Identification of 371 genetic variants for age at first sex and birth linked to externalising behaviour

Melinda C. Mills; Dorret I. Boomsma; Rick Jansen; Michel G. Nivard; Jenny van Dongen; Eco J. C. de Geus; Jouke Jan Hottenga; Hamdi Mbarek; Gonneke Willemsen; eQTLGen Consortium

doi:10.1038/s41562-021-01135-3

Identification of 371 genetic variants for age at first sex and birth linked to externalising behaviour

Melinda C. Mills, Dorret I. Boomsma, Rick Jansen, Michel G. Nivard, Jenny van Dongen, Eco J. C. de Geus, Jouke Jan Hottenga, Hamdi Mbarek, Gonneke Willemsen, eQTLGen Consortium

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Abstract

Age at first sexual intercourse and age at first birth have implications for health and evolutionary fitness. In this genome-wide association study (age at first sexual intercourse, N = 387,338; age at first birth, N = 542,901), we identify 371 single-nucleotide polymorphisms, 11 sex-specific, with a 5–6% polygenic score prediction. Heritability of age at first birth shifted from 9% [CI = 4–14%] for women born in 1940 to 22% [CI = 19–25%] for those born in 1965. Signals are driven by the genetics of reproductive biology and externalising behaviour, with key genes related to follicle stimulating hormone (FSHB), implantation (ESR1), infertility and spermatid differentiation. Our findings suggest that polycystic ovarian syndrome may lead to later age at first birth, linking with infertility. Late age at first birth is associated with parental longevity and reduced incidence of type 2 diabetes and cardiovascular disease. Higher childhood socioeconomic circumstances and those in the highest polygenic score decile (90%+) experience markedly later reproductive onset. Results are relevant for improving teenage and late-life health, understanding longevity and guiding experimentation into mechanisms of infertility.

Original language	English
Pages (from-to)	1717-1730
Number of pages	17
Journal	Nature Human Behaviour
Volume	5
Issue number	12
Early online date	1 Jul 2021
DOIs	https://doi.org/10.1038/s41562-021-01135-3
Publication status	Published - Dec 2021

Funding

A detailed list of funding and other acknowledgements for each cohort can be found in Supplementary Sect. 14. This research was conducted using the UK Biobank resource under application 22276 and 9905. Funding was provided to M.C.M. by the ERC, SOCIOGENOME (615603), CHRONO (835079), ESRC/UKRI SOCGEN (ES/N011856/1), Wellcome Trust ISSF, Leverhulme Trust and Leverhulme Centre for Demographic Science, to N.B. by ERC GENPOP (865356), to F.C.T. by LabEx Ecode, French National Research Agency (ANR) Investissements d’Avenir (ANR-11-LABX-0047), to M.d.H. by Swedish Heart-Lung Foundation (20170872, 20200781, 20140543, 20170678, 20180706 and 20200602), Kjell and Märta Beijer Foundation and Swedish Research Council (2015-03657, 2019-01417). 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, and relevant ethical approval was obtained at the local level for the contributing datasets. The authors thank E. T. Akimova and S. Møllegaard for administrative work in the organization of the cohort information and author list. The main authors declare no competing interests. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. M.I.M. has served on advisory panels for Pfizer, NovoNordisk and Zoe Global, has received honoraria from Merck, Pfizer, Novo Nordisk and Eli Lilly and research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier and Takeda. As of June 2019, M.I.M. is an employee of Genentech and a holder of Roche stock.

Funders	Funder number
CHRONO
ERC GENPOP	865356
SOCIOGENOME
Wellcome Trust ISSF
Eli Lilly and Company
Pfizer
AstraZeneca
Merck
Roche
Sanofi
AbbVie
Boehringer Ingelheim
Takeda Pharmaceutical Company
Janssen Pharmaceuticals
H2020 European Research Council	835079
FP7 Ideas: European Research Council	615603
UK Research and Innovation
Economic and Social Research Council	ES/N011856/1
Leverhulme Trust
European Research Council
Agence Nationale de la Recherche	ANR-11-LABX-0047
Hjärt-Lungfonden	20140543, 20170872, 20200602, 20170678, 20180706, 20200781
Novo Nordisk
Vetenskapsrådet	2015-03657, 2019-01417
Kjell och Märta Beijers Stiftelse
Servier
Labex Ecodec

UN SDGs

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10.1038/s41562-021-01135-3

Identification of 371 genetic variants for age at first sex and birth linked to externalising behaviourFinal published version, 1.77 MBLicence: Article 25fa Dutch Copyright Act

