Genome-wideãssociation study meta-analysis of dizygotic twinning illuminates genetic regulation of female fecundity

Hamdi Mbarek, Scott D. Gordon, David L. Duffy, Nikki Hubers, Sally Mortlock, Jeffrey J. Beck, Jouke Jan Hottenga, René Pool, Conor V. Dolan, Ky'Era V. Actkins, Zachary F. Gerring, Jenny Van Dongen, Erik A. Ehli, William G. Iacono, Matt Mcgue, Daniel I. Chasman, C. Scott Gallagher, Samantha L.P. Schilit, Cynthia C. Morton, Guillaume ParéGonneke Willemsen, David C. Whiteman, Catherine M. Olsen, Catherine Derom, Robert Vlietinck, Daniel Gudbjartsson, Lisa Cannon-Albright, Eva Krapohl, Robert Plomin, Patrik K.E. Magnusson, Nancy L. Pedersen, Pirro Hysi, Massimo Mangino, Timothy D. Spector, Teemu Palviainen, Yuri Milaneschi, Brenda W. Penninnx, Adrian I. Campos, Ken K. Ong, John R.B. Perry, Cornelis B. Lambalk, Jaakko Kaprio, Isleifur Ólafsson, Karine Duroure, Céline Revenu, Miguel E. Rentería, Loic Yengo, Lea Davis, Eske M. Derks, Sarah E. Medland, Hreinn Stefansson, Kari Stefansson, Filippo Del Bene, Bruno Reversade, Grant W. Montgomery, Dorret I. Boomsma, Nicholas G. Martin

