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Identification of 371 genetic variants for age at first sex and birth linked to externalising behaviour.

ABSTRACT: Age at first sexual intercourse and age at first birth have implications for health and evolutionary fitness. In this genome-wide association study (age at first sexual intercourse, N = 387,338; age at first birth, N = 542,901), we identify 371 single-nucleotide polymorphisms, 11 sex-specific, with a 5-6% polygenic score prediction. Heritability of age at first birth shifted from 9% [CI = 4-14%] for women born in 1940 to 22% [CI = 19-25%] for those born in 1965. Signals are driven by the genetics of reproductive biology and externalising behaviour, with key genes related to follicle stimulating hormone (FSHB), implantation (ESR1), infertility and spermatid differentiation. Our findings suggest that polycystic ovarian syndrome may lead to later age at first birth, linking with infertility. Late age at first birth is associated with parental longevity and reduced incidence of type 2 diabetes and cardiovascular disease. Higher childhood socioeconomic circumstances and those in the highest polygenic score decile (90%+) experience markedly later reproductive onset. Results are relevant for improving teenage and late-life health, understanding longevity and guiding experimentation into mechanisms of infertility.

SUBMITTER: Mills MC

PROVIDER: S-EPMC7612120 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Identification of 371 genetic variants for age at first sex and birth linked to externalising behaviour.

Mills Melinda C MC Tropf Felix C FC Brazel David M DM van Zuydam Natalie N Vaez Ahmad A Pers Tune H TH Snieder Harold H Perry John R B JRB Ong Ken K KK den Hoed Marcel M Barban Nicola N Day Felix R FR

Nature human behaviour 20210701 12

Age at first sexual intercourse and age at first birth have implications for health and evolutionary fitness. In this genome-wide association study (age at first sexual intercourse, N = 387,338; age at first birth, N = 542,901), we identify 371 single-nucleotide polymorphisms, 11 sex-specific, with a 5-6% polygenic score prediction. Heritability of age at first birth shifted from 9% [CI = 4-14%] for women born in 1940 to 22% [CI = 19-25%] for those born in 1965. Signals are driven by the genetic ...[more]

PMID: 34211149

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Project description:Growing evidence suggests that various reproductive factors, including early menarche, early menopause, and age at first birth, may increase the risk of developing cardiovascular disease (CVD) later in life. However, the associations between reproductive factors and CVDs are inconsistent and controversial. Therefore, we conducted a two-sample Mendelian randomization (MR) analysis to explore the potential links between age at first sex (AFS) and age at first birth (AFB) and several CVDs. We obtained summary statistics for exposure from the largest genome-wide association studies of AFS and AFB. To serve as instrumental variables, we selected 259 SNPs associated with AFS and 81 SNPs associated with AFB at the genome-wide significance level. We employed a random-effects inverse-variance weighted method to pool estimates, and conducted multivariable MR analysis to determine the direct association between AFS and AFB with CVDs, while accounting for the effects of confounders. The genetic liability to later AFS was associated with decreased risks of heart failure (odd ratio [OR] 0.700; 95% confidence interval [CI] 0.639-0.767; p = 2.23 × 10-14), coronary artery disease (OR 0.728; 95% CI 0.657-0.808; p = 1.82 × 10-9), myocardial infarction (OR 0.731; 95% CI 0.657-0.813; p = 8.33 × 10-9), stroke (OR 0.747; 95% CI 0.684-0.816; p = 6.89 × 10-11), and atrial fibrillation (OR 0.871; 95% CI 0.806-0.941; p = 4.48 × 10-4). The genetic liability to later AFB was also associated with decreased risks of CVDs, including myocardial infarction (OR 0.895; 95% CI 0.852-0.940; p = 8.66 × 10-6), coronary heart disease (OR 0.901; 95% CI 0.860-0.943; p = 9.02 × 10-6), heart failure (OR 0.925; 95% CI 0.891-0.961; p = 5.32 × 10-5), and atrial fibrillation (OR 0.944; 95% CI 0.911-0.978; p = 0.001). However, no association was found between AFB and stroke. The associations remained independent from the effects of AFS and AFB on potential confounders, including smoking, alcohol intake, body mass index, and depression. Mediation analysis suggested that education attainment partly mediates the link from AFS and AFB to CVD outcomes. Our results observed a causal relationship between later AFS, AFB and lower CVDs risk; it emphasizes the importance of providing sex education since early sex and birth may have undesirable effects. Cardiovascular risk stratification that considers reproductive factors may help address CVD risk.

Dataset Information

Identification of 371 genetic variants for age at first sex and birth linked to externalising behaviour.

Publications

Identification of 371 genetic variants for age at first sex and birth linked to externalising behaviour.

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