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@article{9610fe79fe8f4e268217b1c3525a95a2,

title = "Identification of 371 genetic variants for age at first sex and birth linked to externalising behaviour",

abstract = "Age at first sexual intercourse and age at first birth have implications for health and evolutionary fitness. In this genome-wide association study (age at first sexual intercourse, N = 387,338; age at first birth, N = 542,901), we identify 371 single-nucleotide polymorphisms, 11 sex-specific, with a 5–6% polygenic score prediction. Heritability of age at first birth shifted from 9% [CI = 4–14%] for women born in 1940 to 22% [CI = 19–25%] for those born in 1965. Signals are driven by the genetics of reproductive biology and externalising behaviour, with key genes related to follicle stimulating hormone (FSHB), implantation (ESR1), infertility and spermatid differentiation. Our findings suggest that polycystic ovarian syndrome may lead to later age at first birth, linking with infertility. Late age at first birth is associated with parental longevity and reduced incidence of type 2 diabetes and cardiovascular disease. Higher childhood socioeconomic circumstances and those in the highest polygenic score decile (90%+) experience markedly later reproductive onset. Results are relevant for improving teenage and late-life health, understanding longevity and guiding experimentation into mechanisms of infertility.",

author = "Mills, {Melinda C.} and Tropf, {Felix C.} and Brazel, {David M.} and {Van Zuydam}, Natalie and Ahmad Vaez and Mawuss{\'e} Agbessi and Habibul Ahsan and Isabel Alves and Andiappan, {Anand Kumar} and Wibowo Arindrarto and Philip Awadalla and Alexis Battle and Frank Beutner and {Jan Bonder}, Marc and Boomsma, {Dorret I.} and Christiansen, {Mark W.} and Annique Claringbould and Patrick Deelen and T{\~o}nu Esko and Marie-julie Fav{\'e} and Lude Franke and Timothy Frayling and Gharib, {Sina A.} and Greg Gibson and Heijmans, {Bastiaan T.} and Gibran Hemani and Rick Jansen and Mika K{\"a}h{\"o}nen and Anette Kalnapenkis and Silva Kasela and Johannes Kettunen and Yungil Kim and Holger Kirsten and Peter Kovacs and Knut Krohn and Jaanika Kronberg and Viktorija Kukushkina and Zoltan Kutalik and Bernett Lee and Terho Lehtim{\"a}ki and Markus Loeffler and Marigorta, {Urko M.} and Hailang Mei and Lili Milani and Montgomery, {Grant W.} and Martina M{\"u}ller-nurasyid and Matthias Nauck and Nivard, {Michel G.} and Penninx, {Brenda W. J. H.} and Markus Perola and Natalia Pervjakova and Pierce, {Brandon L.} and Joseph Powell and Holger Prokisch and Psaty, {Bruce M.} and Raitakari, {Olli T.} and Samuli Ripatti and Olaf Rotzschke and Sina R{\"u}eger and Ashis Saha and Markus Scholz and Katharina Schramm and Ilkka Sepp{\"a}l{\"a} and Slagboom, {Eline P.} and Stehouwer, {Coen D. A.} and Michael Stumvoll and Patrick Sullivan and {{\textquoteleft}t Hoen}, {Peter A. C.} and Alexander Teumer and Joachim Thiery and Lin Tong and Anke T{\"o}njes and {van Dongen}, Jenny and {Van Iterson}, Maarten and {Van Meurs}, Joyce and Veldink, {Jan H.} and Joost Verlouw and Visscher, {Peter M.} and Uwe V{\"o}lker and Urmo V{\~o}sa and Harm-jan Westra and Cisca Wijmenga and Hanieh Yaghootkar and Jian Yang and Biao Zeng and Futao Zhang and {Van Greevenbroek}, {Marleen M. J.} and Schalkwijk, {Casper G.} and Joris Deelen and {Van Heemst}, Diana and {Van Duijn}, {Cornelia M.} and Hofman, {Bert A.} and Aaron Isaacs and Uitterlinden, {Andr{\'e} G.} and Michael Verbiest and Suchiman, {H. Eka D.} and Marijn Verkerk and {Van Der Breggen}, Ruud and {Van Rooij}, Jeroen and Nico Lakenberg and Hailiang Mei and Jan Bot and Zhernakova, {Dasha V.} and Ren{\'e} Luijk and Bonder, {Marc Jan} and Swertz, {Morris A.} and {Van Zwet}, {Erik. W.} and Akimova, {Evelina T.} and Sven Bergmann and Boardman, {Jason D.} and Buring, {Julie E.} and David Cesarini and Chasman, {Daniel I.} and Chavarro, {Jorge E.} and Massimiliano Cocca and Concas, {Maria Pina} and George Davey-smith and Gail Davies and Deary, {Ian J.} and Gaskins, {Audrey J.} and {de Geus}, {Eco J. C.} and Christian Gieger and Giorgia Girotto and Grabe, {Hans J{\"o}rgen} and Gunderson, {Erica P.} and Harris, {Kathleen Mullan} and Hartwig, {Fernando P.} and Chunyan He and Georg Homuth and Horta, {Bernando Lessa} and {Jan Hottenga}, Jouke and Hongyang Huang and Elina Hyppӧnen and Ikram, {M. Arfan} and Magnus Johannesson and Zoha Kamali and Maryam Kavousi and Peter Kraft and Brigitte K{\"u}hnel and Claudia Langenberg and Study, {Lifelines Cohort} 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 Mcqueen, {Matthew B.} and Medland, {Sarah E.} and Thomas Meitinger and Andres Metspalu and Evelin Mihailov and Missmer, {Stacey A.} 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 Raymond Noordam and Chris Power 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 K{\'a}ri Stef{\'a}nsson and Doris St{\"o}ckl and Konstantin Strauch and Thurik, {A. Roy} and Timpson, {Nicholas J.} and Constance Turman and Wareham, {Nicholas J.} and Gonneke Willemsen and Zhao, {Jing Hau} and Pers, {Tune H.} and Harold Snieder and Perry, {John R. B.} and Ong, {Ken K.} and {Den Hoed}, Marcel and Nicola Barban and Day, {Felix R.} and {eQTLGen Consortium}",

