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Nat Genet. 2016 Dec;48(12):1462-1472. doi: 10.1038/ng.3698. Epub 2016 Oct 31.

Genome-wide analysis identifies 12 loci influencing human reproductive behavior.

Barban N1, Jansen R2, de Vlaming R3,4,5, Vaez A6,7, Mandemakers JJ8, Tropf FC1, Shen X9,10,11, Wilson JF10,11, Chasman DI12, Nolte IM6, Tragante V13, van der Laan SW14, Perry JR15, Kong A16,17; BIOS Consortium, Ahluwalia TS18,19,20, Albrecht E21, Yerges-Armstrong L22, Atzmon G23,24,25, Auro K26,27, Ayers K28, Bakshi A29, Ben-Avraham D24, Berger K30, Bergman A31, Bertram L32,33, Bielak LF34, Bjornsdottir G17, Bonder MJ35, Broer L36, Bui M37, Barbieri C38, Cavadino A39,40, Chavarro JE41,42,43, Turman C43, Concas MP44, Cordell HJ28, Davies G45,46, Eibich P47, Eriksson N48, Esko T49,50, Eriksson J51, Falahi F6, Felix JF4,52,53, Fontana MA54, Franke L35, Gandin I55, Gaskins AJ41, Gieger C56,57, Gunderson EP58, Guo X59, Hayward C10, He C60, Hofer E61,62, Huang H43, Joshi PK11, Kanoni S63, Karlsson R9, Kiechl S64, Kifley A65, Kluttig A66, Kraft P43,67, Lagou V68,69,70, Lecoeur C71, Lahti J72,73,74, Li-Gao R75, Lind PA76, Liu T77, Makalic E37, Mamasoula C28, Matteson L78, Mbarek H79,80, McArdle PF22, McMahon G81, Meddens SF5,82, Mihailov E49, Miller M83, Missmer SA43,84, Monnereau C4,52,53, van der Most PJ6, Myhre R85, Nalls MA86, Nutile T87, Kalafati IP88, Porcu E89,90, Prokopenko I91,92,93, Rajan KB94, Rich-Edwards J42,43,95, Rietveld CA3,4,5, Robino A96, Rose LM12, Rueedi R97,98, Ryan KA22, Saba Y99, Schmidt D37, Smith JA34, Stolk L36, Streeten E22, Tönjes A100, Thorleifsson G17, Ulivi S96, Wedenoja J101, Wellmann J30, Willeit P64,102,103, Yao J59, Yengo L71,104, Zhao JH15, Zhao W34, Zhernakova DV35, Amin N4, Andrews H105, Balkau B71, Barzilai N23, Bergmann S97,98, Biino G106, Bisgaard H20, Bønnelykke K20, Boomsma DI79,80, Buring JE12, Campbell H11, Cappellani S96, Ciullo M87,107, Cox SR45,46, Cucca F89,90, Toniolo D38, Davey-Smith G108, Deary IJ45,46, Dedoussis G88, Deloukas P63,109, van Duijn CM4, de Geus EJ79,80, Eriksson JG74,110,111,112,113, Evans DA94, Faul JD114, Sala CF38, Froguel P71, Gasparini P55,115, Girotto G55,115, Grabe HJ116, Greiser KH117, Groenen PJ5,118, de Haan HG75, Haerting J66, Harris TB119, Heath AC120, Heikkilä K27, Hofman A4,5,43, Homuth G121, Holliday EG122,123, Hopper J37, Hyppönen E39,124,125, Jacobsson B85,126, Jaddoe VW4,52,53, Johannesson M127, Jugessur A85, Kähönen M128, Kajantie E129,130,131, Kardia SL34, Keavney B28,132, Kolcic I133, Koponen P134, Kovacs P135, Kronenberg F136, Kutalik Z98,137, La Bianca M96, Lachance G138, Iacono WG83, Lai S89, Lehtimäki T139, Liewald DC45; LifeLines Cohort Study, Lindgren CM92,93,140,141, Liu Y142, Luben R141, Lucht M110, Luoto R143, Magnus P85, Magnusson PK9, Martin NG76, McGue M83,144, McQuillan R11, Medland SE76, Meisinger C57,145, Mellström D51, Metspalu A49,146, Traglia M38, Milani L49, Mitchell P65, Montgomery GW120,147, Mook-Kanamori D75,148,149, de Mutsert R75, Nohr EA150, Ohlsson C51, Olsen J151, Ong KK15, Paternoster L108, Pattie A46, Penninx BW2,80, Perola M26,27,49, Peyser PA34, Pirastu M44, Polasek O133, Power C39, Kaprio J26,27,101, Raffel LJ152, Räikkönen K72, Raitakari O153, Ridker PM12, Ring SM108, Roll K59, Rudan I11, Ruggiero D87, Rujescu D154, Salomaa V26, Schlessinger D155, Schmidt H99, Schmidt R61, Schupf N156, Smit J2,80, Sorice R87,107, Spector TD138, Starr JM45,157, Stöckl D156, Strauch K21,158, Stumvoll M100,135, Swertz MA35, Thorsteinsdottir U17,159, Thurik AR3,5,160, Timpson NJ108, Tung JY48, Uitterlinden AG3,5,36, Vaccargiu S44, Viikari J161, Vitart V10, Völzke H162, Vollenweider P163, Vuckovic D55,115, Waage J20, Wagner GG164, Wang JJ65, Wareham NJ15, Weir DR114, Willemsen G79,80, Willeit J64, Wright AF10, Zondervan KT165,166, Stefansson K17,159, Krueger RF83, Lee JJ83, Benjamin DJ54,167, Cesarini D168,169, Koellinger PD3,5,82, den Hoed M170, Snieder H6, Mills MC1.

