Genetic trade-offs in fertility and longevity explain the maintenance of disease-associated alleles in humans
Genetic variants that increase the risk for complex diseases persist in human populations despite adverse effects on health and longevity. Life-history theory predicts that such alleles can be maintained by trade-offs arising from pleiotropy, yet direct genomic evidence has been limited.
In this study, we ask whether disease-associated variants persist because they enhance reproduction despite costs to health and lifespan. By analyzing genome-wide data across 62 diseases, longevity, and fertility, we show that disease-risk alleles are, on average, associated with reduced longevity and increased fertility.
Moreover, the subset of alleles that increase both fertility and disease risk appear to have been favored by natural selection over the past 50,000 years. Using Mendelian randomization, we detect a causal effect of genetic liability to disease on longevity, but not robust evidence for a causal effect on fertility. Importantly, these estimates remain stable after adjusting for socioeconomic factors.
At the individual level, a higher polygenic risk for late-onset diseases is associated with having more children, whereas genetic liabilities to early-onset diseases are associated with fewer children, indicating reproductive costs of early morbidity.
Together, these results support antagonistic pleiotropy and help explain the persistence of disease-risk alleles in human populations.
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