Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration

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• dc.contributor.author Liu, Xueping
• dc.contributor.author Bustamante Pineda, Mariona
• dc.contributor.author Vrijheid, Martine
• dc.contributor.author Feenstra, Bjarke
• dc.date.accessioned 2020-02-14T08:26:23Z
• dc.date.available 2020-02-14T08:26:23Z
• dc.date.issued 2019
• dc.description.abstract The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P = 3.96 × 10-14). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.
• dc.description.sponsorship We are grateful for the cooperation of the EGG Consortium and the iPSYCH-BROAD Working Group. Lists of members of the EGG Consortium and collaborators in the iPSYCH-BROAD Working Group are given in the Supplementary Notes 1 and 2, respectively. For study-specific acknowledgements, please see Supplementary Note 3. B.F. received support from an Oak Foundation fellowship, a Novo Nordisk Foundation grant (12955), and a Bill and Melinda Gates Foundation subward (137097); X.L. received support from the Nordic Center of Excellence in Health-Related e-Sciences; D.H., V.A., A.J.S., R.N., T.M.W., and A.D.B. recieved funding from the Lundbeck Foundation (R102-A9118, R155-2014-1724, R248-2017-2003); L.S. reports funding from a Carlsberg Foundation postdoctoral fellowship (CF15-0899); R.M.F. is a Sir Henry Dale Fellow (Wellcome and Royal Society grant: WT104150); R.N.B. is funded by Wellcome and Royal Society (grant: WT104150); M.C.B. and D.A.L. work in a unit that receives UK MRC funding (MC_UU_00011/6); M.C.B. is supported by the MRC Skills Development Fellowship MR/P014054/1; D.A.L.’s contribution to this work was funded by grants from the US NIH and European Research Council under the European Union’s Seventh Framework Programme (FP/2007–2013)/ERC Grant Agreement (Grant number 669545; DevelopObese) and European Union’s Horizon 2020 research and innovation programme under grant agreement 733206 (LIFECYCLE); D.A.L. is also an NIHR senior investigator (NF-SI-0611-10,196); F.R. received partial funding from the Netherlands Organization for Health Research and Development (VIDI 016.136.367); J.F.F. and V.W.V.J. received partial funding from the European Union’s Horizon 2020 research and innovation programme under grant agreements 733206 (LIFECYCLE) and 633595 (DynaHEALTH); V.W.V.J. received partial funding from the Netherlands Organization for Health Research and Development (VIDI 016.136.361) and the European Research Council (ERC Consolidator Grant, ERC-2014-CoG-648916); I.K. reports funding from Sigrid Juselius Foundation and Biomendicum Foundation postdoctoral fellowship; L.J.M. was supported by the March of Dimes Prematurity Research Center Ohio Collaborative, NICHD HD 091527, and the Bill and Melinda Gates Foundation (OPP1113966); M.T.W. was supported by NIH R01 NS099068, NIH R01 GM055479-19A1, a Lupus Research Alliance Novel Approaches award, CCRF Endowed Scholar, a CCHMC CpG Pilot study award, and a CCHMC Trustee award; K.K.R. received support from March of Dimes (21-FY13-19); C.P. was supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre; M.I.M. is a Wellcome Senior Investigator and a NIHR Senior Investigator. His work is supported by Wellcome (090532, 093831, 203141, 106130) and by the NIH (U01DK105535). The views expressed in this article are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. For study-specific funding, please see Supplementary Note 4.
• dc.format.mimetype application/pdf
• dc.identifier.citation Liu X, Helenius D, Skotte L, Beaumont RN, Wielscher M, Geller F et al. Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration. Nat Commun. 2019;10(1):3927. DOI: 10.1038/s41467-019-11881-8
• dc.identifier.doi http://dx.doi.org/10.1038/s41467-019-11881-8
• dc.identifier.issn 2041-1723
• dc.identifier.uri http://hdl.handle.net/10230/43601
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nature Communications. 2019;10(1):3927
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/669545
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/733206
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/633595
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/648916
• dc.rights © The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Genetics research
• dc.subject.keyword Genome-wide association studies
• dc.subject.keyword Reproductive biology
• dc.subject.keyword Reproductive signs and symptoms
• dc.title Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion