. GM-BAG showed the highest heritability enrichment for genetic variants in conserved regions, whereas WM-BAG exhibited the highest heritability enrichment in the 5' untranslated regions; oligodendrocytes and astrocytes, but not neurons, showed significant heritability enrichment in WM and FC-BAG, respectively. Notably, Mendelian randomization identified causal risk effects of triglyceride-to-lipid ratio in very low-density lipoprotein and type 2 diabetes on GM-BAG and AD on WM-BAG. Overall, our results provide valuable insights into the genetic heterogeneity of human brain aging, with clinical implications for potential lifestyle and therapeutic interventions.