Why do we get sick? Genetic evidence for evolutionary trade-offs between fertility, longevity, and disease

Abstract The persistence of genetic variants that increase susceptibility to complex diseases poses an evolutionary paradox: despite their detrimental health effects, these variants are not eliminated by natural selection. Life-history theory proposes that trade-offs and pleiotropic effects across fitness components may explain the evolutionary maintenance of disease-associated alleles. We hypothesize that certain disease-risk alleles might segregate in the population because they confer reproductive advantages, even at the expense of late-life costs on health and longevity. Leveraging genome-wide association studies, we investigated genetic correlations and pleiotropic relationships between 62 complex diseases, longevity, and fertility. In our study, we estimated fertility by meta-analyzing complementary measures of offspring number and used parental lifespan as a proxy for longevity. We found that 85% of diseases showed negative genetic correlations with longevity, whereas 87% of diseases with significant correlations showed positive associations with fertility. Moreover, most disease-risk variants were associated with reduced longevity, even after accounting for socioeconomic confounders. Fertility-increasing alleles exhibited evolutionary signals consistent with adaptive selection despite having pleiotropic effects on disease-risk. Finally, we compared the number of offspring among individuals with high genetic risk of disease and found that, for most diseases, affected individuals had more offspring than disease-free individuals. However, for early-onset conditions, non-affected individuals exhibited higher fertility, highlighting the reproductive cost of early-onset diseases. These findings support the Antagonistic Pleiotropy theory, showing that alleles that enhance early-life reproductive success can persist despite late-life health costs. By uncovering these evolutionary trade-offs between reproduction, longevity, and disease risk, our study shows how Darwinian selection continues to shape contemporary patterns of human disease susceptibility. Understanding these evolutionary trade-offs can inform public health approaches and help anticipate unintended consequences of targeting disease-related genetic pathways.