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

Iain Mathieson, Felix R. Day, Nicola Barban, Felix C. Tropf, David M. Brazel, eQTLGen Consortium, BIOS Consortium, Ahmad Vaez, Natalie van Zuydam, Bárbara D. Bitarello, Harold Snieder, Marcel den Hoed, Ken K. Ong, Melinda C. Mills, John R.B. Perry, on behalf of the Human Reproductive Behaviour Consortium
doi: https://doi.org/10.1101/2020.05.19.104455
Iain Mathieson
1Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
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  • For correspondence: mathi@pennmedicine.upenn.edu melinda.mills@nuffield.ox.ac.uk john.perry@mrc-epid.cam.ac.uk
Felix R. Day
2MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
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Nicola Barban
3Institute of Social and Economic Research, University of Essex, Essex, United Kingdom
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Felix C. Tropf
4Leverhulme Centre for Demographic Science, University of Oxford, Oxford, United Kingdom
5Nuffield College, University of Oxford, Oxford, United Kingdom
6École Nationale de la Statistique et de L’administration Économique (ENSAE), Paris, France
7Center for Research in Economics and Statistics (CREST), Paris, France
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David M. Brazel
4Leverhulme Centre for Demographic Science, University of Oxford, Oxford, United Kingdom
5Nuffield College, University of Oxford, Oxford, United Kingdom
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Ahmad Vaez
8Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
9Department of Bioinformatics, Isfahan University of Medical Sciences, Isfahan, Iran
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Natalie van Zuydam
10The Beijer Laboratory and Department of Immunology, Genetics and Pathology, Uppsala University and SciLifeLab, Uppsala, Sweden
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Bárbara D. Bitarello
1Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
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Harold Snieder
8Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Marcel den Hoed
10The Beijer Laboratory and Department of Immunology, Genetics and Pathology, Uppsala University and SciLifeLab, Uppsala, Sweden
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Ken K. Ong
2MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
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Melinda C. Mills
4Leverhulme Centre for Demographic Science, University of Oxford, Oxford, United Kingdom
5Nuffield College, University of Oxford, Oxford, United Kingdom
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  • For correspondence: mathi@pennmedicine.upenn.edu melinda.mills@nuffield.ox.ac.uk john.perry@mrc-epid.cam.ac.uk
John R.B. Perry
2MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
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  • For correspondence: mathi@pennmedicine.upenn.edu melinda.mills@nuffield.ox.ac.uk john.perry@mrc-epid.cam.ac.uk
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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.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 22, 2020.
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Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus
Iain Mathieson, Felix R. Day, Nicola Barban, Felix C. Tropf, David M. Brazel, eQTLGen Consortium, BIOS Consortium, Ahmad Vaez, Natalie van Zuydam, Bárbara D. Bitarello, Harold Snieder, Marcel den Hoed, Ken K. Ong, Melinda C. Mills, John R.B. Perry, on behalf of the Human Reproductive Behaviour Consortium
bioRxiv 2020.05.19.104455; doi: https://doi.org/10.1101/2020.05.19.104455
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Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus
Iain Mathieson, Felix R. Day, Nicola Barban, Felix C. Tropf, David M. Brazel, eQTLGen Consortium, BIOS Consortium, Ahmad Vaez, Natalie van Zuydam, Bárbara D. Bitarello, Harold Snieder, Marcel den Hoed, Ken K. Ong, Melinda C. Mills, John R.B. Perry, on behalf of the Human Reproductive Behaviour Consortium
bioRxiv 2020.05.19.104455; doi: https://doi.org/10.1101/2020.05.19.104455

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