Abstract

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 selec...

Authors	Mathieson, I; Day, FR; Barban, N; Tropf, FC; Brazel, DM; eQTLGen Consortium; BIOS Consortium; Vaez, A; van Zuydam, N; Bitarello, BD; Gardner, EJ; Akimova, ET; Azad, A; Bergmann, S; Bielak, LF; Boomsma, DI; Bosak, K; Brumat, M; Buring, JE; Cesarini, D; Chasman, DI; Chavarro, JE; Cocca, M; Concas, MP; Davey Smith, G; Davies, G; Deary, IJ; Esko, T; Faul, JD; FinnGen Study; Franco, O; Ganna, A; Gaskins, AJ; Gelemanovic, A; de Geus, EJC; Gieger, C; Girotto, G; Gopinath, B; Grabe, HJ; Gunderson, EP; Hayward, C; He, C; van Heemst, D; Hill, WD; Hoffmann, ER; Homuth, G; Hottenga, JJ; Huang, H; Hypp?nen, E; Ikram, MA; Jansen, R; Johannesson, M; Kamali, Z; Kardia, SLR; Kavousi, M; Kifley, A; Kiiskinen, T; Kraft, P; Kühnel, B; Langenberg, C; Liew, G; Lifelines Cohort Study; Lind, PA; Luan, J; Mägi, R; Magnusson, PKE; Mahajan, A; Martin, NG; Mbarek, H; McCarthy, MI; McMahon, G; Medland, SE; Meitinger, T; Metspalu, A; Mihailov, E; Milani, L; Missmer, SA; Mitchell, P; Møllegaard, S; Mook-Kanamori, DO; Morgan, A; van der Most, PJ; de Mutsert, R; Nauck, M; Nolte, IM; Noordam, R; Penninx, BWJH; Peters, A; Peyser, PA; Polašek, O; Power, C; Pribisalic, A; Redmond, P; Rich-Edwards, JW; Ridker, PM; Rietveld, CA; Ring, SM; Rose, LM; Rueedi, R; Shukla, V; Smith, JA; Stankovic, S; Stefánsson, K; Stöckl, D; Strauch, K; Swertz, MA; Teumer, A; Thorleifsson, G; Thorsteinsdottir, U; Thurik, AR; Timpson, NJ; Turman, C; Uitterlinden, AG; Waldenberger, M; Wareham, NJ; Weir, DR; Willemsen, G; Zhao, JH; Zhao, W; Zhao, Y; Snieder, H; den Hoed, M; Ong, KK; Mills, MC; Perry, JRB
Journal	NATURE HUMAN BEHAVIOUR
Pages	790-801
Volume	7
Date	2/04/2023
Grant ID	MC_UU_00006/2 | Medical Research Council [MRC_] (United Kingdom); MC_UU_00006/1 | Medical Research Council [MRC_] (United Kingdom); MC_UU_00032/1 | Medical Research Council [MRC_] (United Kingdom); MR/T030852/1 | Medical Research Council [MRC_] (United Kingdom); MC_UU_12015/1 | Medical Research Council [MRC_] (United Kingdom); MC_UU_00011/1 | Medical Research Council [MRC_] (United Kingdom); MC_PC_15018 | Medical Research Council [MRC_] (United Kingdom); G9815508 | Medical Research Council [MRC_] (United Kingdom); MC_UU_12015/2 | Medical Research Council [MRC_] (United Kingdom)
Funding Body
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1038/s41562-023-01528-6