Gene-environment interaction for human fertility

Mega-analysis of 31,396 individuals from 6 countries uncovers strong gene-environment interaction for human fertility

Family and twin studies suggest that up to 50% of individual differences in human fertility within a population might be heritable. However, it remains unclear whether the genes associated with fertility outcomes such as number of children ever born (NEB) or age at first birth (AFB) are the same across geographical and historical environments. By not taking this into account, previous genetic studies implicitly assumed that the genetic effects are constant across time and space. We conduct a mega-analysis applying whole genome methods on 31,396 unrelated men and women from six Western countries. Across all individuals and environments, common single-nucleotide polymorphisms (SNPs) explained only ~4% of the variance in NEB and AFB. We then extend these models to test whether genetic effects are shared across different environments or unique to them. For individuals belonging to the same population and demographic cohort (born before or after the 20th century fertility decline), SNP-based heritability was almost five times higher at 22% for NEB and 19% for AFB. We also found no evidence suggesting that genetic effects on fertility are shared across time and space. Our findings imply that the environment strongly modifies genetic effects on the tempo and quantum of fertility, that currently ongoing natural selection is heterogeneous across environments, and that gene-environment interactions may partly account for missing heritability in fertility. Future research needs to combine efforts from genetic research and from the social sciences to better understand human fertility.

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For evolutionary biologists, our findings have at least two important implications. First, the number of children ever born has been used as a proxy for fitness, given the diminishing child mortality rate in contemporary societies [4,23,36]. Additive genetic variance therefore indicates currently ongoing natural selection under environmental equilibrium within populations: if all else equal, genes that lead to a higher number of offspring will have a higher frequency in future generations. Due to natural selection, Fisher predicted additive genetic variance in fertility to be (close to) zero in the absence of gene environment interaction, since genes that reduce fitness are passed on to the next generation to a lesser extent thereby reducing their frequencies [16]. Nevertheless, we find significant additive genetic influences on fitness traits such as NEB and AFB – substantial yet lower than heritabilities observed for morphological traits such as height [14,15,23,43]. Finding significant genetic influences on this these proxies of fitness suggests that, along with sociocultural changes surrounding fertility, genetic variants under selection have also changed [for review see 1,for review see 2,5,7,17,34,for comment see 44–46]. Gene-environment interaction can explain why we find additive genetic variance in fitness related traits despite natural selection.

Second, previous research has uncovered an ongoing natural selection in contemporary societies [3,4,23,47,48] and even attempted to forecast changes in for example height and blood pressure across generations [4]. For valid evolutionary predictions about observable changes in traits across generations due to currently ongoing natural selection, fertility needs to be consistently heritable, the same genes need to be under selection across generations and the direction of the selection needs be similar. Our results demonstrate moderate genetic influences on fertility within populations indicating potentially ongoing human evolution. However, this potential is delimited in at least two ways: First, genetic effects on fertility strongly differ across countries and therefore may lead to heterogeneity across human populations rather than to universal changes in humans. Second, the finding that genetic effects underlying proxies of fitness vary so markedly across time periods suggests that substantial caution is needed when inferring long-term evolutionary predictions.

For social scientists, genetic influences had been originally thought of as biological constraints on human reproductive behavior [42]. Yet some previous studies showed that genetic predispositions may underlie decision making processes on fertility timing and motivation [6,7,49,50]. It has been suspected that genetically based behavioural and psychological traits have become more important than physiological ones in the recent past [6,8,34,51]. This hypothesis remains to be tested, but our results confirm that genetic influences on fertility have evolved with social changes in the reproductive environment and therefore underscore the necessity to integrate social factors into genetic research on fertility.