Welter, D. et al. The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res. 42, D1001–D1006 (2014).

Article 
CAS 
PubMed 

Google Scholar
 

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).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

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).

Article 

Google Scholar
 

Watanabe, K. et al. A global overview of pleiotropy and genetic architecture in complex traits. Nat. Genet. 51, 1339–1348 (2019).

Article 
CAS 
PubMed 

Google Scholar
 

Benton, M. L. et al. The influence of evolutionary history on human health and disease. Nat. Rev. Genet. 22, 269–283 (2021).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

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).

Article 
PubMed 

Google Scholar
 

Smith, J. M. The Effects of temperature and of egg-laying on the longevity of Drosophila subobscura. J. Exp. Biol. 35, 832–842 (1958).

Article 

Google Scholar
 

Rose, M. R. Laboratory evolution of postponed senescence in Drosophila melanogaster. Evolution 38, 1004–1010 (1984).

Article 
PubMed 

Google Scholar
 

Sgrò, C. M. & Partridge, L. A delayed wave of death from reproduction in Drosophila. Science 286, 2521–2524 (1999).

Article 
PubMed 

Google Scholar
 

Harshman, L. G. & Zera, A. J. The cost of reproduction: the devil in the details. Trends Ecol. Evol. 22, 80–86 (2007).

Article 
PubMed 

Google Scholar
 

Kuningas, M. et al. The relationship between fertility and lifespan in humans. Age 33, 615–622 (2011).

Article 
PubMed 
PubMed Central 

Google Scholar
 

Westendorp, R. G. J. & Kirkwood, T. B. L. Human longevity at the cost of reproductive success. Nature 396, 743–746 (1998).

Article 
CAS 
PubMed 

Google Scholar
 

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).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Long, E. & Zhang, J. Evidence for the role of selection for reproductively advantageous alleles in human aging. Sci. Adv. 9, eadh4990 (2023).

Article 
PubMed 
PubMed Central 

Google Scholar
 

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).

Article 
CAS 

Google Scholar
 

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).

Article 

Google Scholar
 

Kirkwood, T. B. L. & Austad, S. N. Why do we age? Nature 408, 233–238 (2000).

Article 
CAS 
PubMed 

Google Scholar
 

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).

Article 
CAS 
PubMed 

Google Scholar
 

Rodríguez, J. A. et al. Antagonistic pleiotropy and mutation accumulation influence human senescence and disease. Nat. Ecol. Evol. 1, 55 (2017).

Article 
PubMed 

Google Scholar
 

Austad, S. N. & Hoffman, J. M. Is antagonistic pleiotropy ubiquitous in aging biology? Evol. Med. Public Health 2018, 287–294 (2018).

Article 
PubMed 
PubMed Central 

Google Scholar
 

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).

Article 
PubMed 

Google Scholar
 

Melzer, D., Pilling, L. C. & Ferrucci, L. The genetics of human ageing. Nat. Rev. Genet. 21, 88–101 (2020).

Article 
CAS 
PubMed 

Google Scholar
 

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).

Article 
PubMed 
PubMed Central 

Google Scholar
 

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).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Barban, N. et al. Genome-wide analysis identifies 12 loci influencing human reproductive behavior. Nat. Genet. 48, 1462–1472 (2016).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

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).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

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).

Article 
PubMed 
PubMed Central 

Google Scholar
 

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).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Watanabe, K., Taskesen, E., van Bochoven, A. & Posthuma, D. Functional mapping and annotation of genetic associations with FUMA. Nat. Commun. 8, 1826 (2017).

Article 
PubMed 
PubMed Central 

Google Scholar
 

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).

Article 
PubMed 
PubMed Central 

Google Scholar
 

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).

Article 

Google Scholar
 

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).

Article 
PubMed 
PubMed Central 

Google Scholar
 

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).

Article 
PubMed 

Google Scholar
 

Byars, S. G. et al. Genetic loci associated with coronary artery disease harbor evidence of selection and antagonistic pleiotropy. PLOS Genet. 13, e1006328 (2017).

Article 
PubMed 
PubMed Central 

Google Scholar
 

Stearns, S. C. Trade-offs in life-history evolution. Funct. Ecol. 3, 259–268 (1989).

Article 

Google Scholar
 

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).

Article 
PubMed 
PubMed Central 

Google Scholar
 

Crespi, B. J. The origins and evolution of genetic disease risk in modern humans. Ann. N. Y. Acad. Sci. 1206, 80–109 (2010).

Article 
PubMed 

Google Scholar
 

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).

Article 
PubMed 

Google Scholar
 

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).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

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).

Article 
PubMed 
PubMed Central 

Google Scholar
 

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).

Article 
PubMed 
PubMed Central 

Google Scholar
 

Deelen, J. et al. A meta-analysis of genome-wide association studies identifies multiple longevity genes. Nat. Commun. 10, 3669 (2019).

