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Identification of 370 loci for age at onset of sexual and reproductive behaviour, highlighting common aetiology with reproductive biology, externalizing behaviour and longevity

View ORCID ProfileMelinda C. Mills, View ORCID ProfileFelix C. Tropf, View ORCID ProfileDavid M. Brazel, View ORCID ProfileNatalie van Zuydam, View ORCID ProfileAhmad Vaez, eQTLGen Consortium, BIOS Consortium, View ORCID ProfileTune H. Pers, View ORCID ProfileHarold Snieder, View ORCID ProfileJohn R.B. Perry, View ORCID ProfileKen K. Ong, View ORCID ProfileMarcel den Hoed, View ORCID ProfileNicola Barban, View ORCID ProfileFelix R. Day, on behalf of the Human Reproductive Behaviour Consortium
doi: https://doi.org/10.1101/2020.05.06.081273
Melinda C. Mills
1Leverhulme Centre for Demographic Science, University of Oxford, Oxford, United Kingdom
2Nuffield College, University of Oxford, Oxford, United Kingdom
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  • For correspondence: melinda.mills@nuffield.ox.ac.uk felix.day@mrc-epid.cam.ac.uk
Felix C. Tropf
1Leverhulme Centre for Demographic Science, University of Oxford, Oxford, United Kingdom
2Nuffield College, University of Oxford, Oxford, United Kingdom
3École Nationale de la Statistique et de L’administration Économique (ENSAE), Paris, France
4Center for Research in Economics and Statistics (CREST), Paris, France
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David M. Brazel
1Leverhulme Centre for Demographic Science, University of Oxford, Oxford, United Kingdom
2Nuffield College, University of Oxford, Oxford, United Kingdom
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Natalie van Zuydam
5The Beijer Laboratory and Department of Immunology, Genetics and Pathology, Uppsala University and SciLifeLab, Uppsala, Sweden
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Ahmad Vaez
6Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
7Department of Bioinformatics, Isfahan University of Medical Sciences, Isfahan, Iran
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Tune H. Pers
8The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
9Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
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Harold Snieder
6Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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John R.B. Perry
10MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
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Ken K. Ong
10MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
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Marcel den Hoed
5The Beijer Laboratory and Department of Immunology, Genetics and Pathology, Uppsala University and SciLifeLab, Uppsala, Sweden
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Nicola Barban
11Institute of Social and Economic Research, University of Essex, Essex, United Kingdom
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Felix R. Day
10MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
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  • ORCID record for Felix R. Day
  • For correspondence: melinda.mills@nuffield.ox.ac.uk felix.day@mrc-epid.cam.ac.uk
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Abstract

The timing of reproductive behaviour – age at first sexual intercourse (AFS) and age at first birth (AFB) – has implications for reproductive health, adolescent development and evolutionary fitness. In the largest genome-wide association study to date (AFS, N=387,338; AFB, N=542,901), we identify 370 independent signals, 11 which are sex-specific, with a 5-6% polygenic score prediction. Heritability shifted from 10% for those born in 1940 to 23% for the 1965 birth cohort. Using Genomic SEM, we show that signals are largely driven by the genetics of reproductive biology and externalizing behaviour. This is supported by extensive biological follow-up that isolates key genes related to follicle stimulating hormone (FSHB), implantation (ESR1), infertility (endometriosis, spontaneous abortion) and spermatid differentiation, morphogenesis and binding (KLF17, ZPBP). Later AFB is protective against later-life disease (type 2 diabetes, cardiovascular) and associated with longevity. Those from higher childhood socioeconomic circumstances and polygenic scores in the highest deciles (90%+) experience markedly later reproductive onset. Results are relevant for interventions in teenage sexual, reproductive and mental health, deepen our understanding of the drivers of later-life health and longevity, and fuel infertility and functional follow-up experiments.

Competing Interest Statement

The main authors declare no competing interests. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. MMcC (Mark McCarthy) has served on advisory panels for Pfizer, NovoNordisk and Zoe Global, has received honoraria from Merck, Pfizer, Novo Nordisk and Eli Lilly, and research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier, and Takeda. As of June 2019, MMcC is an employee of Genentech, and a holder of Roche stock.

Copyright 
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-ND 4.0 International license.
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Posted May 07, 2020.
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Identification of 370 loci for age at onset of sexual and reproductive behaviour, highlighting common aetiology with reproductive biology, externalizing behaviour and longevity
Melinda C. Mills, Felix C. Tropf, David M. Brazel, Natalie van Zuydam, Ahmad Vaez, eQTLGen Consortium, BIOS Consortium, Tune H. Pers, Harold Snieder, John R.B. Perry, Ken K. Ong, Marcel den Hoed, Nicola Barban, Felix R. Day, on behalf of the Human Reproductive Behaviour Consortium
bioRxiv 2020.05.06.081273; doi: https://doi.org/10.1101/2020.05.06.081273
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Identification of 370 loci for age at onset of sexual and reproductive behaviour, highlighting common aetiology with reproductive biology, externalizing behaviour and longevity
Melinda C. Mills, Felix C. Tropf, David M. Brazel, Natalie van Zuydam, Ahmad Vaez, eQTLGen Consortium, BIOS Consortium, Tune H. Pers, Harold Snieder, John R.B. Perry, Ken K. Ong, Marcel den Hoed, Nicola Barban, Felix R. Day, on behalf of the Human Reproductive Behaviour Consortium
bioRxiv 2020.05.06.081273; doi: https://doi.org/10.1101/2020.05.06.081273

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