Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at theFADSlocus

Abstract

Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and also identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identify 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology across the life course, including puberty timing, age at first birth, sex hormone regulation and age at menopause. Missense alleles in ARHGAP27 were associated with increased NEB but reduced reproductive lifespan, suggesting a trade-off between reproductive ageing and intensity. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Accordingly, we find that NEB-increasing alleles have increased in frequency over the past two generations. Furthermore, integration with data from ancient selection scans identifies a unique example of an allele-FADS1/2 gene locus-that has been under selection for thousands of years and remains under selection today. Collectively, our findings demonstrate that diverse biological mechanisms contribute to reproductive success, implicating both neuro-endocrine and behavioural influences.

Estimating direct and indirect genetic effects on offspring phenotypes using genome-wide summary results data: a comparison of multivariate methods

“…Interestingly, we identified a positive genetic correlation between male fertility and subjective well-being and a negative genetic correlation with the sibling effect. We identified six of the previous 28 statistically independent loci for fertility, and one of the 16 loci for childlessness 29 . In addition, we identified a novel locus on chromosome 9 that is associated with female fertility.…”

“…The heritability of number of children ever born has been estimated to be between 0.24-0.43 27 , and the variance explained by common genetic variants (SNP based heritability) is estimated to be approximately 10% 28 . Although there have been two GWAS previously conducted on number of children born 23,29 , no study to date has estimated the conditional male, female and sibling genetic effects at individual genetic loci. Both previous studies observed significant genetic correlations for the number of children between men and women (Barban and colleagues 23 : r g =0.97, SE=0.095; Mathieson and colleagues 29 : r g =0.74, 95%CI=0.66-0.82), which our findings from the conditional analysis are consistent with (r g =0.871, SE=0.023).…”

“…Although there have been two GWAS previously conducted on number of children born 23,29 , no study to date has estimated the conditional male, female and sibling genetic effects at individual genetic loci. Both previous studies observed significant genetic correlations for the number of children between men and women (Barban and colleagues 23 : r g =0.97, SE=0.095; Mathieson and colleagues 29 : r g =0.74, 95%CI=0.66-0.82), which our findings from the conditional analysis are consistent with (r g =0.871, SE=0.023). We also identified a strong negative genetic correlation between both male/female fertility and sibling effects; this is likely to be due to a technical artefact of the analyses as described by Wu and colleagues 30 .…”

Gene-Environment Effects on Female Fertility

“…14 We construct three new scores for our four outcomes, that is, age at first sexual intercourse, age at first birth, and completed fertility (which is used also for childlessness). These scores are based on results from the most recent fertility GWAS, including Barban et al (2016), Mathieson et al (2020), andMills et al (2021). Evidence presented in these studies implicates mechanisms related to reproductive health, puberty timing, and evolutionary fitness in the biological pathways that link the scores to fertility phenotypes.…”

“…We emphasize three. First, since fertility traits and outcomes are known to have some of the highest degrees of polygenicity of any complex phenotype reflecting the influence of many different genes and consistent with a genetic architecture that may be influenced by negative selection (Visscher et al, 2008;O'Connor et al, 2019;Mathieson et al, 2020), polygenic scores acknowledge that each individual falls on a continuum of genetic predisposition which results from small contributions of multiple genetic variants. By contrast, single variants can only be weak predictors of any given fertility phenotype.…”