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

Iain Mathieson; Felix R. Day; Nicola Barban; Dorret I. Boomsma; Eco J.C. de Geus; Jouke Jan Hottenga; Rick Jansen; Hamdi Mbarek; Brenda W.J.H. Penninx; Gonneke Willemsen; Harold Snieder; Marcel den Hoed; Ken K. Ong; Melinda C. Mills; John R.B. Perry; eQTLGen Consortium; BIOS Consortium; FinnGen Study; LifeLines Cohort Study

doi:10.1038/s41562-023-01528-6

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

Iain Mathieson^*, Felix R. Day, Nicola Barban, Dorret I. Boomsma, Eco J.C. de Geus, Jouke Jan Hottenga, Rick Jansen, Hamdi Mbarek, Brenda W.J.H. Penninx, Gonneke Willemsen, Harold Snieder, Marcel den Hoed, Ken K. Ong, Melinda C. Mills^*, John R.B. Perry^*, eQTLGen Consortium, BIOS Consortium, FinnGen Study, LifeLines Cohort Study

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

25 Downloads (Pure)

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.

Original language	English
Pages (from-to)	790-801
Number of pages	12
Journal	Nature Human Behaviour
Volume	7
Issue number	5
Early online date	2 Mar 2023
DOIs	https://doi.org/10.1038/s41562-023-01528-6
Publication status	Published - May 2023

Bibliographical note

Funding Information:
This research was conducted using the UK Biobank Resource under application no. 9905. This work was supported by the Medical Research Council (Unit Programme numbers MC_UU_12015/2 and MC_UU_00006/2); ERC grant nos 615603, 835079 and 865356; ESRC ES/N011856/1; the Leverhulme Trust; the Leverhulme Centre for Demographic Science; and LabEx Ecodec ANR grant no. ANR-11-LABX-0047. Full study-specific and individual acknowledgements can be found in the . The content is solely the responsibility of the authors and does not necessarily represent the official views of any of the funders. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. This study received ethical approval from the Department of Sociology, University of Oxford 2014/01/01/R3, 28 January 2014 (SOCIOGENOME) and revised with extension SOC/R2/001/C1A/21/60 7 July 2022 (CHRONO), and relevant ethical approval was obtained at the local level for the contributing datasets.

Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature Limited.

Funding

This research was conducted using the UK Biobank Resource under application no. 9905. This work was supported by the Medical Research Council (Unit Programme numbers MC_UU_12015/2 and MC_UU_00006/2); ERC grant nos 615603, 835079 and 865356; ESRC ES/N011856/1; the Leverhulme Trust; the Leverhulme Centre for Demographic Science; and LabEx Ecodec ANR grant no. ANR-11-LABX-0047. Full study-specific and individual acknowledgements can be found in the . The content is solely the responsibility of the authors and does not necessarily represent the official views of any of the funders. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. This study received ethical approval from the Department of Sociology, University of Oxford 2014/01/01/R3, 28 January 2014 (SOCIOGENOME) and revised with extension SOC/R2/001/C1A/21/60 7 July 2022 (CHRONO), and relevant ethical approval was obtained at the local level for the contributing datasets.

Funders	Funder number
LabEx Ecodec ANR	ANR-11-LABX-0047
Engineering Research Centers	865356, 615603, 835079
Engineering Research Centers
Medical Research Council	MC_UU_00006/2, MC_UU_12015/2
Medical Research Council
Economic and Social Research Council	ES/N011856/1
Economic and Social Research Council
Leverhulme Trust

Access to Document

10.1038/s41562-023-01528-6

Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locusFinal published version, 2.26 MBLicence: Article 25fa Dutch Copyright Act

Persistent URL (handle)

