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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

By 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

Posted 07 May 2020
bioRxiv DOI: 10.1101/2020.05.06.081273

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.

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