year = "2021",

month = dec,

doi = "10.1038/s41562-021-01135-3",

language = "English",

volume = "5",

pages = "1717--1730",

journal = "Nature Human Behaviour",

issn = "2397-3374",

publisher = "Nature Publishing Group",

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AU - Tropf, Felix C.

AU - Brazel, David M.

AU - Van Zuydam, Natalie

AU - Vaez, Ahmad

AU - Agbessi, Mawussé

AU - Ahsan, Habibul

AU - Alves, Isabel

AU - Andiappan, Anand Kumar

AU - Arindrarto, Wibowo

AU - Awadalla, Philip

AU - Battle, Alexis

AU - Beutner, Frank

AU - Jan Bonder, Marc

AU - Boomsma, Dorret I.

AU - Christiansen, Mark W.

AU - Claringbould, Annique

AU - Deelen, Patrick

AU - Esko, Tõnu

AU - Favé, Marie-julie

AU - Franke, Lude

AU - Frayling, Timothy

AU - Gharib, Sina A.

AU - Gibson, Greg

AU - Heijmans, Bastiaan T.

AU - Hemani, Gibran

AU - Jansen, Rick

AU - Kähönen, Mika

AU - Kalnapenkis, Anette

AU - Kasela, Silva

AU - Kettunen, Johannes

AU - Kim, Yungil

AU - Kirsten, Holger

AU - Kovacs, Peter

AU - Krohn, Knut

AU - Kronberg, Jaanika

AU - Kukushkina, Viktorija

AU - Kutalik, Zoltan

AU - Lee, Bernett

AU - Lehtimäki, Terho

AU - Loeffler, Markus

AU - Marigorta, Urko M.

AU - Mei, Hailang

AU - Milani, Lili

AU - Montgomery, Grant W.

AU - Müller-nurasyid, Martina

AU - Nauck, Matthias

AU - Nivard, Michel G.

AU - Penninx, Brenda W. J. H.

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AU - Pervjakova, Natalia

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AU - Powell, Joseph

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AU - Rotzschke, Olaf

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AU - Saha, Ashis

AU - Scholz, Markus

AU - Schramm, Katharina

AU - Seppälä, Ilkka

AU - Slagboom, Eline P.

AU - Stehouwer, Coen D. A.

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AU - Sullivan, Patrick

AU - ‘t Hoen, Peter A. C.

AU - Teumer, Alexander

AU - Thiery, Joachim

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AU - Völker, Uwe

AU - Võsa, Urmo

AU - Westra, Harm-jan

AU - Wijmenga, Cisca

AU - Yaghootkar, Hanieh

AU - Yang, Jian

AU - Zeng, Biao

AU - Zhang, Futao

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AU - Deelen, Joris

AU - Van Heemst, Diana

AU - Van Duijn, Cornelia M.

AU - Hofman, Bert A.

AU - Isaacs, Aaron

AU - Uitterlinden, André G.

AU - Verbiest, Michael

AU - Suchiman, H. Eka D.