Copy link address

Cite this

Mathieson, I., Day, F. R., Barban, N., Boomsma, D. I., de Geus, E. J. C., Hottenga, J. J., Jansen, R., Mbarek, H., Penninx, B. W. J. H., Willemsen, G., Snieder, H., den Hoed, M., Ong, K. K., Mills, M. C., Perry, J. R. B., eQTLGen Consortium, BIOS Consortium, FinnGen Study, & LifeLines Cohort Study (2023). Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus. Nature Human Behaviour, 7(5), 790-801. https://doi.org/10.1038/s41562-023-01528-6

@article{9d4c5a89fbff44d1a1a975509663bf72,

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.",

author = "Iain Mathieson and Day, {Felix R.} and Nicola Barban and Tropf, {Felix C.} and Brazel, {David M.} and {van Heemst}, Diana and Ahmad Vaez and {van Zuydam}, Natalie and Bitarello, {B{\'a}rbara D.} and Gardner, {Eugene J.} and Akimova, {Evelina T.} and Ajuna Azad and Sven Bergmann and Bielak, {Lawrence F.} and Boomsma, {Dorret I.} and Kristina Bosak and Marco Brumat and Buring, {Julie E.} and David Cesarini and Chasman, {Daniel I.} and Chavarro, {Jorge E.} and Massimiliano Cocca and Concas, {Maria Pina} and {Davey Smith}, George and Gail Davies and Deary, {Ian J.} and T{\~o}nu Esko and Faul, {Jessica D.} and Oscar Franco and Andrea Ganna and Gaskins, {Audrey J.} and Andrea Gelemanovic and {de Geus}, {Eco J.C.} and Christian Gieger and Giorgia Girotto and Bamini Gopinath and Grabe, {Hans J{\"o}rgen} and Gunderson, {Erica P.} and Caroline Hayward and Chunyan He and {van Heemst}, Diana and Hill, {W. David} and Hoffmann, {Eva R.} and Georg Homuth and Hottenga, {Jouke Jan} and Hongyang Huang and Elina Hyppӧnen and Ikram, {M. Arfan} and Rick Jansen and Magnus Johannesson and Zoha Kamali and Kardia, {Sharon L.R.} and Maryam Kavousi and Annette Kifley and Tuomo Kiiskinen and Peter Kraft and Brigitte K{\"u}hnel and Claudia Langenberg and Gerald Liew and {van der Most}, {Peter J.} and Lind, {Penelope A.} and Jian{\textquoteright}an Luan and Reedik M{\"a}gi and Magnusson, {Patrik K.E.} and Anubha Mahajan and Martin, {Nicholas G.} and Hamdi Mbarek and McCarthy, {Mark I.} and George McMahon and Medland, {Sarah E.} and Thomas Meitinger and Andres Metspalu and Evelin Mihailov and Lili Milani and Missmer, {Stacey A.} and Paul Mitchell and Stine M{\o}llegaard and Mook-Kanamori, {Dennis O.} and Anna Morgan and {van der Most}, {Peter J.} and {de Mutsert}, Ren{\'e}e and Matthias Nauck and Nolte, {Ilja M.} and Raymond Noordam and Penninx, {Brenda W.J.H.} and Annette Peters and Peyser, {Patricia A.} and Ozren Pola{\v s}ek and Chris Power and Ajka Pribisalic and Paul Redmond and Rich-Edwards, {Janet W.} and Ridker, {Paul M.} and Rietveld, {Cornelius A.} and Ring, {Susan M.} and Rose, {Lynda M.} and Rico Rueedi and Vallari Shukla and Smith, {Jennifer A.} and Stasa Stankovic and K{\'a}ri Stef{\'a}nsson and Doris St{\"o}ckl and Konstantin Strauch and Swertz, {Morris A.} and Alexander Teumer and Gudmar Thorleifsson and Unnur Thorsteinsdottir and Thurik, {A. Roy} and Timpson, {Nicholas J.} and Constance Turman and Uitterlinden, {Andr{\'e} G.} and Melanie Waldenberger and Wareham, {Nicholas J.} and Weir, {David R.} and Gonneke Willemsen and Zhao, {Jing Hau} and Wei Zhao and Yajie Zhao and Harold Snieder and {den Hoed}, Marcel and Ong, {Ken K.} and Mills, {Melinda C.} and Perry, {John R.B.} and {eQTLGen Consortium} and {BIOS Consortium} and {FinnGen Study} and {LifeLines Cohort Study}",