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2 Scopus citations


STUDY QUESTION: Which genetic factors regulate female propensity for giving birth to spontaneous dizygotic (DZ) twins? SUMMARY ANSWER: We identified four new loci, GNRH1, FSHR, ZFPM1,ãnd IPO8, inãddition to previously identified loci, FSHBãnd SMAD3. WHAT IS KNOWN ALREADY: The propensity to give birth to DZ twins runs in families. Earlier, we reported that FSHBãnd SMAD3ãsãssociated with DZ twinningãnd female fertility measures. STUDY DESIGN, SIZE, DURATION: We conductedã genome-wideãssociation meta-analysis (GWAMA) of mothers of spontaneous dizygotic (DZ) twins (8265 cases, 264 567 controls)ãnd of independent DZ twin offspring (26 252 cases, 417 433 controls). PARTICIPANTS/MATERIALS, SETTING, METHODS: Over 700 000 mothers of DZ twins, twin individualsãnd singletons from large cohorts in Australia/New Zealand, Europe,ãnd the USA were carefully screened to exclude twins bornãfter use of ARTs. Geneticãssociationãnalyses by cohort were followed by meta-analysis, phenome wideãssociation studies (PheWAS), in silicoãnd in vivoãnnotations,ãnd Zebrafish functional validation. MAIN RESULTS AND THE ROLE OF CHANCE: This study enlarges the sample size considerably from previous efforts, finding four genome-wide significant loci, including two novel signalsãndã further two novel genes thatãre implicated by gene level enrichmentãnalyses. The novel loci, GNRH1ãnd FSHR, have well-established roles in female reproduction whereas ZFPM1ãnd IPO8 have not previously been implicated in female fertility. We found significant genetic correlations with multipleãspects of female reproductionãnd body sizeãs wellãs evidence for significant selectionãgainst DZ twinning during human evolution. The 26 top single nucleotide polymorphisms (SNPs) from our GWAMA in European-origin participants weakly predicted the crude twinning rates in 47 non- European populations (r 0.23 between risk scoreãnd population prevalence, s.e. 0.11, 1-tail P 0.058) indicating that genome-wideãssociation studies (GWAS)ãre needed in Africanãnd Asian populations to explore the causes of their respectively highãnd low DZ twinning rates. In vivo functional tests in zebrafish for IPO8 validated its essential role in female, but not male, fertility. In most regions, risk SNPs linked to known expression quantitative trait loci (eQTLs). Top SNPs wereãssociated with in vivo reproductive hormone levels with the top pathways including hormone ligand binding receptorsãnd the ovulation cycle. LARGE SCALE DATA: The full DZT GWAS summary statistics will madeãvailableãfter publication through the GWAS catalog ( LIMITATIONS, REASONS FOR CAUTION: Our study only included Europeanãncestry cohorts. Inclusion of data from Africa (with the highest twining rate)ãnd Asia (with the lowest rate) would illuminate further the biology of twinningãnd female fertility. WIDER IMPLICATIONS OF THE FINDINGS: About one in 40 babies born in the world isã twinãnd there is much speculation on why twinning runs in families. We hope our results will inform investigations of ovarian response in newãnd existing ARTsãnd the causes of female infertility. STUDY FUNDING/COMPETING INTEREST(S): Support for the Netherlands Twin Register came from the Netherlands Organization for Scientific Research (NWO)ãnd The Netherlands Organization for Health Researchãnd Development (ZonMW) grants, 904-61-193, 480-04-004, 400-05-717, Addiction-31160008, 911-09-032, Biobankingãnd Biomolecular Resources Research Infrastructure (BBMRI.NL, 184.021.007), Royal Netherlands Academy of Science Professor Award (PAH/6635) to DIB, European Research Council (ERC-230374), Rutgers University Cellãnd DNA Repository (NIMH U24 MH068457-06), the Avera Institute, Sioux Falls, South Dakota (USA)ãnd the National Institutes of Health (NIH R01 HD042157-01A1)ãnd the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Healthãnd Grand Opportunity grants 1RC2 MH089951. The QIMR Berghofer Medical Research Institute (QIMR) study was supported by grants from the National Healthãnd Medical Research Council (NHMRC) of Australia (241944, 339462, 389927, 389875, 389891, 389892, 389938, 443036, 442915, 442981, 496610, 496739, 552485, 552498, 1050208, 1075175). L.Y. is funded by Australian Research Council (Grant number DE200100425). The Minnesota Center for Twinãnd Family Research (MCTFR) was supported in part by USPHS Grants from the National Institute on Alcohol Abuseãnd Alcoholism (AA09367ãnd AA11886)ãnd the National Institute on Drug Abuse (DA05147, DA13240,ãnd DA024417). The Women's Genome Health Study (WGHS) was funded by the National Heart, Lung,ãnd Blood Institute (HL043851ãnd HL080467)ãnd the National Cancer Institute (CA047988ãnd UM1CA182913), with support for genotyping provided by Amgen. Data collection in the Finnish Twin Registry has been supported by the Wellcome Trust Sanger Institute, the Broad Institute, ENGAGE-European Network for Geneticãnd Genomic Epidemiology, FP7- HEALTH-F4-2007, grantãgreement number 201413, National Institute of Alcohol Abuseãnd Alcoholism (grants AA-12502, AA-00145, AA-09203, AA15416,ãnd K02AA018755)ãnd the Academy of Finland (grants 100499, 205585, 118555, 141054, 264146, 308248, 312073ãnd 336823 to J. Kaprio). TwinsUK is funded by the Wellcome Trust, Medical Research Council, Versus Arthritis, European Union Horizon 2020, Chronic Disease Research Foundation (CDRF), Zoe Ltdãnd the National Institute for Health Research (NIHR) Clinical Research Network (CRN)ãnd Biomedical Research Centre basedãt Guy'sãnd St Thomas' NHS Foundation Trust in partnership with King's College London. For NESDA, funding was obtained from the Netherlands Organization for Scientific Research (Geestkracht program grant 10000-1002), the Center for Medical Systems Biology (CSMB, NVVO Genomics), Biobankingãnd Biomolecular Resources Research Infrastructure (BBMRI-NL), VU University's Institutes for Healthãnd Care Research (EMGO )ãnd Neuroscience Campus Amsterdam, University Medical Center Groningen, Leiden University Medical Center, National Institutes of Health (NIH, ROI D0042157-01A, MH081802, Grand Opportunity grants 1 RC2 Ml-1089951ãnd IRC2 MH089995). Part of the genotypingãndãnalyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. Computing was supported by BiG Grid, the Dutch e-Science Grid, which is financially supported by NWO. Work in the Del Bene lab was supported by the Programme Investissements d'Avenir IHU FOReSIGHT (ANR-18-IAHU-01). C.R. was supported byãn EU Horizon 2020 Marie Sklodowska-Curie Action fellowship (H2020-MSCA-IF-2014 #661527). H.S.ãnd K.S.ãre employees of deCODE Genetics/ Amgen. The otherãuthors declare no competing financial interests.

Original languageEnglish (US)
Pages (from-to)240-257
Number of pages18
JournalHuman Reproduction
Issue number1
StatePublished - Jan 1 2024

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  • dizygotic twinning
  • female fecundity
  • fertility
  • genetics
  • genome-wideãssociationãnalysis


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