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Genome-wide analysis identifies 12 loci influencing human reproductive behavior

Abstract

The genetic architecture of human reproductive behavior—age at first birth (AFB) and number of children ever born (NEB)—has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.

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Figure 1: Manhattan plots of SNPs for age at first birth and number of children ever born in single-genomic-control meta-analysis.
Figure 2: Quantile–quantile plots.
Figure 3: Genetic overlap between AFB or NEB and other related traits.

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Acknowledgements

For full acknowledgments, see the Supplementary Note. Funding to lead this consortium was provided by grants awarded to M.C.M.: ERC Consolidator Grant SOCIOGENOME (615603), a Dutch Science Foundation (NWO) grant (VIDI grant 452-10-012), a UK ESRC/NCRM SOCGEN grant (ES/N011856/1), the European Union's FP7 Families And Societies project (320116), and the Wellcome Trust ISSF and John Fell Fund. M.d.H. was supported by grants from the Swedish Research Council (2015-03657) and the Swedish Heart-Lung Foundation (20140543). Research was carried out in collaboration with the Social Science Genetic Association Consortium (SSGAC), with funding from the US National Science Foundation (EAGER: 'Workshop for the Formation of a Social Science Genetic Association Consortium'), a Supplementary grant from the National Institutes of Health Office of Behavioral and Social Science Research, the Ragnar Söderberg Foundation (E9/11), the Swedish Research Council (421-2013-1061), the Jan Wallander and Tom Hedelius Foundation, an ERC Consolidator Grant (647648 EdGe), the Pershing Square Fund of the Foundations of Human Behavior and the NIA/NIH through grants P01-AG005842, P01-AG005842-20S2, P30-AG012810 and T32-AG000186-23 to NBER and R01-AG042568-02 to the University of Southern California. X.S. was supported by a grant from the Swedish Research Council (537-2014-371). We thank X. Ding for research assistance, N. Pirastu, K. Coward and L. Layman for valuable comments, and the University of Oxford Advanced Research Computing (ARC) facility (http://dx.doi.org/10.5281/zenodo.22558). This research has been conducted using the UK Biobank Resource.

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Senior investigators who led writing, analysis and study design: M.C.M., H. Snieder and M.d.H. Senior investigators who participated in study design: P.D.K., D.J.B. and D.C. Junior investigator who contributed to the study design and management: N. Barban. Population stratification: N. Barban and F.C.T. Genetic correlations and polygenic score prediction: N. Barban. Meta-analysis and quality control: N. Barban, R.d.V., J.J.M. and I.M.N. Biological annotation: R.J., M.d.H. and A.V. Sex-specific genetic effects: N. Barban and F.C.T. Bivariate and conditional analysis of the two fertility traits: X.S., J.F.W. and D.I.C. Gene-based analysis V.T. and S.W.v.d.L. Authors not listed contributed to recruitment, genotyping or data processing for the meta-analysis (Supplementary Table 43).

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Correspondence to Nicola Barban, Marcel den Hoed, Harold Snieder or Melinda C Mills.

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A list of members and affiliations appears in the Supplementary Note.

A list of members and affiliations appears in the Supplementary Note.

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Barban, N., Jansen, R., de Vlaming, R. et al. Genome-wide analysis identifies 12 loci influencing human reproductive behavior. Nat Genet 48, 1462–1472 (2016). https://doi.org/10.1038/ng.3698

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