Integrating the environmental and genetic architectures of mortality and aging

In this study, we aimed to quantify the relative roles of the genome and exposome in aging and mortality. We conducted an exposome-wide analysis in the UK Biobank (n=492,567) using independent discovery and replication sets to systematically identify exposures that are associated with mortality (median 12.5 follow-up years), 25 age-related diseases, 25 aging biomarkers, and 3 cardiometabolic risk factors. We identified 41 independent exposures that were associated with mortality, most of which were associated with consistent biological and multimorbidity signatures. Compared with a simple model composed of age and sex, polygenic risk scores for 22 major causes of death and aging phenotypes explained an additional 2% of mortality variation, whereas the exposome explained an additional 19% of variation. While genetics explained a high proportion of variation in dementias, breast, ovarian, and colorectal cancers, the exposome explained a high proportion of variation for diseases of the lung, heart, and liver. Our findings provide a comprehensive map of the relative contributions of environment and genetics to mortality and common age-related diseases, and suggest that environment-focused interventions are likely to have the highest impact on ameliorating premature mortality. One Sentence Summary The exposome is a major mortality determinant irrespective of genetic disease risk via shaping distinct biological and multimorbidity patterns. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement A.N-H. receives research funding from Novo Nordisk, GSK, and Ono Pharma. A.D. is supported by the Wellcome Trust [223100/Z/21/Z], Novo Nordisk, Swiss Re, the British Heart Foundation Centre of Research Excellence (grant number RE/18/3/34214), and Health Data Research UK, an initiative funded by UK Research and Innovation, Department of Health and Social Care (England) and the devolved administrations, and leading medical research charities. C.M.vD. is supported by the common mechanisms and pathways in Stroke and Alzheimer's disease (CoSTREAM) project ([www.costream.eu][1], grant agreement No. 667375) and ZonMW Memorabel program (project number 733050814). The computational aspects of this research were supported by the Wellcome Trust Core Award Grant Number 203141/Z/16/Z and the NIHR Oxford BRC. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: UK Biobank data use (Project Application Number 61054) was approved by the UK Biobank according to their established access procedures. UK Biobank has approval from the North West Multi-centre Research Ethics Committee (MREC) as a Research Tissue Bank (RTB), and as such researchers using UK Biobank data do not require separate ethical clearance and can operate under the RTB approval. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes UK Biobank data are available through a procedure described at . [1]: https://www.costream.eu