Welter, D. et al. The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res. 42, D1001–D1006 (2014).
Abdellaoui, A., Yengo, L., Verweij, K. J. H. & Visscher, P. M. 15 years of GWAS discovery: realizing the promise. Am. J. Hum. Genet. 110, 179–194 (2023).
Nesse, R. M. & Williams, G. C. Why We Get Sick: The New Science of Darwinian Medicine (Vintage Books, 1996).
Rose, M. R. Antagonistic pleiotropy, dominance, and genetic variation. Heredity 48, 63–78 (1982).
Watanabe, K. et al. A global overview of pleiotropy and genetic architecture in complex traits. Nat. Genet. 51, 1339–1348 (2019).
Benton, M. L. et al. The influence of evolutionary history on human health and disease. Nat. Rev. Genet. 22, 269–283 (2021).
Charlesworth, B. Evolution in Age-Structured Populations (Cambridge Univ. Press, 1994).
Giaimo, S. & Traulsen, A. Generation time measures the trade-off between survival and reproduction in a life cycle. Am. Nat. 194, 285–290 (2019).
Smith, J. M. The Effects of temperature and of egg-laying on the longevity of Drosophila subobscura. J. Exp. Biol. 35, 832–842 (1958).
Rose, M. R. Laboratory evolution of postponed senescence in Drosophila melanogaster. Evolution 38, 1004–1010 (1984).
Sgrò, C. M. & Partridge, L. A delayed wave of death from reproduction in Drosophila. Science 286, 2521–2524 (1999).
Harshman, L. G. & Zera, A. J. The cost of reproduction: the devil in the details. Trends Ecol. Evol. 22, 80–86 (2007).
Kuningas, M. et al. The relationship between fertility and lifespan in humans. Age 33, 615–622 (2011).
Westendorp, R. G. J. & Kirkwood, T. B. L. Human longevity at the cost of reproductive success. Nature 396, 743–746 (1998).
Hsu, C.-H., Posegga, O., Fischbach, K. & Engelhardt, H. Examining the trade-offs between human fertility and longevity over three centuries using crowdsourced genealogy data. PLoS ONE 16, e0255528 (2021).
Long, E. & Zhang, J. Evidence for the role of selection for reproductively advantageous alleles in human aging. Sci. Adv. 9, eadh4990 (2023).
Lycett, J. E., Dunbar, R. I. M. & Voland, E. Longevity and the costs of reproduction in a historical human population. Proc. R. Soc. Lond. B 267, 31–35 (2000).
Medawar, P. B. An Unsolved Problem of Biology: An Inaugural Lecture Delivered at University College, London, 6 December, 1951 (H.K. Lewis and Co., 1952).
Williams, G. Pleiotropy, natural selection, and the evolution of senescence. Evol. NY 11, 398–411 (1957).
Kirkwood, T. B. L. & Austad, S. N. Why do we age? Nature 408, 233–238 (2000).
Charlesworth, B. Patterns of age-specific means and genetic variances of mortality rates predicted by the mutation-accumulation theory of ageing. J. Theor. Biol. 210, 47–65 (2001).
Rodríguez, J. A. et al. Antagonistic pleiotropy and mutation accumulation influence human senescence and disease. Nat. Ecol. Evol. 1, 55 (2017).
Austad, S. N. & Hoffman, J. M. Is antagonistic pleiotropy ubiquitous in aging biology? Evol. Med. Public Health 2018, 287–294 (2018).
Mathieson, I. et al. Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus. Nat. Hum. Behav. 7, 790–801 (2023).
Melzer, D., Pilling, L. C. & Ferrucci, L. The genetics of human ageing. Nat. Rev. Genet. 21, 88–101 (2020).
Joshi, P. K. et al. Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity. Nat. Commun. 8, 910 (2017).
Burgess, S. et al. Dissecting causal pathways using Mendelian randomization with summarized genetic data: application to age at menarche and risk of breast cancer. Genetics 207, 481–487 (2017).
Barban, N. et al. Genome-wide analysis identifies 12 loci influencing human reproductive behavior. Nat. Genet. 48, 1462–1472 (2016).
GTEx Consortium. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science 369, 1318–1330 (2020).
Field, Y. et al. Detection of human adaptation during the past 2000 years. Science 354, 760–764 (2016).
Voight, B. F., Kudaravalli, S., Wen, X. & Pritchard, J. K. A map of recent positive selection in the human genome. PLOS Biol. 4, e72 (2006).
Ferrer-Admetlla, A., Liang, M., Korneliussen, T. & Nielsen, R. On detecting incomplete soft or hard selective sweeps using haplotype structure. Mol. Biol. Evol. 31, 1275–1291 (2014).
Watanabe, K., Taskesen, E., van Bochoven, A. & Posthuma, D. Functional mapping and annotation of genetic associations with FUMA. Nat. Commun. 8, 1826 (2017).
de Leeuw, C. A., Mooij, J. M., Heskes, T. & Posthuma, D. MAGMA: generalized gene-set analysis of GWAS data. PLOS Comput. Biol. 11, e1004219 (2015).