note = "Funding Information: This research was conducted using the UK Biobank Resource under application no. 9905. This work was supported by the Medical Research Council (Unit Programme numbers MC_UU_12015/2 and MC_UU_00006/2); ERC grant nos 615603, 835079 and 865356; ESRC ES/N011856/1; the Leverhulme Trust; the Leverhulme Centre for Demographic Science; and LabEx Ecodec ANR grant no. ANR-11-LABX-0047. Full study-specific and individual acknowledgements can be found in the . The content is solely the responsibility of the authors and does not necessarily represent the official views of any of the funders. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. This study received ethical approval from the Department of Sociology, University of Oxford 2014/01/01/R3, 28 January 2014 (SOCIOGENOME) and revised with extension SOC/R2/001/C1A/21/60 7 July 2022 (CHRONO), and relevant ethical approval was obtained at the local level for the contributing datasets. Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2023",

month = may,

doi = "10.1038/s41562-023-01528-6",

language = "English",

volume = "7",

pages = "790--801",

journal = "Nature Human Behaviour",

issn = "2397-3374",

publisher = "Springer Nature",

number = "5",

}

Mathieson, I, Day, FR, Barban, N, Boomsma, DI , de Geus, EJC , Hottenga, JJ, Jansen, R, Mbarek, H, Penninx, BWJH, Willemsen, G, Snieder, H, den Hoed, M, Ong, KK, Mills, MC, Perry, JRB, eQTLGen Consortium, BIOS Consortium, FinnGen Study & LifeLines Cohort Study 2023, 'Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus', Nature Human Behaviour, vol. 7, no. 5, pp. 790-801. https://doi.org/10.1038/s41562-023-01528-6

TY - JOUR

T1 - Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus

AU - Mathieson, Iain

AU - Day, Felix R.

AU - Barban, Nicola

AU - Tropf, Felix C.

AU - Brazel, David M.

AU - van Heemst, Diana

AU - Vaez, Ahmad

AU - van Zuydam, Natalie

AU - Bitarello, Bárbara D.

AU - Gardner, Eugene J.

AU - Akimova, Evelina T.

AU - Azad, Ajuna

AU - Bergmann, Sven

AU - Bielak, Lawrence F.

AU - Boomsma, Dorret I.

AU - Bosak, Kristina

AU - Brumat, Marco

AU - Buring, Julie E.

AU - Cesarini, David

AU - Chasman, Daniel I.

AU - Chavarro, Jorge E.

AU - Cocca, Massimiliano

AU - Concas, Maria Pina

AU - Davey Smith, George

AU - Davies, Gail

AU - Deary, Ian J.

AU - Esko, Tõnu

AU - Faul, Jessica D.

AU - Franco, Oscar

AU - Ganna, Andrea

AU - Gaskins, Audrey J.

AU - Gelemanovic, Andrea

AU - de Geus, Eco J.C.

AU - Gieger, Christian

AU - Girotto, Giorgia

AU - Gopinath, Bamini

AU - Grabe, Hans Jörgen

AU - Gunderson, Erica P.

AU - Hayward, Caroline

AU - He, Chunyan

AU - van Heemst, Diana

AU - Hill, W. David

AU - Hoffmann, Eva R.

AU - Homuth, Georg

AU - Hottenga, Jouke Jan

AU - Huang, Hongyang

AU - Hyppӧnen, Elina

AU - Ikram, M. Arfan

AU - Jansen, Rick

AU - Johannesson, Magnus

AU - Kamali, Zoha

AU - Kardia, Sharon L.R.

AU - Kavousi, Maryam

AU - Kifley, Annette

AU - Kiiskinen, Tuomo

AU - Kraft, Peter

AU - Kühnel, Brigitte

AU - Langenberg, Claudia

AU - Liew, Gerald

AU - van der Most, Peter J.