Article 
PubMed 
PubMed Central 

Google Scholar
 

Hu, D. et al. Genetic trade-offs between complex diseases and longevity. Aging Cell 21, e13654 (2022).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

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).

Article 
PubMed 
PubMed Central 

Google Scholar
 

Wu, D. et al. An antagonistic pleiotropic gene regulates the reproduction and longevity tradeoff. Proc. Natl Acad. Sci. USA 119, e2120311119 (2022).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

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).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Tabatabaie, V. et al. Exceptional longevity is associated with decreased reproduction. Aging 3, 1202–1205 (2011).

Article 
PubMed 
PubMed Central 

Google Scholar
 

Dillin, A., Crawford, D. K. & Kenyon, C. Timing requirements for insulin/IGF-1 signaling in C. elegans. Science 298, 830–834 (2002).

Article 
CAS 
PubMed 

Google Scholar
 

Partridge, L., Gems, D. & Withers, D. J. Sex and death: what is the connection? Cell 120, 461–472 (2005).

Article 
CAS 
PubMed 

Google Scholar
 

Wu, R. A. et al. TRAIP is a master regulator of DNA interstrand crosslink repair. Nature 567, 267–272 (2019).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Sabeti, P. C. et al. Positive natural selection in the human lineage. Science 312, 1614–1620 (2006).

Article 
CAS 
PubMed 

Google Scholar
 

Tropf, F. C. et al. Human fertility, molecular genetics, and natural selection in modern societies. PLoS ONE 10, e0126821 (2015).

Article 
PubMed 
PubMed Central 

Google Scholar
 

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).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

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).

Article 
PubMed 
PubMed Central 

Google Scholar
 

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).

Article 
PubMed 

Google Scholar
 

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).

Article 
PubMed 
PubMed Central 

Google Scholar
 

Smith, D. G. & Hemani, G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum. Mol. Genet. 23, R89–R98 (2014).

Article 

Google Scholar
 

Hemani, G., Bowden, J. & Davey Smith, G. Evaluating the potential role of pleiotropy in Mendelian randomization studies. Hum. Mol. Genet. 27, R195–R208 (2018).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

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).

Article 
PubMed 
PubMed Central 

Google Scholar
 

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).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

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).

Article 
PubMed 
PubMed Central 

Google Scholar
 

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).

Article 
PubMed 

Google Scholar
 

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).

Article 
PubMed 
PubMed Central 

Google Scholar
 

Gkatzionis, A. & Burgess, S. Contextualizing selection bias in Mendelian randomization: how bad is it likely to be? Int. J. Epidemiol. 48, 691–701 (2019).

Article 
PubMed 
PubMed Central 

Google Scholar
 

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).

Article 
PubMed 

Google Scholar
 

Sanderson, E. Multivariable Mendelian randomization and mediation. Cold Spring Harb. Perspect. Med. 11, a038984 (2021).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Carter, A. R. et al. Mendelian randomisation for mediation analysis: current methods and challenges for implementation. Eur. J. Epidemiol. 36, 465–478 (2021).

Article 
PubMed 
PubMed Central 

Google Scholar
 

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).

Article 
PubMed 

Google Scholar
 

Barrie, W. et al. Elevated genetic risk for multiple sclerosis emerged in steppe pastoralist populations. Nature 625, 321–328 (2024).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Bernabeu, E. et al. Sex differences in genetic architecture in the UK Biobank. Nat. Genet. 53, 1283–1289 (2021).

Article 
CAS 
PubMed 

Google Scholar
 

Gardner, E. J. et al. Reduced reproductive success is associated with selective constraint on human genes. Nature 603, 858–863 (2022).

Article 
CAS 
PubMed 

Google Scholar
 

Kaptijn, R. et al. The trade-off between female fertility and longevity during the epidemiological transition in the Netherlands. PLoS ONE 10, e0144353 (2015).

Article 
PubMed 
PubMed Central 

Google Scholar
 

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).

Article 

Google Scholar
 

Willer, C. J., Li, Y. & Abecasis, G. R. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190–2191 (2010).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Sullivan, P. F. The Psychiatric GWAS Consortium: big science comes to psychiatry. Neuron 68, 182–186 (2010).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Cerezo, M. et al. The NHGRI-EBI GWAS Catalog: standards for reusability, sustainability and diversity. Nucleic Acids Res. 53, D998–D1005 (2025).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

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).

Article 
PubMed 
PubMed Central 

Google Scholar
 

Jia, G. et al. Estimating heritability and genetic correlations from large health datasets in the absence of genetic data. Nat. Commun. 10, 5508 (2019).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Bulik-Sullivan, B. et al. An atlas of genetic correlations across human diseases and traits. Nat. Genet. 47, 1236–1241 (2015).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

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).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

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).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

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).

Article 
PubMed 
PubMed Central 

Google Scholar
 

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).