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

Xueping Liu, Dorte Helenius, Line Skotte, Robin N. Beaumont, Matthias Wielscher, Frank Geller, Julius Juodakis, Anubha Mahajan, Jonathan P. Bradfield, Frederick T. J. Lin, Suzanne Vogelezang, Mariona Bustamante, Tarunveer S. Ahluwalia, Niina Pitkänen, Carol A. Wang, Jonas Bacelis, Maria C. Borges, Ge Zhang, Bruce A. Bedell, Robert M. Rossi, Kristin Skogstrand, Shouneng Peng, Wesley K. Thompson, Vivek Appadurai, Debbie A. Lawlor, Ilkka Kalliala, Christine Power, Mark I. McCarthy, Heather A. Boyd, Mary L. Marazita, Hakon Hakonarson, M. Geoffrey Hayes, Denise M. Scholtens, Fernando Rivadeneira, Vincent W. V. Jaddoe, Rebecca K. Vinding, Hans Bisgaard, Bridget A. Knight, Katja Pahkala, Olli Raitakari, Øyvind Helgeland, Stefan Johansson, Pål R. Njølstad, João Fadista, Andrew J. Schork, Ron Nudel, Daniel E. Miller, Xiaoting Chen, Matthew T. Weirauch, Preben Bo Mortensen, Anders D. Børglum, Merete Nordentoft, Ole Mors, Ke Hao, Kelli K. Ryckman, David M. Hougaard, Leah C. Kottyan, Craig E. Pennell, Leo-Pekka Lyytikainen, Klaus Bønnelykke, Martine Vrijheid, Janine F. Felix, William L. Lowe, Struan F. A. Grant, Elina Hyppönen, Bo Jacobsson, Marjo-Riitta Jarvelin, Louis J. Muglia, Jeffrey C. Murray, Rachel M. Freathy, Thomas M. Werge, Mads Melbye, Alfonso Buil and Bjarke Feenstra ()
Additional contact information
Xueping Liu: Statens Serum Institut
Dorte Helenius: iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Line Skotte: Statens Serum Institut
Robin N. Beaumont: University of Exeter, Royal Devon and Exeter Hospital
Matthias Wielscher: Imperial College London
Frank Geller: Statens Serum Institut
Julius Juodakis: University of Gothenburg
Anubha Mahajan: University of Oxford
Jonathan P. Bradfield: The Children’s Hospital of Philadelphia
Frederick T. J. Lin: Northwestern University Feinberg School of Medicine
Suzanne Vogelezang: University Medical Center Rotterdam
Mariona Bustamante: ISGlobal, Barcelona Institute for Global Health
Tarunveer S. Ahluwalia: University of Copenhagen
Niina Pitkänen: University of Turku
Carol A. Wang: The University of Newcastle
Jonas Bacelis: Sahlgrenska University Hospital
Maria C. Borges: MRC Integrative Epidemiology Unit at the University of Bristol
Ge Zhang: Cincinnati Children’s Hospital Medical Center
Bruce A. Bedell: University of Iowa
Robert M. Rossi: March of Dimes Prematurity Research Center Ohio Collaborative
Kristin Skogstrand: iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Shouneng Peng: Icahn School of Medicine at Mount Sinai
Wesley K. Thompson: iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Vivek Appadurai: iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Debbie A. Lawlor: MRC Integrative Epidemiology Unit at the University of Bristol
Ilkka Kalliala: Imperial College
Christine Power: University College London
Mark I. McCarthy: University of Oxford
Heather A. Boyd: Statens Serum Institut
Mary L. Marazita: University of Pittsburgh
Hakon Hakonarson: The Children’s Hospital of Philadelphia
M. Geoffrey Hayes: Northwestern University Feinberg School of Medicine
Denise M. Scholtens: Northwestern University Feinberg School of Medicine
Fernando Rivadeneira: University Medical Center Rotterdam
Vincent W. V. Jaddoe: University Medical Center Rotterdam
Rebecca K. Vinding: University of Copenhagen
Hans Bisgaard: University of Copenhagen
Bridget A. Knight: University of Exeter, Royal Devon and Exeter Hospital
Katja Pahkala: University of Turku
Olli Raitakari: University of Turku
Øyvind Helgeland: University of Bergen
Stefan Johansson: University of Bergen
Pål R. Njølstad: University of Bergen
João Fadista: Statens Serum Institut
Andrew J. Schork: iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Ron Nudel: iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Daniel E. Miller: Cincinnati Children’s Hospital Medical Center
Xiaoting Chen: Cincinnati Children’s Hospital Medical Center
Matthew T. Weirauch: University of Cincinnati College of Medicine
Preben Bo Mortensen: iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Anders D. Børglum: iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Merete Nordentoft: iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Ole Mors: iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Ke Hao: Icahn School of Medicine at Mount Sinai
Kelli K. Ryckman: University of Iowa
David M. Hougaard: iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Leah C. Kottyan: University of Cincinnati College of Medicine
Craig E. Pennell: The University of Newcastle
Leo-Pekka Lyytikainen: Fimlab Laboratories
Klaus Bønnelykke: University of Copenhagen
Martine Vrijheid: ISGlobal, Barcelona Institute for Global Health
Janine F. Felix: University Medical Center Rotterdam
William L. Lowe: Northwestern University Feinberg School of Medicine
Struan F. A. Grant: The Children’s Hospital of Philadelphia
Elina Hyppönen: University College London
Bo Jacobsson: University of Gothenburg
Marjo-Riitta Jarvelin: University of Oulu
Louis J. Muglia: Cincinnati Children’s Hospital Medical Center
Jeffrey C. Murray: University of Iowa
Rachel M. Freathy: University of Exeter, Royal Devon and Exeter Hospital
Thomas M. Werge: iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Mads Melbye: Statens Serum Institut
Alfonso Buil: iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Bjarke Feenstra: Statens Serum Institut

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11881-8

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