Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
36864135
TITLE
Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus.
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 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.
© 2023. The Author(s), under exclusive licence to Springer Nature Limited.
DATE PUBLISHED
2023 Mar 02
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2021/06/30
accepted 2023/01/12
entrez 2023/03/02 23:20
pubmed 2023/03/03 06:00
medline 2023/03/03 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Mathieson I Mathieson Iain I Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. mathi@pennmedicine.upenn.edu.
Day FR Day Felix R FR MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Barban N Barban Nicola N Alma Mater Studiorum University of Bologna, Bologna, Italy.
Tropf FC Tropf Felix C FC Center for Research in Economics and Statistics (CREST), Paris, France.
Brazel DM Brazel David M DM Leverhulme Centre for Demographic Science, University of Oxford, Oxford, UK.
eQTLGen Consortium
BIOS Consortium
Vaez A Vaez Ahmad A Department of Bioinformatics, Isfahan University of Medical Sciences, Isfahan, Iran.
van Zuydam N van Zuydam Natalie N Beijer Laboratory and Department of Immunology, Genetics and Pathology, Uppsala University and SciLifeLab, Uppsala, Sweden.
Bitarello BD Bitarello Bárbara D BD Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Gardner EJ Gardner Eugene J EJ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Akimova ET Akimova Evelina T ET Leverhulme Centre for Demographic Science, University of Oxford, Oxford, UK.
Azad A Azad Ajuna A DNRF Center for Chromosome Stability, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Bergmann S Bergmann Sven S Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa.
Bielak LF Bielak Lawrence F LF Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
Boomsma DI Boomsma Dorret I DI Amsterdam Reproduction and Development (AR&D) Research Institute, Amsterdam, the Netherlands.
Bosak K Bosak Kristina K Psychiatric Hospital 'Sveti Ivan', Zagreb, Croatia.
Brumat M Brumat Marco M Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.
Buring JE Buring Julie E JE Harvard Medical School, Boston, MA, USA.
Cesarini D Cesarini David D National Bureau of Economic Research, Cambridge, MA, USA.
Chasman DI Chasman Daniel I DI Harvard Medical School, Boston, MA, USA.
Chavarro JE Chavarro Jorge E JE Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Cocca M Cocca Massimiliano M Institute for Maternal and Child Health, IRCCS 'Burlo Garofolo', Trieste, Italy.
Concas MP Concas Maria Pina MP Institute for Maternal and Child Health, IRCCS 'Burlo Garofolo', Trieste, Italy.
Davey Smith G Davey Smith George G MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
Davies G Davies Gail G Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, Edinburgh, UK.
Deary IJ Deary Ian J IJ Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, Edinburgh, UK.
Esko T Esko Tõnu T Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA.
Faul JD Faul Jessica D JD Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
FinnGen Study
Franco O Franco Oscar O Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
Ganna A Ganna Andrea A Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Gaskins AJ Gaskins Audrey J AJ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
Gelemanovic A Gelemanovic Andrea A University of Split School of Medicine, Split, Croatia.
de Geus EJC de Geus Eco J C EJC Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
Gieger C Gieger Christian C Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Girotto G Girotto Giorgia G Institute for Maternal and Child Health, IRCCS 'Burlo Garofolo', Trieste, Italy.
Gopinath B Gopinath Bamini B Centre for Vision Research, Westmead Institute for Medical Research and Department of Ophthalmology, University of Sydney, Sydney, New South Wales, Australia.
Grabe HJ Grabe Hans Jörgen HJ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
Gunderson EP Gunderson Erica P EP Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
Hayward C Hayward Caroline C Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
He C He Chunyan C Department of Internal Medicine, Division of Medical Oncology, University of Kentucky College of Medicine, Lexington, KY, USA.
van Heemst D van Heemst Diana D Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
Hill WD Hill W David WD Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, Edinburgh, UK.
Hoffmann ER Hoffmann Eva R ER DNRF Center for Chromosome Stability, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Homuth G Homuth Georg G Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany.
Hottenga JJ Hottenga Jouke Jan JJ Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
Huang H Huang Hongyang H Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Hyppӧnen E Hyppӧnen Elina E South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
Ikram MA Ikram M Arfan MA Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
Jansen R Jansen Rick R Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit, Amsterdam, the Netherlands.
Johannesson M Johannesson Magnus M Department of Economics, Stockholm School of Economics, Stockholm, Sweden.
Kamali Z Kamali Zoha Z Department of Bioinformatics, Isfahan University of Medical Sciences, Isfahan, Iran.
Kardia SLR Kardia Sharon L R SLR Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
Kavousi M Kavousi Maryam M Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
Kifley A Kifley Annette A Centre for Vision Research, Westmead Institute for Medical Research and Department of Ophthalmology, University of Sydney, Sydney, New South Wales, Australia.
Kiiskinen T Kiiskinen Tuomo T National Institute for Health and Welfare, Helsinki, Finland.
Kraft P Kraft Peter P Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Kühnel B Kühnel Brigitte B Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Langenberg C Langenberg Claudia C MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Liew G Liew Gerald G Centre for Vision Research, Westmead Institute for Medical Research and Department of Ophthalmology, University of Sydney, Sydney, New South Wales, Australia.
