Laboratory of AI and Biomedical Science (LABS), Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, USA.
Department of Statistics and Data Science, University of Pennsylvania, Philadelphia, PA, USA.
Nat Commun. 2024 Mar 23;15(1):2604. doi: 10.1038/s41467-024-46796-6.
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). 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 https://labs.loni.usc.edu/medicine .
人类大脑衰老的复杂生物学机制仍不完全清楚。本研究调查了三个脑龄差距（BAG）的遗传结构，这些差距来自于灰质体积（GM-BAG）、白质微观结构（WM-BAG）和功能连接（FC-BAG）。我们确定了 16 个达到全基因组意义的基因组位点（P 值 < 5×10）。一个基因-药物-疾病网络突出了与 GM-BAG 相关的基因，用于治疗神经退行性和神经精神疾病，以及与 WM-BAG 相关的基因，用于癌症治疗。GM-BAG 在保守区域内的遗传变异中表现出最显著的遗传富集。少突胶质细胞和星形胶质细胞，而不是神经元，在 WM 和 FC-BAG 中分别表现出明显的遗传富集。孟德尔随机化确定了几种慢性疾病对大脑衰老的潜在因果影响，如 2 型糖尿病对 GM-BAG 的影响和 AD 对 WM-BAG 的影响。我们的研究结果为人类大脑衰老的遗传学提供了深入了解，对潜在的生活方式和治疗干预具有临床意义。所有结果都可在 https://labs.loni.usc.edu/medicine 上公开获取。
