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Identification of 371 genetic variants for age at first sex and birth linked to externalising behaviour

2021; Nature Portfolio; Volume: 5; Issue: 12 Linguagem: Inglês

10.1038/s41562-021-01135-3

2397-3374

Melinda Mills, Felix C. Tropf, David M. Brazel, Natalie R. van Zuydam, Ahmad Vaez, Mawussé Agbessi, Habibul Ahsan, Isabel Alves, Anand Kumar Andiappan, Wibowo Arindrarto, Philip Awadalla, Alexis Battle, Frank Beutner, Marc Jan Bonder, Dorret I. Boomsma, Mark Christiansen, Annique Claringbould, Patrick Deelen, Tõnu Esko, Marie-Julie Favé, Lude Franke, Timothy M. Frayling, Sina A. Gharib, Greg Gibson, Bastiaan T. Heijmans, Gibran Hemani, Rick Jansen, Mika Kähönen, Anette Kalnapenkis, Silva Kasela, Johannes Kettunen, Yungil Kim, Holger Kirsten, Péter Kovács, Knut Krohn, Jaanika Kronberg, Viktorija Kukushkina, Zoltán Kutalik, Bernett Lee, Terho Lehtimäki, Markus Loeffler, Urko M. Marigorta, Hailang Mei, Lili Milani, Grant W. Montgomery, Martina Müller‐Nurasyid, Matthias Nauck, Michel G. Nivard, Brenda W.J.H. Penninx, Markus Perola, Natalia Pervjakova, Brandon L. Pierce, Joseph E. Powell, Holger Prokisch, Bruce M. Psaty, Olli T. Raitakari, Samuli Ripatti, Olaf Rötzschke, Sina Rüeger, Ashis Saha, Markus Scholz, Katharina Schramm, Ilkka Seppälä, P. Eline Slagboom, Coen D.A. Stehouwer, Michael Stümvoll, Patrick Sullivan, Peter A.C. ‘t Hoen, Alexander Teumer, Joachim Thiery, Tong Lin, Anke Tönjes, Jenny van Dongen, Maarten van Iterson, Joyce B. J. van Meurs, Jan H. Veldink, Joost Verlouw, Peter M. Visscher, Uwe Völker, Urmo Võsa, Harm-Jan Westra, Cisca Wijmenga, Hanieh Yaghootkar, Jian Yang, Biao Zeng, Futao Zhang, Bastiaan T. Heijmans, Peter A.C. ‘t Hoen, Joyce B. J. van Meurs, Aaron Isaacs, Rick Jansen, Lude Franke, Dorret I. Boomsma, René Pool, Jenny van Dongen, Jouke‐Jan Hottenga, Marleen M. J. van Greevenbroek, Coen D.A. Stehouwer, Carla Kallen, Casper G. Schalkwijk, Cisca Wijmenga, Lude Franke, Sasha Zhernakova, Ettje F. Tigchelaar, P. Eline Slagboom, Marian Beekman, Joris Deelen, Diana van Heemst, Jan H. Veldink, Leonard H. van den Berg, Cornelia M. van Duijn, Bert A. Hofman, Aaron Isaacs, André G. Uitterlinden, Joyce B. J. van Meurs, P. Mila Jhamai, Michaël Verbiest, H. Eka D. Suchiman, Marijn Verkerk, Ruud van der Breggen, Jeroen van Rooij, Nico Lakenberg, Hailiang Mei, Maarten van Iterson, Michiel van Galen, Jan Bot, Dasha V. Zhernakova, Rick Jansen, Peter van ‘t Hof, Patrick Deelen, Irene Nooren, Peter A.C. ‘t Hoen, Bastiaan T. Heijmans, Matthijs Moed, Lude Franke, Martijn Vermaat, Dasha V. Zhernakova, René Luijk, Marc Jan Bonder, Maarten van Iterson, Patrick Deelen, Freerk van Dijk, Michiel van Galen, Wibowo Arindrarto, Szymon M. Kiełbasa, Morris A. Swertz, Erik W. van Zwet, Rick Jansen, Peter A.C. ‘t Hoen, Bastiaan T. Heijmans, Evelina T. Akimova, Sven Bergmann, Jason D. Boardman, Dorret I. Boomsma, Marco 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, Oscar H. Franco, Audrey J. Gaskins, Eco J. C. de Geus, Christian Gieger, Giorgia Girotto, Hans J. Grabe, Erica P. Gunderson, Kathleen Mullan Harris, Fernando Pires Hartwig, Chunyan He, Diana van Heemst, W. David Hill, Georg Homuth, Bernando Lessa Horta, Jouke‐Jan Hottenga, Hongyang Huang, Elina Hyppönen, M. Arfan Ikram, Rick Jansen, Magnus Johannesson, Zoha Kamali, Maryam Kavousi, Peter Kraft, Brigitte Kühnel, Claudia Langenberg, Penelope A. Lind, Jian’an Luan, Reedik Mägi, Patrik K. E. Magnusson, Anubha Mahajan, Nicholas G. Martin, Hamdi Mbarek, Mark I. McCarthy, George McMahon, Matthew B. McQueen, Sarah E. Medland, Thomas Meitinger, Andres Metspalu, Evelin Mihailov, Lili Milani, Stacey A. Missmer, Stine Møllegaard, Dennis O. Mook‐Kanamori, Anna Morgan, Peter J. van der Most, Renée de Mutsert, Matthias Nauck, Ilja M. Nolte, Raymond Noordam, Brenda W.J.H. Penninx, Annette Peters, Chris Power, Paul Redmond, Janet W. Rich‐Edwards, Paul M. Ridker, Cornelius A. Rietveld, Susan M. Ring, Lynda M. Rose, Rico Rueedi, Kári Stéfansson, Doris Stöckl, Konstantin Strauch, Morris A. Swertz, Alexander Teumer, Guðmar Þorleifsson, Unnur Þorsteinsdóttir, Roy Thurik, Nicholas J. Timpson, Constance Turman, André G. Uitterlinden, Mélanie Waldenberger, Nicholas J. Wareham, Gonneke Willemsen, Jing Zhao, Tune H. Pers, Harold Snieder, John R. B. Perry, Ken K. Ong, Marcel den Hoed, Nicola Barban, Felix R. Day,

Ovarian function and disorders

Age at first sexual intercourse and age at first birth have implications for health and evolutionary fitness. In this genome-wide association study (age at first sexual intercourse, N = 387,338; age at first birth, N = 542,901), we identify 371 single-nucleotide polymorphisms, 11 sex-specific, with a 5–6% polygenic score prediction. Heritability of age at first birth shifted from 9% [CI = 4–14%] for women born in 1940 to 22% [CI = 19–25%] for those born in 1965. Signals are driven by the genetics of reproductive biology and externalising behaviour, with key genes related to follicle stimulating hormone (FSHB), implantation (ESR1), infertility and spermatid differentiation. Our findings suggest that polycystic ovarian syndrome may lead to later age at first birth, linking with infertility. Late age at first birth is associated with parental longevity and reduced incidence of type 2 diabetes and cardiovascular disease. Higher childhood socioeconomic circumstances and those in the highest polygenic score decile (90%+) experience markedly later reproductive onset. Results are relevant for improving teenage and late-life health, understanding longevity and guiding experimentation into mechanisms of infertility. This genome-wide study of age at first sexual intercourse and first birth identifies 371 signals driven by reproductive biology, externalising behaviour and environmental effects, with later onset associated with lower incidence of some diseases.