Author information

1
Department of Sociology and Nuffield College, University of Oxford, Oxford, UK.
2
Department of Psychiatry, VU University Medical Center, Amsterdam, the Netherlands.
3
Department of Applied Economics, Erasmus School of Economics, Rotterdam, the Netherlands.
4
Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
5
Erasmus University Rotterdam Institute for Behavior and Biology, Rotterdam, the Netherlands.
6
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
7
Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran.
8
Sociology of Consumption and Households, Wageningen University Research, Wageningen, the Netherlands.
9
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
10
MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
11
Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
12
Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
13
Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands.
14
Laboratory of Experimental Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands.
15
MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
16
School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
17
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
18
Novo Nordisk Foundation Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
19
Steno Diabetes Center, Gentofte, Denmark.
20
COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
21
Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
22
Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland, USA.
23
Department of Medicine, Institute for Aging Research and the Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York, USA.
24
Department of Genetics, Institute for Aging Research and the Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York, USA.
25
Department of Natural Science, University of Haifa, Haifa, Israel.
26
Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
27
Institute for Molecular Medicine (FIMM), University of Helsinki, Helsinki, Finland.
28
Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK.
29
Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
30
Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.
31
Departments of Systems and Computational Biology, of Pathology and of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, USA.
32
Lübeck Interdisciplinary Platform for Genome Analytics, Institutes of Neurogenetics and of Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany.
33
School of Public Health, Faculty of Medicine, Imperial College, London, UK.
34
Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, USA.
35
Department of Genetics, Genomics Coordination Center, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
36
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
37
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.
38
Division of Genetics and Cell Biology, San Raffaele Research Institute, Milan, Italy.
39
Population, Policy and Practice, UCL Institute of Child Health, London, UK.
40
Centre for Environmental and Preventive Medicine, Wolfson Institute of Preventative Medicine, Queen Mary University of London, London, UK.
41
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
42
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
43
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
44
Institute of Genetic and Biomedical Research, National Research Council, UOS of Sassari, Sassari, Italy.
45
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
46
Department of Psychology, University of Edinburgh, Edinburgh, UK.
47
Health Economics Research Centre, University of Oxford, Oxford, UK.
48
23andMe, Inc., Mountain View, California, USA.
49
Estonian Genome Center, University of Tartu, Tartu, Estonia.
50
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
51
Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
52
Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
53
Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
54
Center for Economic and Social Research, University of Southern California, Los Angeles, California, USA.
55
Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.
56
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
57
Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
58
Cardiovascular and Metabolic Conditions Section, Division of Research, Kaiser Permanente Northern California, Oakland, California, USA.
59
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA.
60
Department of Epidemiology, Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, Indiana, USA.
61
Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Graz, Austria.
62
Institute of Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria.
63
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
64
Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
65
Centre for Vision Research, Department of Ophthalmology and Westmead Institute for Medical Research, University of Sydney, Westmead, New South Wales, Australia.
66
Institute of Medical Epidemiology, Biostatistics and Informatics, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
67
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
68
Department of Neurosciences, KU Leuven, Leuven, Belgium.
69
Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium.
70
Translational Immunology Laboratory, VIB, Leuven, Belgium.
71
University of Lille, CNRS, Institut Pasteur of Lille, Lille, France.
72
Institute of Behavioral Sciences, University of Helsinki, Helsinki, Finland.
73
Helsinki Collegium for Advanced Studies, University of Helsinki, Helsinki, Finland.
74
Folkhälsan Research Centre, Helsinki, Finland.
75
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
76
Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Herston Brisbane, Queensland, Australia.
77
Center for Lifespan Psychology, Max Planck Institute for Human Development and Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
78
Minnesota Center for Twin and Family Research, Department of Psychology, University of Minnesota, Minneapolis, Minnesota, USA.
79
Department of Biological Psychology, VU University, Amsterdam, the Netherlands.
80
EMGO+ Institute for Health and Care Research, Amsterdam, the Netherlands.
81
School of Social and Community Medicine, University of Bristol, Bristol, UK.
82
Complex Trait Genetics, VU University, Amsterdam, the Netherlands.
83
Department of Psychology, University of Minnesota, Minneapolis, Minnesota, USA.
84
Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
85
Department of Genetics and Bioinformatics, Area of Health Data and Digitalization, Institute of Public Health, Oslo, Norway.
86
Laboratory of Neurogenetics, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA.