AU - Verkerk, Marijn

AU - Van Der Breggen, Ruud

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AU - Lakenberg, Nico

AU - Mei, Hailiang

AU - Bot, Jan

AU - Zhernakova, Dasha V.

AU - Luijk, René

AU - Bonder, Marc Jan

AU - Swertz, Morris A.

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AU - Akimova, Evelina T.

AU - Bergmann, Sven

AU - Boardman, Jason D.

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 - Gaskins, Audrey J.

AU - de Geus, Eco J. C.

AU - Gieger, Christian

AU - Girotto, Giorgia

AU - Grabe, Hans Jörgen

AU - Gunderson, Erica P.

AU - Harris, Kathleen Mullan

AU - Hartwig, Fernando P.

AU - He, Chunyan

AU - Homuth, Georg

AU - Horta, Bernando Lessa

AU - Jan Hottenga, Jouke

AU - Huang, Hongyang

AU - Hyppӧnen, Elina

AU - Ikram, M. Arfan

AU - Johannesson, Magnus

AU - Kamali, Zoha

AU - Kavousi, Maryam

AU - Kraft, Peter

AU - Kühnel, Brigitte

AU - Langenberg, Claudia

AU - Study, Lifelines Cohort

AU - Lind, Penelope A.

AU - Luan, Jian’an

AU - Mägi, Reedik

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AU - Missmer, Stacey A.

AU - Møllegaard, Stine

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AU - Morgan, Anna

AU - Van Der Most, Peter J.

AU - De Mutsert, Renée

AU - Noordam, Raymond

AU - Power, Chris

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 - Stefánsson, Kári

AU - Stöckl, Doris

AU - Strauch, Konstantin

AU - Thurik, A. Roy

AU - Timpson, Nicholas J.

AU - Turman, Constance

AU - Wareham, Nicholas J.

AU - Willemsen, Gonneke

AU - Zhao, Jing Hau

AU - Pers, Tune H.

AU - Snieder, Harold

AU - Perry, John R. B.

AU - Ong, Ken K.

AU - Den Hoed, Marcel

AU - Barban, Nicola

AU - Day, Felix R.

AU - eQTLGen Consortium

PY - 2021/12

Y1 - 2021/12

N2 - Age at first sexual intercourse and age at first birth have implications for health and evolutionary fitness. In this genome-wide association study (age at first sexual intercourse, N = 387,338; age at first birth, N = 542,901), we identify 371 single-nucleotide polymorphisms, 11 sex-specific, with a 5–6% polygenic score prediction. Heritability of age at first birth shifted from 9% [CI = 4–14%] for women born in 1940 to 22% [CI = 19–25%] for those born in 1965. Signals are driven by the genetics of reproductive biology and externalising behaviour, with key genes related to follicle stimulating hormone (FSHB), implantation (ESR1), infertility and spermatid differentiation. Our findings suggest that polycystic ovarian syndrome may lead to later age at first birth, linking with infertility. Late age at first birth is associated with parental longevity and reduced incidence of type 2 diabetes and cardiovascular disease. Higher childhood socioeconomic circumstances and those in the highest polygenic score decile (90%+) experience markedly later reproductive onset. Results are relevant for improving teenage and late-life health, understanding longevity and guiding experimentation into mechanisms of infertility.

AB - Age at first sexual intercourse and age at first birth have implications for health and evolutionary fitness. In this genome-wide association study (age at first sexual intercourse, N = 387,338; age at first birth, N = 542,901), we identify 371 single-nucleotide polymorphisms, 11 sex-specific, with a 5–6% polygenic score prediction. Heritability of age at first birth shifted from 9% [CI = 4–14%] for women born in 1940 to 22% [CI = 19–25%] for those born in 1965. Signals are driven by the genetics of reproductive biology and externalising behaviour, with key genes related to follicle stimulating hormone (FSHB), implantation (ESR1), infertility and spermatid differentiation. Our findings suggest that polycystic ovarian syndrome may lead to later age at first birth, linking with infertility. Late age at first birth is associated with parental longevity and reduced incidence of type 2 diabetes and cardiovascular disease. Higher childhood socioeconomic circumstances and those in the highest polygenic score decile (90%+) experience markedly later reproductive onset. Results are relevant for improving teenage and late-life health, understanding longevity and guiding experimentation into mechanisms of infertility.

U2 - 10.1038/s41562-021-01135-3

DO - 10.1038/s41562-021-01135-3

M3 - Article

SN - 2397-3374

VL - 5

SP - 1717

EP - 1730

JO - Nature Human Behaviour

JF - Nature Human Behaviour

IS - 12

ER -

Identification of 371 genetic variants for age at first sex and birth linked to externalising behaviour

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