Integrating the environmental and genetic architectures of mortality and aging

Abstract It has long been suggested that environmental exposures (i.e., the exposome) play a dominant role in shaping trajectories of human aging and premature mortality. Here we aimed to quantify the contribution of the exposome and genome to aging and mortality. We conducted an exposome-wide analysis in the UK Biobank (n=492,567) to systematically identify exposures associated with mortality while accounting for exposure correlation and mismeasurement. We found that the exposome is a major mortality determinant irrespective of genetic disease risk via shaping distinct biological and multimorbidity patterns. We identified 41 independent exposures associated with mortality, and demonstrate that most identified exposures are associated with a common signature of age-related multimorbidity, aging biomarkers, and major cardiometabolic risk factors. Compared with age and sex, polygenic risk for 22 major diseases and aging phenotypes explained an additional 2% of mortality variation, whereas the exposome explained an additional 19%. While genetics explained the majority of variation in dementias and breast, prostate, and colorectal cancers, the exposome explained the majority of variation for diseases of the lung, heart, and liver. Our findings provide a comprehensive map of the contributions of environment and genetics to mortality and common age-related diseases.