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

doi:10.1038/s41562-023-01528-6

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

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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 language	English
Pages (from-to)	790-801
Number of pages	12
Journal	Nature Human Behaviour
Volume	7
Issue number	5
DOIs	https://doi.org/10.1038/s41562-023-01528-6
State	Published - May 2023

Bibliographical note

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

Funding

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. 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.

Funders	Funder number
Leverhulme Trust
Engineering Research Centers
European Commission
UK Industrial Decarbonization Research and Innovation Centre
???publication-publication-funding-organisation-not-added???	HRZZ-IP-11-2013-8875
Economic and Social Research Council	ES/S008349/1, ES/N011856/1
???publication-publication-funding-organisation-not-added???	400-05-717
UK Medical Research Council, Engineering and Physical Sciences Research Council	MC_UU_00006/2, MC_UU_12015/2
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung	105993, 139468
LabEx Ecodec ANR	2014/01/01/R3
Australian Research Council	DP0212016
???publication-publication-funding-organisation-not-added???	ANR-11-LABX-0047
Horizon 2020 Framework Programme	865356, 835079, 615603
Wellcome Trust	203141, 095219, 098381
Australian National Health and Medical Research Council	552498, 389891, 442915, 302068

ASJC Scopus subject areas

Social Psychology
Experimental and Cognitive Psychology
Behavioral Neuroscience

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10.1038/s41562-023-01528-6

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

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.",

author = "Iain Mathieson and Day, \{Felix R.\} and Nicola Barban and Tropf, \{Felix C.\} and Brazel, \{David M.\} and \{van Heemst\}, Diana and Ahmad Vaez and \{van Zuydam\}, Natalie and Bitarello, \{B{\'a}rbara D.\} and Gardner, \{Eugene J.\} and Akimova, \{Evelina T.\} and Ajuna Azad and Sven Bergmann and Bielak, \{Lawrence F.\} and Boomsma, \{Dorret I.\} and Kristina Bosak and Marco Brumat and Buring, \{Julie E.\} and David Cesarini and Chasman, \{Daniel I.\} and Chavarro, \{Jorge E.\} and Massimiliano Cocca and Concas, \{Maria Pina\} and \{Davey Smith\}, George and Gail Davies and Deary, \{Ian J.\} and T{\~o}nu Esko and Faul, \{Jessica D.\} and Oscar Franco and Andrea Ganna and Gaskins, \{Audrey J.\} and Andrea Gelemanovic and \{de Geus\}, \{Eco J.C.\} and Christian Gieger and Giorgia Girotto and Bamini Gopinath and Grabe, \{Hans J{\"o}rgen\} and Gunderson, \{Erica P.\} and Caroline Hayward and Chunyan He and \{van Heemst\}, Diana and Hill, \{W. David\} and Hoffmann, \{Eva R.\} and Georg Homuth and Hottenga, \{Jouke Jan\} and Hongyang Huang and Elina Hyppӧnen and Ikram, \{M. Arfan\} and Rick Jansen and Magnus Johannesson",

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AU - Brazel, David M.

AU - van Heemst, Diana

AU - Vaez, Ahmad

AU - van Zuydam, Natalie

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AU - Concas, Maria Pina

AU - Davey Smith, George

AU - Davies, Gail

AU - Deary, Ian J.

AU - Esko, Tõnu

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AU - Franco, Oscar

AU - Ganna, Andrea

AU - Gaskins, Audrey J.

AU - Gelemanovic, Andrea

AU - de Geus, Eco J.C.

AU - Gieger, Christian

AU - Girotto, Giorgia

AU - Gopinath, Bamini

AU - Grabe, Hans Jörgen

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AU - Hoffmann, Eva R.

AU - Homuth, Georg

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AU - Huang, Hongyang

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AU - Ikram, M. Arfan

AU - Jansen, Rick

AU - Johannesson, Magnus

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

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

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