Senescence has long been a public health challenge as well as a fascinating evolutionary problem. There is neither a universally accepted theory for its ultimate causes, nor a consensus about what may be its impact on human health. Here we test the predictions of two evolutionary explanations of senescence—mutation accumulation and antagonistic pleiotropy—which postulate that genetic variants with harmful effects in old ages can be tolerated, or even favoured, by natural selection at early ages. Using data from genome-wide association studies (GWAS), we study the effects of genetic variants associated with diseases appearing at different periods in life, when they are expected to have different impacts on fitness. Data fit theoretical expectations. Namely, we observe higher risk allele frequencies combined with large effect sizes for late-onset diseases, and detect a significant excess of early–late antagonistically pleiotropic variants that, strikingly, tend to be harboured by genes related to ageing. Beyond providing systematic, genome-wide evidence for evolutionary theories of senescence in our species and contributing to the long-standing question of whether senescence is the result of adaptation, our approach reveals relationships between previously unrelated pathologies, potentially contributing to tackling the problem of an ageing population.
This work was supported by Ministerio de Ciencia e Innovación, Spain (SAF2011-29239 to E.B., and BFU2012-38236 and BFU2015-68649-P to A.N.), by Direcció General de Recerca, Generalitat de Catalunya (2014SGR1311 and 2014SGR866), by the Spanish National Institute of Bioinfomatics of the Instituto de Salud Carlos III (PT13/0001/0026) and by FEDER (Fondo Europeo de Desarrollo Regional)/FSE (Fondo Social Europeo). U.M.M. is supported by Project 3 of NIGMS P01 GM099568 (B. Weir, University of Washington). E.B. is the recipient of an ICREA Academia Award. The authors thank J. Bertranpetit, P. Muñoz-Cánoves, R. Nesse and B. Charlesworth for helpful comments and advice. We also thank H. Laayouni, F. Casals and F. Calafell for comments on the manuscript, and the Navarro Lab members, especially D. Hartasánchez and M. Brasó, for discussion and comments.
Estimated age of onset for the diseases used in the present study.
List of the associations SNP-disease retrieved from the GWAS Catalog and used for the present study.
List of the 266 pleiotropies found in the present study. These include both, the ones involving the same SNP in two diseases and these involving pairs of SNPs with r2 ≥ 0.8.
Chi square 2×2 tables for number of pleiotropies inside each defined category, considering early–late thresholds from 10 to 60.
Antagonistic early–late pleiotropies (r2 ≥ 0.8.) (n = 26) for an age threshold of 46 years as transition early–late.
Pleiotropy and comorbidity overlap.
Excess of pleiotropy in different gene sets at different levels, compared to genome-wide.
Genes in the Sousa-Victor et al. ageing gene set28.
Disease–SNP associations reported after crossing ageing genes from Sousa-Victor et al.28 with the GWAS Catalog used in present study.
Pleiotropies found in the Sousa-Victor et al. ageing gene set28.
Genes in the Magalhães et al. ageing gene set29.
Disease–SNP associations reported after crossing genes from Magalhães et al.29 with the GWAS Catalog used in present study.
Pleiotropies found in the Magalhães et al. ageing gene set29.
Genes in the Harries et al. age expression changing gene set30.
Disease–SNP associations reported after crossing ageing genes from Harries et al.30 with the GWAS Catalog used in the present study.
Pleiotropies found in the Harries et al. age expression changing gene set30.
Number of SNPs, diseases and average risk allelic frequency for early and late at each age threshold (10 to 60 years) from Fig. 1a.
Number of SNPs, diseases and average genetic variance for early and late at each age threshold (10 to 60 years) from Fig. 1b.