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

Mathieson, Iain; Day, Felix R; Barban, Nicola; Tropf, Felix C; Brazel, David M; Vaez, Ahmad; van Zuydam, Natalie; Bitarello, Bárbara D; Gardner, Eugene J; Akimova, Evelina T; Azad, Ajuna; Bergmann, Sven; Bielak, Lawrence F; Boomsma, Dorret I; Bosak, Kristina; Brumat, Marco; Buring, Julie E; Cesarini, David; Chasman, Daniel I; Chavarro, Jorge E; Cocca, Massimiliano; Concas, Maria Pina; Davey Smith, George; Davies, Gail; Deary, Ian J; Esko, Tõnu; Faul, Jessica D; Franco, Oscar; Ganna, Andrea; Gaskins, Audrey J; Gelemanovic, Andrea; de Geus, Eco J C; Gieger, Christian; Girotto, Giorgia; Gopinath, Bamini; Grabe, Hans Jörgen; Gunderson, Erica P; Hayward, Caroline; Chunyan, He; van Heemst, Diana; Hill, W David; Hoffmann, Eva R; Homuth, Georg; Hottenga, Jouke Jan; Huang, Hongyang; Hyppӧnen, Elina; Ikram, M Arfan; Jansen, Rick; Johannesson, Magnus; Kamali, Zoha; Kardia, Sharon L R; Kavousi, Maryam; Kifley, Annette; Kiiskinen, Tuomo; Kraft, Peter; Kühnel, Brigitte; Langenberg, Claudia; Liew, Gerald; Lind, Penelope A; Luan, Jian'An; Mägi, Reedik; Magnusson, Patrik K E; Mahajan, Anubha; Martin, Nicholas G; Mbarek, Hamdi; Mccarthy, Mark I; Mcmahon, George; Medland, Sarah E; Meitinger, Thomas; Metspalu, Andres; Mihailov, Evelin; Milani, Lili; Missmer, Stacey A; Mitchell, Paul; Møllegaard, Stine; Mook-Kanamori, Dennis O; Morgan, Anna; van der Most, Peter J; de Mutsert, Renée; Nauck, Matthias; Nolte, Ilja M; Noordam, Raymond; Penninx, Brenda W J H; Peters, Annette; Peyser, Patricia A; Polašek, Ozren; Power, Chris; Pribisalic, Ajka; Redmond, Paul; Rich-Edwards, Janet W; Ridker, Paul M; Rietveld, Cornelius A; Ring, Susan M; Rose, Lynda M; Rueedi, Rico; Shukla, Vallari; Smith, Jennifer A; Stankovic, Stasa; Stefánsson, Kári; Stöckl, Doris; Strauch, Konstantin; Swertz, Morris A; Teumer, Alexander; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Thurik, A Roy; Timpson, Nicholas J; Turman, Constance; Uitterlinden, André G; Waldenberger, Melanie; Wareham, Nicholas J; Weir, David R; Willemsen, Gonneke; Zhao, Jing Hau; Zhao, Wei; Zhao, Yajie; Snieder, Harold; den Hoed, Marcel; Ong, Ken K; Mills, Melinda C; Perry, John R B

doi:10.1038/s41562-023-01528-6

: 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.

Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus / Mathieson, Iain; Day, Felix R; Barban, Nicola; Tropf, Felix C; Brazel, David M; Vaez, Ahmad; van Zuydam, Natalie; Bitarello, Bárbara D; Gardner, Eugene J; Akimova, Evelina T; Azad, Ajuna; Bergmann, Sven; Bielak, Lawrence F; Boomsma, Dorret I; Bosak, Kristina; Brumat, Marco; Buring, Julie E; Cesarini, David; Chasman, Daniel I; Chavarro, Jorge E; Cocca, Massimiliano; Concas, Maria Pina; Davey Smith, George; Davies, Gail; Deary, Ian J; Esko, Tõnu; Faul, Jessica D; Franco, Oscar; Ganna, Andrea; Gaskins, Audrey J; Gelemanovic, Andrea; de Geus, Eco J C; Gieger, Christian; Girotto, Giorgia; Gopinath, Bamini; Grabe, Hans Jörgen; Gunderson, Erica P; Hayward, Caroline; He, Chunyan; van Heemst, Diana; Hill, W David; Hoffmann, Eva R; Homuth, Georg; Hottenga, Jouke Jan; Huang, Hongyang; Hyppӧnen, Elina; Ikram, M Arfan; Jansen, Rick; Johannesson, Magnus; Kamali, Zoha; Kardia, Sharon L R; Kavousi, Maryam; Kifley, Annette; Kiiskinen, Tuomo; Kraft, Peter; Kühnel, Brigitte; Langenberg, Claudia; Liew, Gerald; Lind, Penelope A; Luan, Jian'an; Mägi, Reedik; Magnusson, Patrik K E; Mahajan, Anubha; Martin, Nicholas G; Mbarek, Hamdi; McCarthy, Mark I; McMahon, George; Medland, Sarah E; Meitinger, Thomas; Metspalu, Andres; Mihailov, Evelin; Milani, Lili; Missmer, Stacey A; Mitchell, Paul; Møllegaard, Stine; Mook-Kanamori, Dennis O; Morgan, Anna; van der Most, Peter J; de Mutsert, Renée; Nauck, Matthias; Nolte, Ilja M; Noordam, Raymond; Penninx, Brenda W J H; Peters, Annette; Peyser, Patricia A; Polašek, Ozren; Power, Chris; Pribisalic, Ajka; Redmond, Paul; Rich-Edwards, Janet W; Ridker, Paul M; Rietveld, Cornelius A; Ring, Susan M; Rose, Lynda M; Rueedi, Rico; Shukla, Vallari; Smith, Jennifer A; Stankovic, Stasa; Stefánsson, Kári; Stöckl, Doris; Strauch, Konstantin; Swertz, Morris A; Teumer, Alexander; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Thurik, A Roy; Timpson, Nicholas J; Turman, Constance; Uitterlinden, André G; Waldenberger, Melanie; Wareham, Nicholas J; Weir, David R; Willemsen, Gonneke; Zhao, Jing Hau; Zhao, Wei; Zhao, Yajie; Snieder, Harold; den Hoed, Marcel; Ong, Ken K; Mills, Melinda C; Perry, John R B. - In: NATURE HUMAN BEHAVIOUR. - ISSN 2397-3374. - STAMPA. - 7:(2023), pp. 790-801. [10.1038/s41562-023-01528-6]