Wen Junhao, Tian Ye Ella, Skampardoni Ioanna, Yang Zhijian, Cui Yuhan, Anagnostakis Filippos, Mamourian Elizabeth, Zhao Bingxin, Toga Arthur W, Zaleskey Andrew, Davatzikos Christos
Laboratory of AI and Biomedical Science (LABS), Keck School of Medicine of USC, University of Southern California, Los Angeles, California, USA.
Melbourne Neuropsychiatry Centre, Department of Psychiatry, Melbourne Medical School, The University of Melbourne, Melbourne, Victoria, Australia.
medRxiv. 2024 Jun 11:2023.06.08.23291168. doi: 10.1101/2023.06.08.23291168.
Understanding the genetic basis of biological aging in multi-organ systems is vital for elucidating age-related disease mechanisms and identifying therapeutic interventions. This study characterized the genetic architecture of the biological age gap (BAG) across nine human organ systems in 377,028 individuals of European ancestry from the UK Biobank. We discovered 393 genomic loci-BAG pairs (P-value<5×10) linked to the brain, eye, cardiovascular, hepatic, immune, metabolic, musculoskeletal, pulmonary, and renal systems. We observed BAG-organ specificity and inter-organ connections. Genetic variants associated with the nine BAGs are predominantly specific to the respective organ system while exerting pleiotropic effects on traits linked to multiple organ systems. A gene-drug-disease network confirmed the involvement of the metabolic BAG-associated genes in drugs targeting various metabolic disorders. Genetic correlation analyses supported Cheverud's Conjecture - the genetic correlation between BAGs mirrors their phenotypic correlation. A causal network revealed potential causal effects linking chronic diseases (e.g., Alzheimer's disease), body weight, and sleep duration to the BAG of multiple organ systems. Our findings shed light on promising therapeutic interventions to enhance human organ health within a complex multi-organ network, including lifestyle modifications and potential drug repositioning strategies for treating chronic diseases. All results are publicly available at https://labs-laboratory.com/medicine.
了解多器官系统中生物衰老的遗传基础对于阐明与年龄相关的疾病机制和确定治疗干预措施至关重要。本研究对英国生物银行中377,028名欧洲血统个体的九个人类器官系统中的生物年龄差距（BAG）的遗传结构进行了表征。我们发现了393个与大脑、眼睛、心血管、肝脏、免疫、代谢、肌肉骨骼、肺部和肾脏系统相关的基因组位点 - BAG对（P值<5×10）。我们观察到了BAG - 器官特异性和器官间的联系。与九个BAG相关的遗传变异主要特定于各自的器官系统，同时对与多个器官系统相关的性状产生多效性影响。一个基因 - 药物 - 疾病网络证实了与代谢BAG相关的基因参与了针对各种代谢紊乱的药物作用。遗传相关性分析支持了切弗鲁德猜想——BAG之间的遗传相关性反映了它们的表型相关性。一个因果网络揭示了将慢性疾病（如阿尔茨海默病）、体重和睡眠时间与多个器官系统的BAG联系起来的潜在因果效应。我们的研究结果揭示了在复杂的多器官网络中增强人体器官健康的有前景的治疗干预措施，包括生活方式的改变以及治疗慢性疾病的潜在药物重新定位策略。所有结果可在https://labs-laboratory.com/medicine上公开获取。
