Genome-wide association study of placental weight in 179,025 children and parents reveals distinct and shared genetic influences between placental and fetal growth

A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight after term delivery as a proxy for placental growth, we report genome-wide association analyses in the fetal ( n = 65,405), maternal ( n = 61,228), and paternal ( n = 52,392) genomes, yielding 40 independent association signals. Twenty-six signals are confidently classified as fetal only, four maternal only, and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1 . Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but twelve loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with risk of preeclampsia or shorter gestational duration. Moreover, these analyses support a role for insulin produced by the fetus in regulating the growth of the placenta, providing a key link between fetal and placental growth. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The content of this manuscript and supplementary material is solely the responsibility of the authors and does not necessarily represent the official views of the funders. Personal funding of coauthors R.N.B. and R.M.F. were funded by a Wellcome Trust and Royal Society Sir Henry Dale Fellowship (WT104150). G.H.M. is the recipient of an Australian Research Council Discovery Early Career Award (Project number: DE220101226) funded by the Australian Government and supported by the Research Council of Norway (Project grant: 325640). L.S. received support from a Carlsberg Foundation postdoctoral fellowship (CF15-0899). K.B. acknowledges the Novo Nordisk Foundation (grants NNF17OC0027594 and NNF14CC0001). C.Albinana was supported by the Danish National Research Foundation, via a Niels Bohr Professorship to John McGrath. J.R., S.Sebert and M.R.J. acknowledge the European Union Horizon 2020 research and innovation program under grant agreements No 874739 (LongITools), 733206 (LifeCycle) and 633595 (DynaHEALTH), and the Academy of Finland under grant agreement No 285547 (EGEA). M.R.J. acknowledges the European Union Horizon 2020 research and innovation program under grant agreements No. 825762 (EDCMET) and EarlyCaur (848158). M.R.J. also acknowledges the Joint Programming Initiative a Healthy Diet for a Healthy Life (JPI HDHL) (PREcisE proposal 655), the Medical Research Council (MRC) and the Biotechnology and Biological Sciences Research Council (BBSRC) (grant reference: MR/S03658X/1). D.W. acknowledges the Novo Nordisk Foundation (grants NNF17OC0027594 and NNF14CC0001). C.S.S. is supported by a PhD studentship award from the Medical Research Council (MR/N013166/1). D.J.L. and R.M.F. are funded by a Wellcome Trust Senior Research Fellowship (WT220390). P.E.J. is a J2 research scholar from the Fonds de la recherche du Quebec en sante (FRQS) and members of the CR-CHUS, a FRQS-funded Research Center. L.Bouchard is a senior research scholar from the Fonds de la recherche du Quebec en sante (FRQS) and members of the CR-CHUS, a FRQS-funded Research Center. H.C. and K.Hao were supported by NIH/NIEHS R01 ES029212. L.Bhatta and B.M.B. work in a research unit funded by Stiftelsen Kristian Gerhard Jebsen; Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU); the Liaison Committee for Education, Research, and Innovation in Central Norway; and the Joint Research Committee between St. Olavs Hospital and the Faculty of Medicine and Health Sciences, NTNU. S.B. acknowledges the Novo Nordisk Foundation (grants NNF17OC0027594 and NNF14CC0001). R.G. received funding from the Dutch Diabetes Foundation (grant number 2017.81.002), the Netherlands Organization for Health Research and Development (NWO, ZonMW, grant number 543003109, grant number 09150172110034) and from the European Union Horizon 2020 research and innovation programme under the ERA-NET Cofund action (no 727565), EndObesity, ZonMW the Netherlands (no. 529051026). V.W.V.J. received a Consolidator Grant from the European Research Council (ERC-2014-CoG-648916). F.R. was supported by LEGENDARE ERC-ADG 2020 101021500. M.Vaarasmaki was supported by the Finnish Government Subsidiary for Health Care Research. B.J.V. was supported by a Lundbeck Foundation Fellowship (R335-2019-2339). A.T.H. was supported by a NIHR Senior Investigator award and also a Wellcome Trust Senior Investigator award (098395/Z/12/Z). D.A.L. contribution was supported by The European Research Council under the European Union Horizon 2020 research and innovation program (grant agreement No 101021566), The British Heart Foundation (CH/F/20/90003 and AA/18/7/34219) and Medical Research Council (MC\_UU\_00011/6). D.M.E. is funded by an Australian National Health and Medical Research Council Senior Research Fellowship (APP1137714) and NHMRC project grants (GNT1157714, GNT1183074). B.J. received funding from The Swedish Research Council, Stockholm, Sweden (2019-01004), The Research Council of Norway, Oslo, Norway (FRIMEDBIO #547711), The Swedish Research Council, Stockholm, Sweden (2015-02559). G.Z. is supported by a grant from the Eunice Kennedy Shriver National Institute Of Child Health & Human Development of the National Institutes of Health under Award Number R01HD101669, a grant from the Burroughs Wellcome Fund (Grant 10172896), the March of Dimes Prematurity Research Center Ohio Collaborative and the Bill & Melinda Gates Foundation. S.J. was supported by Helse Vest Open Research Grant (grants #912250 and F-12144), the Novo Nordisk Foundation (NNF20OC0063872) and the Research Council of Norway (grant #315599). B.F. received support from Independent Research Fund Denmark (0134-00244B) and from the Oak Foundation (OCAY-18-598). P.R.N. was supported by grants from the European Research Council (AdG SELECTionPREDISPOSED #293574), the Bergen Research Foundation (Utilizing the Mother and Child Cohort and the Medical Birth Registry for Better Health), Stiftelsen Kristian Gerhard Jebsen (Translational Medical Center), Trond Mohn Stiftelsen (Mohn Center for Diabetes Precision Medicine), the University of Bergen, the Research Council of Norway (FRIPRO grant #240413), the Western Norway Regional Health Authority (Strategic Fund Personalized Medicine for Children and Adults), the Novo Nordisk Foundation (grant #54741), and the Norwegian Diabetes Association. This research was funded in part, by the Wellcome Trust (Grant numbers WT104150 and WT220390). 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The Local Research Ethics Committee of North and East Devon Health Trusts gave ethical approval for this work. The Centre Hospitalier Universitaire de Sherbrooke of the University of Sherbrooke gave ethical approval for this work. The Medical Ethics Committee of Erasmus Medical Center of the University Medical Center Rotterdam gave ethical consent for this work. The local ethics committee of the NHS Tayside Caldicott Guardians gave ethical approval to this work. The Regional Committee for Medical Research Ethics Region Middle of the Norwegian University Science and Technology gave ethical approval to this work. The Regional Committee for Medical Research Ethics Region West of the Norwegian University of Bergengave ethical approval to this work. The Regional Committee for Medical Research Ethics Region East of the University of Oslo The Ethics Committees of the Regional Hospitals of Valencia, Barcelona, and Bilbao gave ethical approval to this work. The Northern Ostrobothnia Hospital District Ethical Committee of the Northern Ostrobothnia Hospital gave ethical approval to this work. The Research Ethics Committee of the Hospital District of Northern Savo gave ethical approval to this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Individual cohorts contributing to the meta-analysis should be contacted directly as each cohort has different data access policies. GWAS summary statistics from this study are available via the EGG website (https://egg-consortium.org/).