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

Author

Listed:
  • Iain Mathieson

    (University of Pennsylvania)

  • Felix R. Day

    (University of Cambridge)

  • Nicola Barban

    (Alma Mater Studiorum University of Bologna)

  • Felix C. Tropf

    (University of Oxford
    École Nationale de la Statistique et de L’administration Économique (ENSAE)
    Center for Research in Economics and Statistics (CREST))

  • David M. Brazel

    (University of Oxford
    University of Oxford)

  • Ahmad Vaez

    (University Medical Center Groningen
    Isfahan University of Medical Sciences)

  • Natalie Zuydam

    (Uppsala University and SciLifeLab)

  • Bárbara D. Bitarello

    (University of Pennsylvania)

  • Eugene J. Gardner

    (University of Cambridge)

  • Evelina T. Akimova

    (University of Oxford
    University of Oxford)

  • Ajuna Azad

    (University of Copenhagen)

  • Sven Bergmann

    (University of Lausanne
    Swiss Institute of Bioinformatics
    University of Cape Town)

  • Lawrence F. Bielak

    (University of Michigan)

  • Dorret I. Boomsma

    (Vrije Universiteit Amsterdam
    Amsterdam Reproduction and Development (AR&D) Research Institute)

  • Kristina Bosak

    (Psychiatric Hospital ‘Sveti Ivan’)

  • Marco Brumat

    (University of Trieste)

  • Julie E. Buring

    (Brigham and Women’s Hospital
    Harvard Medical School)

  • David Cesarini

    (New York University
    Research Institute for Industrial Economics
    National Bureau of Economic Research)

  • Daniel I. Chasman

    (Brigham and Women’s Hospital
    Harvard Medical School)

  • Jorge E. Chavarro

    (Harvard T.H. Chan School of Public Health
    Harvard T.H. Chan School of Public Health
    Brigham and Women’s Hospital and Harvard Medical School)

  • Massimiliano Cocca

    (IRCCS ‘Burlo Garofolo’)

  • Maria Pina Concas

    (IRCCS ‘Burlo Garofolo’)

  • George Davey Smith

    (University of Bristol)

  • Gail Davies

    (University of Edinburgh)

  • Ian J. Deary

    (University of Edinburgh)

  • Tõnu Esko

    (University of Tartu
    Broad Institute of the Massachusetts Institute of Technology and Harvard University)

  • Jessica D. Faul

    (University of Michigan)

  • Oscar Franco

    (University Medical Center Rotterdam
    Utrecht University)

  • Andrea Ganna

    (University of Helsinki
    Massachusetts General Hospital)

  • Audrey J. Gaskins

    (Emory University)

  • Andrea Gelemanovic

    (University of Split School of Medicine)

  • Eco J. C. Geus

    (Vrije Universiteit Amsterdam)

  • Christian Gieger

    (German Research Center for Environmental Health)

  • Giorgia Girotto

    (University of Trieste
    IRCCS ‘Burlo Garofolo’)

  • Bamini Gopinath

    (University of Sydney)

  • Hans Jörgen Grabe

    (University Medicine Greifswald)

  • Erica P. Gunderson

    (Kaiser Permanente Northern California)

  • Caroline Hayward

    (University of Edinburgh)

  • Chunyan He

    (University of Kentucky
    University of Kentucky College of Medicine)

  • Diana Heemst

    (Leiden University Medical Center)

  • W. David Hill

    (University of Edinburgh)

  • Eva R. Hoffmann

    (University of Copenhagen)

  • Georg Homuth

    (University of Greifswald)

  • Jouke Jan Hottenga

    (Vrije Universiteit Amsterdam)

  • Hongyang Huang

    (Harvard T.H. Chan School of Public Health)

  • Elina Hyppӧnen

    (University of South Australia Cancer Research Institute
    South Australian Health and Medical Research Institute)

  • M. Arfan Ikram

    (University Medical Center Rotterdam)

  • Rick Jansen

    (Vrije Universiteit)

  • Magnus Johannesson

    (Stockholm School of Economics)

  • Zoha Kamali

    (University Medical Center Groningen
    Isfahan University of Medical Sciences)

  • Sharon L. R. Kardia

    (University of Michigan)

  • Maryam Kavousi

    (University Medical Center Rotterdam)

  • Annette Kifley

    (University of Sydney)

  • Tuomo Kiiskinen

    (University of Helsinki
    National Institute for Health and Welfare)

  • Peter Kraft

    (Harvard T.H. Chan School of Public Health
    Harvard T.H. Chan School of Public Health)

  • Brigitte Kühnel

    (German Research Center for Environmental Health)

  • Claudia Langenberg

    (University of Cambridge)

  • Gerald Liew

    (University of Sydney)

  • Penelope A. Lind

    (QIMR Berghofer Medical Research Institute)

  • Jian’an Luan

    (University of Cambridge)

  • Reedik Mägi

    (University of Tartu)

  • Patrik K. E. Magnusson

    (Karolinska Institutet)

  • Anubha Mahajan

    (University of Oxford
    University of Oxford)

  • Nicholas G. Martin

    (QIMR Berghofer Medical Research Institute)

  • Hamdi Mbarek

    (Vrije Universiteit Amsterdam
    Qatar Foundation)

  • Mark I. McCarthy

    (University of Oxford
    University of Oxford)

  • George McMahon

    (University of Bristol)

  • Sarah E. Medland

    (QIMR Berghofer Medical Research Institute)