AU - Lind, Penelope A.

AU - Luan, Jian’an

AU - Mägi, Reedik

AU - Magnusson, Patrik K.E.

AU - Mahajan, Anubha

AU - Martin, Nicholas G.

AU - Mbarek, Hamdi

AU - McCarthy, Mark I.

AU - McMahon, George

AU - Medland, Sarah E.

AU - Meitinger, Thomas

AU - Metspalu, Andres

AU - Mihailov, Evelin

AU - Milani, Lili

AU - Missmer, Stacey A.

AU - Mitchell, Paul

AU - Møllegaard, Stine

AU - Mook-Kanamori, Dennis O.

AU - Morgan, Anna

AU - van der Most, Peter J.

AU - de Mutsert, Renée

AU - Nauck, Matthias

AU - Nolte, Ilja M.

AU - Noordam, Raymond

AU - Penninx, Brenda W.J.H.

AU - Peters, Annette

AU - Peyser, Patricia A.

AU - Polašek, Ozren

AU - Power, Chris

AU - Pribisalic, Ajka

AU - Redmond, Paul

AU - Rich-Edwards, Janet W.

AU - Ridker, Paul M.

AU - Rietveld, Cornelius A.

AU - Ring, Susan M.

AU - Rose, Lynda M.

AU - Rueedi, Rico

AU - Shukla, Vallari

AU - Smith, Jennifer A.

AU - Stankovic, Stasa

AU - Stefánsson, Kári

AU - Stöckl, Doris

AU - Strauch, Konstantin

AU - Swertz, Morris A.

AU - Teumer, Alexander

AU - Thorleifsson, Gudmar

AU - Thorsteinsdottir, Unnur

AU - Thurik, A. Roy

AU - Timpson, Nicholas J.

AU - Turman, Constance

AU - Uitterlinden, André G.

AU - Waldenberger, Melanie

AU - Wareham, Nicholas J.

AU - Weir, David R.

AU - Willemsen, Gonneke

AU - Zhao, Jing Hau

AU - Zhao, Wei

AU - Zhao, Yajie

AU - Snieder, Harold

AU - den Hoed, Marcel

AU - Ong, Ken K.

AU - Mills, Melinda C.

AU - Perry, John R.B.

AU - eQTLGen Consortium

AU - BIOS Consortium

AU - FinnGen Study

AU - LifeLines Cohort Study

N1 - Funding Information: This research was conducted using the UK Biobank Resource under application no. 9905. This work was supported by the Medical Research Council (Unit Programme numbers MC_UU_12015/2 and MC_UU_00006/2); ERC grant nos 615603, 835079 and 865356; ESRC ES/N011856/1; the Leverhulme Trust; the Leverhulme Centre for Demographic Science; and LabEx Ecodec ANR grant no. ANR-11-LABX-0047. Full study-specific and individual acknowledgements can be found in the . The content is solely the responsibility of the authors and does not necessarily represent the official views of any of the funders. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. This study received ethical approval from the Department of Sociology, University of Oxford 2014/01/01/R3, 28 January 2014 (SOCIOGENOME) and revised with extension SOC/R2/001/C1A/21/60 7 July 2022 (CHRONO), and relevant ethical approval was obtained at the local level for the contributing datasets. Publisher Copyright: © 2023, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2023/5

Y1 - 2023/5

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85149255018&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85149255018&partnerID=8YFLogxK

U2 - 10.1038/s41562-023-01528-6

DO - 10.1038/s41562-023-01528-6

M3 - Article

C2 - 36864135

AN - SCOPUS:85149255018

SN - 2397-3374

VL - 7

SP - 790

EP - 801

JO - Nature Human Behaviour

JF - Nature Human Behaviour

IS - 5

ER -

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

Abstract

Bibliographical note

Funding

Access to Document

Persistent URL (handle)

Other files and links

Fingerprint

Cite this