The Genetic Architecture of Biological Age in Nine Human Organ Systems

Abstract

AbstractUnderstanding 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, including 143 novel loci, associated with the BAG of the brain, eye, cardiovascular, hepatic, immune, metabolic, musculoskeletal, pulmonary, and renal systems. We also observed BAG-organ specificity and inter-organ crosstalk. 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 Conjecture1– 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.loni.usc.edu/medicine.One-sentence summariesAcross nine human organ systems, the genetic architectures of the biological age gap (BAG) revealed BAG-organ specificity and inter-organ crosstalk, highlighting the interconnections among multiple organ systems, chronic diseases, body weight, and lifestyle factors.