Lifelines Cohort Study
Lind PA Lind Penelope A PA Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Luan J Luan Jian'an J MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Mägi R Mägi Reedik R Estonian Genome Center, University of Tartu, Tartu, Estonia.
Magnusson PKE Magnusson Patrik K E PKE Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Mahajan A Mahajan Anubha A Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Martin NG Martin Nicholas G NG Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Mbarek H Mbarek Hamdi H Qatar Genome Programme, Qatar Foundation Research, Development and Innovation, Qatar Foundation, Doha, Qatar.
McCarthy MI McCarthy Mark I MI Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
McMahon G McMahon George G School of Social and Community Medicine, University of Bristol, Bristol, UK.
Medland SE Medland Sarah E SE Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Meitinger T Meitinger Thomas T Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Metspalu A Metspalu Andres A Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
Mihailov E Mihailov Evelin E Estonian Genome Center, University of Tartu, Tartu, Estonia.
Milani L Milani Lili L Estonian Genome Center, University of Tartu, Tartu, Estonia.
Missmer SA Missmer Stacey A SA Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA.
Mitchell P Mitchell Paul P Centre for Vision Research, Westmead Institute for Medical Research and Department of Ophthalmology, University of Sydney, Sydney, New South Wales, Australia.
Møllegaard S Møllegaard Stine S Department of Sociology, University of Copenhagen, Copenhagen, Denmark.
Mook-Kanamori DO Mook-Kanamori Dennis O DO Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands.
Morgan A Morgan Anna A Institute for Maternal and Child Health, IRCCS 'Burlo Garofolo', Trieste, Italy.
van der Most PJ van der Most Peter J PJ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
de Mutsert R de Mutsert Renée R Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
Nauck M Nauck Matthias M Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
Nolte IM Nolte Ilja M IM Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Noordam R Noordam Raymond R Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
Penninx BWJH Penninx Brenda W J H BWJH Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest, Amsterdam, the Netherlands.
Peters A Peters Annette A Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Peyser PA Peyser Patricia A PA Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
Polašek O Polašek Ozren O Algebra University College, Zagreb, Croatia.
Power C Power Chris C Population, Policy and Practice Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK.
Pribisalic A Pribisalic Ajka A University of Split School of Medicine, Split, Croatia.
Redmond P Redmond Paul P Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, Edinburgh, UK.
Rich-Edwards JW Rich-Edwards Janet W JW Division of Women's Health, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Ridker PM Ridker Paul M PM Harvard Medical School, Boston, MA, USA.
Rietveld CA Rietveld Cornelius A CA Department of Applied Economics, Erasmus School of Economics, Rotterdam, the Netherlands.
Ring SM Ring Susan M SM MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
Rose LM Rose Lynda M LM Brigham and Women's Hospital, Boston, MA, USA.
Rueedi R Rueedi Rico R Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Shukla V Shukla Vallari V DNRF Center for Chromosome Stability, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Smith JA Smith Jennifer A JA Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
Stankovic S Stankovic Stasa S MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Stefánsson K Stefánsson Kári K deCODE Genetics/Amgen Inc., Reykjavik, Iceland.
Stöckl D Stöckl Doris D Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Strauch K Strauch Konstantin K Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU, Munich, Germany.
Swertz MA Swertz Morris A MA Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Teumer A Teumer Alexander A Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
Thorleifsson G Thorleifsson Gudmar G deCODE Genetics/Amgen Inc., Reykjavik, Iceland.
Thorsteinsdottir U Thorsteinsdottir Unnur U deCODE Genetics/Amgen Inc., Reykjavik, Iceland.
Thurik AR Thurik A Roy AR Montpellier Business School, Montpellier, France.
Timpson NJ Timpson Nicholas J NJ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
Turman C Turman Constance C Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Uitterlinden AG Uitterlinden André G AG Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
Waldenberger M Waldenberger Melanie M Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Wareham NJ Wareham Nicholas J NJ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Weir DR Weir David R DR Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
Willemsen G Willemsen Gonneke G Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
Zhao JH Zhao Jing Hau JH MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Zhao W Zhao Wei W Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
Zhao Y Zhao Yajie Y MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Snieder H Snieder Harold H Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
den Hoed M den Hoed Marcel M Beijer Laboratory and Department of Immunology, Genetics and Pathology, Uppsala University and SciLifeLab, Uppsala, Sweden.
Ong KK Ong Ken K KK MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Mills MC Mills Melinda C MC Department of Economics, Econometrics and Finance, University of Groningen, Groningen, the Netherlands. melinda.mills@nuffield.ox.ac.uk.
Perry JRB Perry John R B JRB MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK. john.perry@mrc-epid.cam.ac.uk.
INVESTIGATORS
LASTNAME FORENAME INITIALS AFFILIATION
van Heemst Diana D
van der Most Peter J PJ
JOURNAL
VOLUME:
ISSUE:
TITLE: Nature human behaviour
ISOABBREVIATION: Nat Hum Behav
YEAR: 2023
MONTH: Mar
DAY: 02
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 2397-3374
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Nat Hum Behav
COUNTRY: England
ISSNLINKING: 2397-3374
NLMUNIQUEID: 101697750
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Journal Article
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