University of Oulu

Liu, X., Helenius, D., Skotte, L. et al. Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration. Nat Commun 10, 3927 (2019).

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

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Author: Liu, Xueping1; Helenius, Dorte2,3; Skotte, Line1;
Beaumont, Robin N.4; Wielscher, Matthias5; Geller, Frank1; Juodakis, Julius6; Mahajan, Anubha7; Bradfield, Jonathan P.8,9; Lin, Frederick Tj10; Vogelezang, Suzanne11,12,13; Bustamante, Mariona14,15,16; Ahluwalia, Tarunveer S.17; Pitkanen, Niina18; Wang, Carol A.19; Bacelis, Jonas20; Borges, Maria C.21,22; Zhang, Ge23,24,25; Bedell, Bruce A.26; Rossi, Robert M.25,27; Skogstrand, Kristin2,28; Peng, Shouneng29,30; Thompson, Wesley K.2,3; Appadurai, Vivek2,3; Lawlor, Debbie A.21,22,31; Kalliala, Ilkka32,33,34; Power, Christine35; McCarthy, Mark, I7,36,37; Boyd, Heather A.1; Marazita, Mary L.38,39; Hakonarson, Hakon8,40,41; Hayes, M. Geoffrey10,42,43; Scholtens, Denise M.44; Rivadeneira, Fernando11,13,45; Jaddoe, Vincent W. V.11,12,13; Vinding, Rebecca K.17; Bisgaard, Hans17; Knight, Bridget A.46; Pahkala, Katja18,47; Raitakari, Olli18,48; Helgeland, Oyvind49,50,51; Johansson, Stefan49,52; Njolstad, Pal R.49,50; Fadista, Joao1,53; Schork, Andrew J.2,3; Nudel, Ron2,3; Miller, Daniel E.54; Chen, Xiaoting54; Weirauch, Matthew T.27,54,55,56; Mortensen, Preben Bo2,57,58; Borglum, Anders D.2,58,59; Nordentoft, Merete2,60,61; Mors, Ole2,62; Hao, Ke29,30; Ryckman, Kelli K.26,63; Hougaard, David M.2,28; Kottyan, Leah C.27,54; Pennell, Craig E.19; Lyytikainen, Leo-Pekka64,65; Bonnelykke, Klaus17; Vrijheid, Martine14,15,16; Felix, Janine F.11,12,13; Lowe, William L., Jr.10; Grant, Struan Fa8,40,41; Hypponen, Elina35,66,67; Jacobsson, Bo6,68; Järvelin, Marjo-Riitta69,70; Muglia, Louis J.23,24,26,27; Murray, Jeffrey C.26; Freathy, Rachel M.4,71; Werge, Thomas M.2,3,61; Melbye, Mads1,61,72; Buil, Alfonso2,3; Feenstra, Bjarke1
Organizations: 1Statens Serum Inst, Dept Epidemiol Res, Copenhagen, Denmark.
2Lundbeck Fdn Initiat Integrat Psychiat Res, iPSYCH, Aarhus, Denmark.
3Mental Hlth Serv Copenhagen, Inst Biol Psychiat, Mental Hlth Ctr Sct Hans, Roskilde, Denmark.
4Univ Exeter, Med Sch, Royal Devon & Exeter Hosp, Inst Biomed & Clin Sci,Coll Med & Hlth, Barrack Rd, Exeter EX2 5DW, Devon, England.
5Imperial Coll London, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.
6Univ Gothenburg, Sahlgrenska Acad, Dept Obstet & Gynecol, Gothenburg, Sweden.
7Univ Oxford, Wellcome Ctr Human Genet, Oxford OX3 7BN, England.
8Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA.
9Quantinuum Res LLC, San Diego, CA USA.
10Northwestern Univ, Dept Med, Div Endocrinol Metab & Mol Med, Feinberg Sch Med, Chicago, IL 60611 USA.
11Univ Med Ctr Rotterdam, Erasmus MC, Generat Study Grp R, Rotterdam, Netherlands.
12Univ Med Ctr Rotterdam, Dept Pediat, Erasmus MC, Rotterdam, Netherlands.
13Univ Med Ctr Rotterdam, Dept Epidemiol, Erasmus MC, Rotterdam, Netherlands.
14Barcelona Inst Global Hlth, ISGlobal, Barcelona, Spain.
15Univ Pompeu Fabra, Barcelona, Spain.
16CIBERESP, Madrid, Spain.
17Univ Copenhagen, Herlev & Gentofte Hosp, Copenhagen Prospect Studies Asthma Childhood, COPSAC, Copenhagen, Denmark.
18Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, FIN-20520 Turku, Finland.
19Univ Newcastle, Fac Med & Hlth, Sch Med & Publ Hlth, Newcastle, NSW, Australia.
20Sahlgrens Univ Hosp, Dept Obstet & Gynecol, Gothenburg, Sweden.
21Univ Bristol, MRC Integrat Epidemiol Unit, Bristol, Avon, England.
22Univ Bristol, Bristol Med Sch, Populat Hlth Sci, Bristol, Avon, England.
23Cincinnati Childrens Hosp Med Ctr, Div Human Genet, Cincinnati, OH 45229 USA.
24Cincinnati Childrens Hosp Med Ctr, Ctr Prevent Preterm Birth, Perinatal Inst, Cincinnati, OH 45229 USA.
25March Dimes Prematur Res Ctr Ohio Collaborat, Cincinnati, OH USA.
26Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA.
27Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH USA.
28Statens Serum Inst, Ctr Neonatal Screening, Dept Congenital Disorders, Copenhagen, Denmark.
29Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, 1425 Madison Ave, New York, NY 10029 USA.
30Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, 1425 Madison Ave, New York, NY 10029 USA.
31NIHR Bristol Biomed Res Ctr, Bristol, Avon, England.
32Imperial Coll, Fac Med, Dept Surg & Canc, IRDB, London W12 0NN, England.
33Univ Helsinki, Dept Obstet & Gynaecol, Haartmaninkatu 2, Helsinki 00029, Finland.
34Helsinki Univ Hosp, Haartmaninkatu 2, Helsinki 00029, Finland.
35UCL, Great Ormond St Inst Child Hlth, Populat Policy & Practice, London, England.
36Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7LJ, England.
37Churchill Hosp, NIHR Oxford Biomed Res Ctr, Oxford OX3 7LJ, England.
38Univ Pittsburgh, Sch Dent Med, Dept Oral Biol, Ctr Craniofacial & Dent Genet, Pittsburgh, PA USA.
39Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA.
40Childrens Hosp Philadelphia, Div Human Genet, Philadelphia, PA 19104 USA.
41Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA.
42Northwestern Univ, Dept Anthropol, Evanston, IL 60208 USA.
43Northwestern Univ, Feinberg Sch Med, Ctr Genet Med, Chicago, IL 60611 USA.
44Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Div Biostat, Chicago, IL 60611 USA.
45Univ Med Ctr Rotterdam, Dept Internal Med, Erasmus MC, Rotterdam, Netherlands.
46Univ Exeter, Med Sch, Royal Devon & Exeter Hosp, NIHR Exeter Clin Res Facil, Barrack Rd, Exeter EX2 5DW, Devon, England.
47Univ Turku, Paavo Nurmi Ctr, Sports & Exercise Med Unit, Dept Hlth & Phys Act, FIN-20520 Turku, Finland.
48Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku 20521, Finland.
49Univ Bergen, KG Jebsen Ctr Diabet Res, Dept Clin Sci, Bergen, Norway.
50Haukeland Hosp, Dept Pediat, Bergen, Norway.
51Norwegian Inst Publ Hlth, Dept Genet Res & Bioinformat, Div Hlth Data & Digitalizat, Oslo, Norway.
52Haukeland Hosp, Ctr Med Genet & Mol Med, Bergen, Norway.
53Lund Univ, Diabet Ctr, Dept Clin Sci, Malmo, Sweden.
54Cincinnati Childrens Hosp Med Ctr, Ctr Autoimmune Genom & Etiol, Cincinnati, OH 45229 USA.
55Cincinnati Childrens Hosp, Div Biomed Informat, Cincinnati, OH USA.
56Cincinnati Childrens Hosp, Div Dev Biol, Cincinnati, OH USA.
57Aarhus Univ, Natl Ctr Register Based Res, Aarhus, Denmark.
58Aarhus Univ, Ctr Integrat Sequencing, iSEQ, Aarhus, Denmark.
59Aarhus Univ, Dept Biomed Human Genet, Aarhus, Denmark.
60Mental Hlth Ctr Copenhagen, Mental Hlth Serv Capital Reg Denmark, Copenhagen, Denmark.
61Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark.
62Aarhus Univ Hosp, Psychosis Res Unit, Risskov, Denmark.
63Univ Iowa, Dept Epidemiol, Iowa City, IA USA.
64Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.
65Univ Tampere, Dept Clin Chem, Finnish Cardiovasc Res Ctr Tampere, Fac Med & Life Sci, Tampere 33014, Finland.
66Univ South Australia, Australian Ctr Precis Hlth, Canc Res Inst, Adelaide, SA, Australia.
67South Australian Hlth & Med Res Inst, Adelaide, SA, Australia.
68Norwegian Inst Publ Hlth, Dept Genes & Environm, Div Epidemiol, Oslo, Norway.
69Univ Oulu, Inst Hlth Sci, Oulu, Finland.
70Imperial Coll London, Fac Med, Med Res Council Hlth Protect Agcy Ctr Environm &, Sch Publ Hlth,Dept Epidemiol & Biostat, London, England.
71Univ Bristol, Med Res Council Integrat Epidemiol Unit, Oakfield House, Bristol BS8 2BN, Avon, England.
72Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA.
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.5 MB)
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Language: English
Published: Springer Nature, 2019
Publish Date: 2020-03-11


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.

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Series: Nature communications
ISSN: 2041-1723
ISSN-E: 2041-1723
ISSN-L: 2041-1723
Volume: 10
Article number: 3927
DOI: 10.1038/s41467-019-11881-8
Type of Publication: A1 Journal article – refereed
Field of Science: 3123 Gynaecology and paediatrics
Funding: 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.
EU Grant Number: (633595) DYNAHEALTH - Understanding the dynamic determinants of glucose homeostasis and social capability to promote Healthy and active aging
(733206) LIFECYCLE - Early-life stressors and LifeCycle health
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