Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus

Iain Mathieson*, Felix R. Day, eQTLgen Consortium, the Biobank-based Integrative Omics Study (BIOS) Consortium, FinnGen study, The LifeLines Cohort Study, Nicola Barban, Felix C. Tropf, David M. Brazel, Diana van Heemst, Ahmad Vaez, Natalie van Zuydam, Bárbara D. Bitarello, Eugene J. Gardner, Evelina T. Akimova, Ajuna Azad, Sven Bergmann, Lawrence F. Bielak, Dorret I. Boomsma, Kristina BosakMarco Brumat, Julie E. Buring, David Cesarini, Daniel I. Chasman, Jorge E. Chavarro, Massimiliano Cocca, Maria Pina Concas, George Davey Smith, Gail Davies, Ian J. Deary, Tõnu Esko, Jessica D. Faul, Oscar Franco, Andrea Ganna, Audrey J. Gaskins, Andrea Gelemanovic, Eco J.C. de Geus, Christian Gieger, Giorgia Girotto, Bamini Gopinath, Hans Jörgen Grabe, Jouke Jan Hottenga, M. Arfan Ikram, Rick Jansen, Maryam Kavousi, Peter Kraft, Raymond Noordam, Cornelius A. Rietveld, Alexander Teumer, André G. Uitterlinden, Jing Hau Zhao, Wei Zhao, Marcel den Hoed, Melinda C. Mills*, John R.B. Perry*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

7 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)790-801
Number of pages12
JournalNature Human Behaviour
Volume7
Issue number5
Early online date2 Mar 2023
DOIs
Publication statusPublished - May 2023

Bibliographical note

Funding Information:
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 . 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.

Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature Limited.

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