  • Thomas Meitinger

    (German Research Center for Environmental Health)

  • Andres Metspalu

    (University of Tartu
    University of Tartu)

  • Evelin Mihailov

    (University of Tartu)

  • Lili Milani

    (University of Tartu)

  • Stacey A. Missmer

    (Harvard T.H. Chan School of Public Health
    Boston Children’s Hospital and Harvard Medical School
    Michigan State University)

  • Paul Mitchell

    (University of Sydney)

  • Stine Møllegaard

    (University of Copenhagen)

  • Dennis O. Mook-Kanamori

    (Leiden University Medical Center
    Leiden University Medical Center)

  • Anna Morgan

    (IRCCS ‘Burlo Garofolo’)

  • Peter J. Most

    (University Medical Center Groningen)

  • Renée Mutsert

    (Leiden University Medical Center)

  • Matthias Nauck

    (University Medicine Greifswald)

  • Ilja M. Nolte

    (University Medical Center Groningen)

  • Raymond Noordam

    (Leiden University Medical Center)

  • Brenda W. J. H. Penninx

    (VU University Medical Center/GGZ inGeest)

  • Annette Peters

    (German Research Center for Environmental Health)

  • Patricia A. Peyser

    (University of Michigan)

  • Ozren Polašek

    (University of Split School of Medicine
    Algebra University College)

  • Chris Power

    (UCL Great Ormond Street Institute of Child Health)

  • Ajka Pribisalic

    (University of Split School of Medicine)

  • Paul Redmond

    (University of Edinburgh)

  • Janet W. Rich-Edwards

    (Harvard T.H. Chan School of Public Health
    Brigham and Women’s Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School)

  • Paul M. Ridker

    (Brigham and Women’s Hospital
    Harvard Medical School)

  • Cornelius A. Rietveld

    (Erasmus University Rotterdam Institute for Behavior and Biology
    Erasmus School of Economics)

  • Susan M. Ring

    (University of Bristol)

  • Lynda M. Rose

    (Brigham and Women’s Hospital)

  • Rico Rueedi

    (University of Lausanne
    Swiss Institute of Bioinformatics)

  • Vallari Shukla

    (University of Copenhagen)

  • Jennifer A. Smith

    (University of Michigan
    University of Michigan)

  • Stasa Stankovic

    (University of Cambridge)

  • Kári Stefánsson

    (deCODE Genetics/Amgen Inc.)

  • Doris Stöckl

    (German Research Center for Environmental Health)

  • Konstantin Strauch

    (Johannes Gutenberg University
    German Research Center for Environmental Health
    LMU)

  • Morris A. Swertz

    (University Medical Center Groningen)

  • Alexander Teumer

    (University Medicine Greifswald)

  • Gudmar Thorleifsson

    (deCODE Genetics/Amgen Inc.)

  • Unnur Thorsteinsdottir

    (deCODE Genetics/Amgen Inc.)

  • A. Roy Thurik

    (Erasmus University Rotterdam Institute for Behavior and Biology
    Erasmus School of Economics
    Montpellier Business School)

  • Nicholas J. Timpson

    (University of Bristol)

  • Constance Turman

    (Harvard T.H. Chan School of Public Health)

  • André G. Uitterlinden

    (Erasmus University Rotterdam Institute for Behavior and Biology
    University Medical Center Rotterdam)

  • Melanie Waldenberger

    (German Research Center for Environmental Health
    German Research Center for Environmental Health)

  • Nicholas J. Wareham

    (University of Cambridge)

  • David R. Weir

    (University of Michigan)

  • Gonneke Willemsen

    (Vrije Universiteit Amsterdam)

  • Jing Hau Zhao

    (University of Cambridge)

  • Wei Zhao

    (University of Michigan)

  • Yajie Zhao

    (University of Cambridge)

  • Harold Snieder

    (University Medical Center Groningen)

  • Marcel Hoed

    (Uppsala University and SciLifeLab)

  • Ken K. Ong

    (University of Cambridge)

  • Melinda C. Mills

    (University of Oxford
    University of Oxford
    University Medical Center Groningen
    University of Groningen)

  • John R. B. Perry

    (University of Cambridge)

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.

Suggested Citation

  • Iain Mathieson & Felix R. Day & Nicola Barban & Felix C. Tropf & David M. Brazel & Ahmad Vaez & Natalie Zuydam & Bárbara D. Bitarello & Eugene J. Gardner & Evelina T. Akimova & Ajuna Azad & Sven Bergm, 2023. "Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus," Nature Human Behaviour, Nature, vol. 7(5), pages 790-801, May.
    • Handle: RePEc:nat:nathum:v:7:y:2023:i:5:d:10.1038_s41562-023-01528-6
    DOI: 10.1038/s41562-023-01528-6
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    Cited by:

    1. Gemma L. Clayton & Maria Carolina Borges & Deborah A. Lawlor, 2024. "The impact of reproductive factors on the metabolic profile of females from menarche to menopause," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Aoxing Liu & Evelina T. Akimova & Xuejie Ding & Sakari Jukarainen & Pekka Vartiainen & Tuomo Kiiskinen & Sara Koskelainen & Aki S. Havulinna & Mika Gissler & Stefano Lombardi & Tove Fall & Melinda C. , 2024. "Evidence from Finland and Sweden on the relationship between early-life diseases and lifetime childlessness in men and women," Nature Human Behaviour, Nature, vol. 8(2), pages 276-287, February.

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