Genetic liability for cardiovascular disease, physical activity, and mortality – findings from The Finnish Twin Cohort

Background An overall healthy lifestyle may mitigate the risk of all-cause and cardiovascular disease (CVD) mortality despite the inherited risk for CVD. We assessed if similar phenomenon is observed independently with physical activity (PA). Methods In a prospective older Finnish Twin Cohort, genetic liability for coronary heart disease, systolic and diastolic blood pressure was estimated with polygenic risk scores (PRSs) derived from the Pan UK Biobank (N≈400,000) and >1,000,000 genetic variants, and leisure-time PA longitudinally with validated and structured questionnaires three times during 1975–1990 among 4,897 participants aged 33–60-years (54.3% women). Interactions of PRSs and PA with mortality and the independent main effects of different PA metrics with mortality were evaluated with Cox proportional hazards models. A co-twin control design with 180 monozygotic twin pairs discordant for physical activity was used for causal inference. Results During the 17.4-y (mean) follow-up (85,136 person-years), 1,195 participants died with 389 CVD deaths. Although the favorable associations of an overall healthy lifestyle with mortality risk reduction replicated in the cohort, no interactions or significant independent main effects were observed with any of the assessed PA metrics. Adherence to World Health Organizations PA guidelines or vigorous PA during the 15-year observational period did not decrease mortality in more active twins compared to their less active identical twin brother or sister. The findings did not vary with genetic CVD risk. Conclusions No evidence was found that PA mitigates inherited CVD risk or is causally associated with mortality challenging some of our current understanding. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Academy of Finland; Juho Vainio, Paivikki and Sakari Sohlberg, and Sigrid Juselius Foundations to E.S. Phenotype and genotype data collection by the Wellcome Trust Sanger Institute, the Broad Institute, ENGAGE - European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, grant agreement number 201413, and the Academy of Finland (grants 100499, 205585, 118555, 141054, 264146, 308248, 312073, 336823, and 352792 to J.K). Academy of Finland (grants 265240, 263278) and the Sigrid Juselius Foundation to J.K ### 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: The FTC study was evaluated by ethics committees of the University of Helsinki (113/E3/01 and 346/E0/05), Helsinki University Central Hospital (136/E3/01, 01/2011, 270/ 13/03/01/2008, and 154/13/03/00/2011) 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 All data produced in the present study are available upon reasonable request to the authors.