Abstract
Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identified 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology, including puberty timing, age at first birth, sex hormone regulation, endometriosis and age at menopause. Missense variants in ARHGAP27 were associated with higher NEB but shorter reproductive lifespan, suggesting a trade-off at this locus between reproductive ageing and intensity. Other genes implicated by coding variants include PIK3IP1, ZFP82 and LRP4, and our results suggest a new role for the melanocortin 1 receptor (MC1R) in reproductive biology. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Integration with data from historical selection scans highlighted an allele in the FADS1/2 gene locus that has been under selection for thousands of years and remains so today. Collectively, our findings demonstrate that a broad range of biological mechanisms contribute to reproductive success.
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Data availability
Upon publication, the GWAS summary statistics will be made available at https://doi.org/10.17863/CAM.88397. Access to individual-level data from the multiple sources used in this GWAS can be obtained by bona fide scientists through application to each specific data provider; each data source is described in the Supplementary Note. Source data are provided with this paper.
Code availability
No custom code was used in this study. All analyses and modelling used standard software as described in the Methods and the Supplementary Information.
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Acknowledgements
This research was conducted using the UK Biobank Resource under application no. 9905. This work was supported by the Medical Research Council (Unit Programme numbers MC_UU_12015/2 and MC_UU_00006/2); ERC grant nos 615603, 835079 and 865356; ESRC ES/N011856/1; the Leverhulme Trust; the Leverhulme Centre for Demographic Science; and LabEx Ecodec ANR grant no. ANR-11-LABX-0047. Full study-specific and individual acknowledgements can be found in the Supplementary Information. The content is solely the responsibility of the authors and does not necessarily represent the official views of any of the funders. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. This study received ethical approval from the Department of Sociology, University of Oxford 2014/01/01/R3, 28 January 2014 (SOCIOGENOME) and revised with extension SOC/R2/001/C1A/21/60 7 July 2022 (CHRONO), and relevant ethical approval was obtained at the local level for the contributing datasets.
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I.M., H.S., M.d.H., K.K.O., M.C.M. and J.R.B.P. designed the study. I.M., F.R.D., N.B., F.C.T., D.M.B., A.V., N.v.Z., B.D.B., E.J.G., M.d.H. and J.R.B.P. performed the analyses. All authors contributed to the data collection and curation and critically reviewed the manuscript.
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J.R.B.P. and E.J.G. are employees of Adrestia Therapeutics. M.I.M. has served on advisory panels for Pfizer, NovoNordisk and Zoe Global; has received honoraria from Merck, Pfizer, Novo Nordisk and Eli Lilly; and has received research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier and Takeda. As of June 2019, M.I.M. is an employee of Genentech and a holder of Roche stock. H.J.G. has received travel grants and speakers’ honoraria from Fresenius Medical Care, Neuraxpharm, Servier and Janssen Cilag as well as research funding from Fresenius Medical Care. The otherauthors declare no competing interests.
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Mathieson, I., Day, F.R., Barban, N. et al. Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus. Nat Hum Behav 7, 790–801 (2023). https://doi.org/10.1038/s41562-023-01528-6
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DOI: https://doi.org/10.1038/s41562-023-01528-6