Paskulin, D. D., Cunha-Filho, J. S., Paskulin, L. D., Souza, C. A. B. & Ashton-Prolla, P. ESR1 rs9340799 is associated with endometriosis-related infertility and in vitro fertilization failure. Dis. Markers 35, 796290 (2013).
Ge, Y.-Z. et al. Association of polymorphisms in estrogen receptors (ESR1 and ESR2) with male infertility: a meta-analysis and systematic review. J. Assist. Reprod. Genet. 31, 601–611 (2014).
Benonisdottir, S., Straub, V. J., Kong, A. & Mills, M. C. Genetics of female and male reproductive traits and their relationship with health, longevity and consequences for offspring. Nat. Aging 4, 1745–1759 (2024).
Byars, S. G. et al. Genetic loci associated with coronary artery disease harbor evidence of selection and antagonistic pleiotropy. PLOS Genet. 13, e1006328 (2017).
Stearns, S. C. Trade-offs in life-history evolution. Funct. Ecol. 3, 259–268 (1989).
Gagnon, A. et al. Is there a trade-off between fertility and longevity? A comparative study of women from three large historical databases accounting for mortality selection. Am. J. Hum. Biol. 21, 533–540 (2009).
Crespi, B. J. The origins and evolution of genetic disease risk in modern humans. Ann. N. Y. Acad. Sci. 1206, 80–109 (2010).
Abrams, E. T. & Miller, E. M. The roles of the immune system in women’s reproduction: evolutionary constraints and life history trade-offs. Am. J. Phys. Anthropol. 146, 134–154 (2011).
Aktipis, C. A., Boddy, A. M., Gatenby, R. A., Brown, J. S. & Maley, C. C. Life history trade-offs in cancer evolution. Nat. Rev. Cancer 13, 883–892 (2013).
Fan, C. C. et al. Spousal correlations for nine psychiatric disorders are consistent across cultures and persistent over generations. Nat. Hum. Behav. https://doi.org/10.1038/s41562-025-02298-z (2025).
Timmers, P. R. et al. Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances. eLife 8, e39856 (2019).
Deelen, J. et al. A meta-analysis of genome-wide association studies identifies multiple longevity genes. Nat. Commun. 10, 3669 (2019).
Hu, D. et al. Genetic trade-offs between complex diseases and longevity. Aging Cell 21, e13654 (2022).
Dönertaş, H. M., Fabian, D. K., Fuentealba, M., Partridge, L. & Thornton, J. M. Common genetic associations between age-related diseases. Nat. Aging 1, 400–412 (2021).
Wu, D. et al. An antagonistic pleiotropic gene regulates the reproduction and longevity tradeoff. Proc. Natl Acad. Sci. USA 119, e2120311119 (2022).
Pettay, J. E., Kruuk, L. E. B., Jokela, J. & Lummaa, V. Heritability and genetic constraints of life-history trait evolution in preindustrial humans. Proc. Natl Acad. Sci. USA 102, 2838–2843 (2005).
Tabatabaie, V. et al. Exceptional longevity is associated with decreased reproduction. Aging 3, 1202–1205 (2011).
Dillin, A., Crawford, D. K. & Kenyon, C. Timing requirements for insulin/IGF-1 signaling in C. elegans. Science 298, 830–834 (2002).
Partridge, L., Gems, D. & Withers, D. J. Sex and death: what is the connection? Cell 120, 461–472 (2005).
Wu, R. A. et al. TRAIP is a master regulator of DNA interstrand crosslink repair. Nature 567, 267–272 (2019).
Sabeti, P. C. et al. Positive natural selection in the human lineage. Science 312, 1614–1620 (2006).
Tropf, F. C. et al. Human fertility, molecular genetics, and natural selection in modern societies. PLoS ONE 10, e0126821 (2015).
Gao, Z. Unveiling recent and ongoing adaptive selection in human populations. PLoS Biol. 22, e3002469 (2024).
Irving-Pease, E. K. et al. The selection landscape and genetic legacy of ancient Eurasians. Nature 625, 312–320 (2024).
Pankratov, V. et al. Ancestral genetic components are consistently associated with the complex trait landscape in European biobanks. Eur. J. Hum. Genet. 32, 1492–1499 (2024).
Fisher, R. A. The Genetical Theory of Natural Selection (Clarendon, 1930).
Liu, A. et al. Evidence from Finland and Sweden on the relationship between early-life diseases and lifetime childlessness in men and women. Nat. Hum. Behav. 8, 276–287 (2024).
Frejka, T. The Demographic Transition Revisited: A Cohort Perspective WP-2016-012 (Max Planck Institute for Demographic Research, 2016); https://www.demogr.mpg.de/en/publications_databases_6118/publications_1904/mpidr_working_papers/the_demographic_transition_revisited_a_cohort_perspective_5712
Jensen, M. B., Priskorn, L., Jensen, T. K., Juul, A. & Skakkebaek, N. E. Temporal trends in fertility rates: a nationwide registry based study from 1901 to 2014. PLoS ONE 10, e0143722 (2015).