87
Institute of Genetics and Biophysics 'A. Buzzati-Traverso', CNR, Naples, Italy.
88
Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece.
89
Istituto di Ricerca Genetica e Biomedica, CMR, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy.
90
Dipartimento di Scienze Biomediche, Università di Sassari, Sassari, Italy.
91
Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, UK.
92
Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
93
Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
94
Rush University Medical Center, Chicago, Illinois, USA.
95
Connors Center for Women's Health and Gender Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
96
Institute for Maternal and Child Health, IRCCS 'Burlo Garofolo', Trieste, Italy.
97
Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
98
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
99
Institute of Molecular Biology and Biochemistry, Centre for Molecular Medicine, Medical University of Graz, Graz, Austria.
100
Department of Medicine, University of Leipzig, Leipzig, Germany.
101
Department of Public Health, University of Helsinki, Helsinki, Finland.
102
King's British Heart Foundation Centre, King's College London, London, UK.
103
Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
104
Centre for Neurogenetics and Statistical Genomics, University of Queensland, Brisbane, Queensland, Australia.
105
Data Coordinating Center, New York State Psychiatric Institute, New York, New York, USA.
106
Institute of Molecular Genetics, National Research Council of Italy, Pavia, Italy.
107
IRCCS Neuromed, Pozzilli, Isernia, Italy.
108
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
109
Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.
110
Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
111
Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland.
112
Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland.
113
Vasa Central Hospital, Vasa, Finland.
114
Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, Michigan, USA.
115
Division of Experimental Genetics, Sidra, Doha, Qatar.
116
Department of Psychiatry, University Medicine Greifswald, Greifswald, Germany.
117
Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
118
Econometric Institute, Erasmus School of Economics, Erasmus University Rotterdam, Rotterdam, the Netherlands.
119
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, Maryland, USA.
120
Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
121
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
122
School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia.
123
Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
124
Centre for Population Health Research, Sansom Institute of Health Research and School of Health Sciences, University of South Australia, Adelaide, South Australia, Australia.
125
South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
126
Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
127
Department of Economics, Stockholm School of Economics, Stockholm, Sweden.
128
Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland.
129
Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland.
130
Children's Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
131
Department of Obstetrics and Gynecology, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
132
Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK.
133
Department of Public Health, Faculty of Medicine, University of Split, Split, Croatia.
134
Health Monitoring Unit, National Institute for Health and Welfare, Helsinki, Finland.
135
IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany.
136
Division of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria.
137
Institute of Social and Preventive Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
138
Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
139
Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine, University of Tampere, Tampere, Finland.
140
NIHR Oxford Biomedical Research Centre, Oxford, UK.
141
Strangeways Research Laboratory, University of Cambridge, Cambridge, UK.
142
Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
143
UKK Institute for Health Promotion,Tampere, Finland.
144
Danish Aging Research Center and Danish Twin Registry, Institute of Public Health, University of Southern Denmark, Odense, Denmark.
145
MONICA/KORA Myocardial Infarction Registry, Central Hospital of Augsburg, Augsburg, Germany.
146
Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
147
Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
148
Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands.
149
Department of BESC, Epidemiology Section, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
150
Research Unit for Gynecology and Obstetrics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
151
Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark.
152
Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
153
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku and Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
154
Department of Psychiatry, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
155
Laboratory of Genetics, National Institute on Aging, Baltimore, Maryland, USA.
156
Departments of Epidemiology and Psychiatry, Columbia University Medical Center, New York, New York, USA.
157
Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.
158
Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig Maximilians Universität, Munich, Germany.
159
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
160
Montpellier Business School, Montpellier, France.
161
Department of Medicine, University of Turku and Division of Medicine, Turku University Hospital, Turku, Finland.
162
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
163
Department of Internal Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
164
German Socio-Economic Panel Study (SOEP), Max Planck Institute for Human Development and Berlin University of Technology (TUB), Berlin, Germany.
165
Genetic and Genomic Epidemiology Unit, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
166
Endometriosis CaRe Centre, Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford, UK.
167
National Bureau of Economic Research, Cambridge, Massachusetts, USA.
168
Department of Economics, New York University, New York, New York, USA.
169
Research Institute for Industrial Economics, Stockholm, Sweden.
170
Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

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.

PMID:
27798627
PMCID:
PMC5695684
DOI:
10.1038/ng.3698
[Indexed for MEDLINE]
Free PMC Article

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