The genetic architecture of multimodal human brain age

Junhao Wen, Bingxin Zhao, Zhijian Yang, Guray Erus, Ioanna Skampardoni, Elizabeth Mamourian, Yuhan Cui, Gyujoon Hwang, Jingxuan Bao, Aleix Boquet-Pujadas, Zhen Zhou, Yogasudha Veturi, Marylyn D. Ritchie, Haochang Shou, Paul M. Thompson, Li Shen, Arthur W. Toga, Christos Davatzikos

Research output: Contribution to journalArticlepeer-review


The complex biological mechanisms underlying human brain aging remain incompletely understood. This study investigated the genetic architecture of three brain age gaps (BAG) derived from gray matter volume (GM-BAG), white matter microstructure (WM-BAG), and functional connectivity (FC-BAG). We identified sixteen genomic loci that reached genome-wide significance (P-value < 5×10−8). 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 displayed the most pronounced heritability enrichment in genetic variants within conserved regions. Oligodendrocytes and astrocytes, but not neurons, exhibited notable heritability enrichment in WM and FC-BAG, respectively. Mendelian randomization identified potential causal effects of several chronic diseases on brain aging, such as type 2 diabetes on GM-BAG and AD on WM-BAG. Our results provide insights into the genetics of human brain aging, with clinical implications for potential lifestyle and therapeutic interventions. All results are publicly available at

Original languageEnglish (US)
Article number2604
JournalNature communications
Issue number1
StatePublished - Dec 2024

All Science Journal Classification (ASJC) codes

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy

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