Smith, D. G. & Hemani, G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum. Mol. Genet. 23, R89–R98 (2014).
Hemani, G., Bowden, J. & Davey Smith, G. Evaluating the potential role of pleiotropy in Mendelian randomization studies. Hum. Mol. Genet. 27, R195–R208 (2018).
Arsenault, B. J. et al. Association of long-term exposure to elevated lipoprotein(a) levels with parental life span, chronic disease-free survival, and mortality risk: a Mendelian randomization analysis. JAMA Netw. Open 3, e200129 (2020).
Chan, I. I., Kwok, M. K. & Schooling, C. M. The total and direct effects of systolic and diastolic blood pressure on cardiovascular disease and longevity using Mendelian randomisation. Sci. Rep. 11, 21799 (2021).
Richardson, T. G. et al. Effects of apolipoprotein B on lifespan and risks of major diseases including type 2 diabetes: a Mendelian randomisation analysis using outcomes in first-degree relatives. Lancet Healthy Longev. 2, e317–e326 (2021).
Burgess, S., Thompson, S. G. & CRP CHD Genetics Collaboration Avoiding bias from weak instruments in Mendelian randomization studies. Int. J. Epidemiol. 40, 755–764 (2011).
Pierce, B. L. & Burgess, S. Efficient design for Mendelian randomization studies: subsample and 2-sample instrumental variable estimators. Am. J. Epidemiol. 178, 1177–1184 (2013).
Gkatzionis, A. & Burgess, S. Contextualizing selection bias in Mendelian randomization: how bad is it likely to be? Int. J. Epidemiol. 48, 691–701 (2019).
Ye, C.-J. et al. Mendelian randomization evidence for the causal effects of socio-economic inequality on human longevity among Europeans. Nat. Hum. Behav. 7, 1357–1370 (2023).
Sanderson, E. Multivariable Mendelian randomization and mediation. Cold Spring Harb. Perspect. Med. 11, a038984 (2021).
Carter, A. R. et al. Mendelian randomisation for mediation analysis: current methods and challenges for implementation. Eur. J. Epidemiol. 36, 465–478 (2021).
Rodríguez, J. A. et al. Reply to: Retesting the influences of mutation accumulation and antagonistic pleiotropy on human senescence and disease. Nat. Ecol. Evol. 3, 994–995 (2019).
Barrie, W. et al. Elevated genetic risk for multiple sclerosis emerged in steppe pastoralist populations. Nature 625, 321–328 (2024).
Bernabeu, E. et al. Sex differences in genetic architecture in the UK Biobank. Nat. Genet. 53, 1283–1289 (2021).
Gardner, E. J. et al. Reduced reproductive success is associated with selective constraint on human genes. Nature 603, 858–863 (2022).
Kaptijn, R. et al. The trade-off between female fertility and longevity during the epidemiological transition in the Netherlands. PLoS ONE 10, e0144353 (2015).
Morita, M. Demographic studies enhance the understanding of evolutionarily (mal)adaptive behaviors and phenomena in humans: a review on fertility decline and an integrated model. Popul. Ecol. 60, 143–154 (2018).
Willer, C. J., Li, Y. & Abecasis, G. R. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190–2191 (2010).
Sullivan, P. F. The Psychiatric GWAS Consortium: big science comes to psychiatry. Neuron 68, 182–186 (2010).
Cerezo, M. et al. The NHGRI-EBI GWAS Catalog: standards for reusability, sustainability and diversity. Nucleic Acids Res. 53, D998–D1005 (2025).
World Health Assembly, 43. Report of the International Conference for the Tenth Revision of the International Classification of Diseases (World Health Organization, 1990); https://iris.who.int/handle/10665/173188
Viippola, E. et al. Data resource profile: nationwide registry data for high-throughput epidemiology and machine learning (FinRegistry). Int. J. Epidemiol. 52, e195–e200 (2023).
Jia, G. et al. Estimating heritability and genetic correlations from large health datasets in the absence of genetic data. Nat. Commun. 10, 5508 (2019).
Bulik-Sullivan, B. et al. An atlas of genetic correlations across human diseases and traits. Nat. Genet. 47, 1236–1241 (2015).
Andreassen, O. A. et al. Improved detection of common variants associated with schizophrenia and bipolar disorder using pleiotropy-informed conditional false discovery rate. PLoS Genet 9, e1003455 (2013).
Burgess, S. et al. MendelianRandomization: Mendelian randomization package. R version 3.6.0 https://cran.r-project.org/web/packages/MendelianRandomization/index.html (2024).
Verbanck, M., Chen, C.-Y., Neale, B. & Do, R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat. Genet. 50, 693–698 (2018).
Sudlow, C. et al. UK Biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLOS Med. 12, e1001779 (2015).
Brigos, E. et al. Supplementary Tables S1–S16. figshare https://doi.org/10.6084/m9.figshare.32403876 (2026).
Brigos, E. et al. ecgenomics/whywegetsick: Reproducibility release for published manuscript. Zenodo https://doi.org/10.5281/zenodo.20439635 (2026).