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

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 Bergmann, Lawrence F. Bielak, Dorret I. Boomsma, Kristina Bosak, Marco Brumat, Julie E. Buring, David Cesarini, Daniel I. Chasman, Jorge E. Chavarro, Massimiliano Cocca, Maria Pina Concas, George Davey Smith, Gail Davies, Ian J. Deary, Tõnu Esko, Jessica D. Faul, Oscar Franco, Andrea Ganna, Audrey J. Gaskins, Andrea Gelemanovic, Eco J. C. Geus, Christian Gieger, Giorgia Girotto, Bamini Gopinath, Hans Jörgen Grabe, Erica P. Gunderson, Caroline Hayward, Chunyan He, Diana Heemst, W. David Hill, Eva R. Hoffmann, Georg Homuth, Jouke Jan Hottenga, Hongyang Huang, Elina Hyppӧnen, M. Arfan Ikram, Rick Jansen, Magnus Johannesson, Zoha Kamali, Sharon L. R. Kardia, Maryam Kavousi, Annette Kifley, Tuomo Kiiskinen, Peter Kraft, Brigitte Kühnel, Claudia Langenberg, Gerald Liew, Penelope A. Lind, Jian’an Luan, Reedik Mägi, Patrik K. E. Magnusson, Anubha Mahajan, Nicholas G. Martin, Hamdi Mbarek, Mark I. McCarthy, George McMahon, Sarah E. Medland, Thomas Meitinger, Andres Metspalu, Evelin Mihailov, Lili Milani, Stacey A. Missmer, Paul Mitchell, Stine Møllegaard, Dennis O. Mook-Kanamori, Anna Morgan, Peter J. Most, Renée Mutsert, Matthias Nauck, Ilja M. Nolte, Raymond Noordam, Brenda W. J. H. Penninx, Annette Peters, Patricia A. Peyser, Ozren Polašek, Chris Power, Ajka Pribisalic, Paul Redmond, Janet W. Rich-Edwards, Paul M. Ridker, Cornelius A. Rietveld, Susan M. Ring, Lynda M. Rose, Rico Rueedi, Vallari Shukla, Jennifer A. Smith, Stasa Stankovic, Kári Stefánsson, Doris Stöckl, Konstantin Strauch, Morris A. Swertz, Alexander Teumer, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Roy Thurik, Nicholas J. Timpson, Constance Turman, André G. Uitterlinden, Melanie Waldenberger, Nicholas J. Wareham, David R. Weir, Gonneke Willemsen, Jing Hau Zhao, Wei Zhao, Yajie Zhao, Harold Snieder, Marcel Hoed, Ken K. Ong, Melinda C. Mills () and John R. B. Perry ()
Additional contact information
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
David M. Brazel: University of Oxford
Ahmad Vaez: University Medical Center Groningen
Natalie Zuydam: Uppsala University and SciLifeLab
Bárbara D. Bitarello: University of Pennsylvania
Eugene J. Gardner: University of Cambridge
Evelina T. Akimova: University of Oxford
Ajuna Azad: University of Copenhagen
Sven Bergmann: University of Lausanne
Lawrence F. Bielak: University of Michigan
Dorret I. Boomsma: Vrije Universiteit Amsterdam
Kristina Bosak: Psychiatric Hospital ‘Sveti Ivan’
Marco Brumat: University of Trieste
Julie E. Buring: Brigham and Women’s Hospital
Daniel I. Chasman: Brigham and Women’s Hospital
Jorge E. Chavarro: Harvard T.H. Chan School of Public Health
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
Jessica D. Faul: University of Michigan
Oscar Franco: University Medical Center Rotterdam
Andrea Ganna: University of Helsinki
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
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
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
M. Arfan Ikram: University Medical Center Rotterdam
Rick Jansen: Vrije Universiteit
Zoha Kamali: University Medical Center Groningen
Sharon L. R. Kardia: University of Michigan
Maryam Kavousi: University Medical Center Rotterdam
Annette Kifley: University of Sydney
Tuomo Kiiskinen: University of Helsinki
Peter Kraft: 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
Nicholas G. Martin: QIMR Berghofer Medical Research Institute
Hamdi Mbarek: Vrije Universiteit Amsterdam
Mark I. McCarthy: 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
Evelin Mihailov: University of Tartu
Lili Milani: University of Tartu
Stacey A. Missmer: Harvard T.H. Chan School of Public Health
Paul Mitchell: University of Sydney
Stine Møllegaard: University of Copenhagen
Dennis O. Mook-Kanamori: 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
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
Paul M. Ridker: Brigham and Women’s Hospital
Cornelius A. Rietveld: Erasmus University Rotterdam Institute for Behavior and Biology
Susan M. Ring: University of Bristol
Lynda M. Rose: Brigham and Women’s Hospital
Rico Rueedi: University of Lausanne
Vallari Shukla: University of Copenhagen
Jennifer A. Smith: 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
Morris A. Swertz: University Medical Center Groningen
Alexander Teumer: University Medicine Greifswald
Gudmar Thorleifsson: deCODE Genetics/Amgen Inc.
Unnur Thorsteinsdottir: deCODE Genetics/Amgen Inc.
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
Melanie Waldenberger: 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
John R. B. Perry: University of Cambridge

Nature Human Behaviour, 2023, vol. 7, issue 5, 790-801

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41562-023-01528-6

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