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. RossiKristin 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, Bjarke Feenstra*

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Article number3927
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

Fingerprint

genome
genes
Genes
Mothers
Genome
loci
Cytokines
Public health
Chromosomes
Interleukin-1
Parturition
interleukins
public health
Pregnancy
mortality
Genome-Wide Association Study
chromosomes
pregnancy
Premature Birth
Single Nucleotide Polymorphism

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Liu, X., Helenius, D., Skotte, L., Beaumont, R. N., Wielscher, M., Geller, F., ... Feenstra, B. (2019). Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration. Nature communications, 10(1), [3927]. https://doi.org/10.1038/s41467-019-11881-8
Liu, Xueping ; Helenius, Dorte ; Skotte, Line ; Beaumont, Robin N. ; Wielscher, Matthias ; Geller, Frank ; Juodakis, Julius ; Mahajan, Anubha ; Bradfield, Jonathan P. ; Lin, Frederick T.J. ; Vogelezang, Suzanne ; Bustamante, Mariona ; Ahluwalia, Tarunveer S. ; Pitkänen, Niina ; Wang, Carol A. ; Bacelis, Jonas ; Borges, Maria C. ; Zhang, Ge ; Bedell, Bruce A. ; Rossi, Robert M. ; Skogstrand, Kristin ; Peng, Shouneng ; Thompson, Wesley K. ; Appadurai, Vivek ; Lawlor, Debbie A. ; Kalliala, Ilkka ; Power, Christine ; McCarthy, Mark I. ; Boyd, Heather A. ; Marazita, Mary L. ; Hakonarson, Hakon ; Hayes, M. Geoffrey ; Scholtens, Denise M. ; Rivadeneira, Fernando ; Jaddoe, Vincent W.V. ; Vinding, Rebecca K. ; Bisgaard, Hans ; Knight, Bridget A. ; Pahkala, Katja ; Raitakari, Olli ; Helgeland, Øyvind ; Johansson, Stefan ; Njølstad, Pål R. ; Fadista, João ; Schork, Andrew J. ; Nudel, Ron ; Miller, Daniel E. ; Chen, Xiaoting ; Weirauch, Matthew T. ; Mortensen, Preben Bo ; Børglum, Anders D. ; Nordentoft, Merete ; Mors, Ole ; Hao, Ke ; Ryckman, Kelli K. ; Hougaard, David M. ; Kottyan, Leah C. ; Pennell, Craig E. ; Lyytikainen, Leo Pekka ; Bønnelykke, Klaus ; Vrijheid, Martine ; Felix, Janine F. ; Lowe, William L. ; Grant, Struan F.A. ; Hyppönen, Elina ; Jacobsson, Bo ; Jarvelin, Marjo Riitta ; Muglia, Louis J. ; Murray, Jeffrey C. ; Freathy, Rachel M. ; Werge, Thomas M. ; Melbye, Mads ; Buil, Alfonso ; Feenstra, Bjarke. / Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration. In: Nature communications. 2019 ; Vol. 10, No. 1.
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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.",
author = "Xueping Liu and Dorte Helenius and Line Skotte and Beaumont, {Robin N.} and Matthias Wielscher and Frank Geller and Julius Juodakis and Anubha Mahajan and Bradfield, {Jonathan P.} and Lin, {Frederick T.J.} and Suzanne Vogelezang and Mariona Bustamante and Ahluwalia, {Tarunveer S.} and Niina Pitk{\"a}nen and Wang, {Carol A.} and Jonas Bacelis and Borges, {Maria C.} and Ge Zhang and Bedell, {Bruce A.} and Rossi, {Robert M.} and Kristin Skogstrand and Shouneng Peng and Thompson, {Wesley K.} and Vivek Appadurai and Lawlor, {Debbie A.} and Ilkka Kalliala and Christine Power and McCarthy, {Mark I.} and Boyd, {Heather A.} and Marazita, {Mary L.} and Hakon Hakonarson and Hayes, {M. Geoffrey} and Scholtens, {Denise M.} and Fernando Rivadeneira and Jaddoe, {Vincent W.V.} and Vinding, {Rebecca K.} and Hans Bisgaard and Knight, {Bridget A.} and Katja Pahkala and Olli Raitakari and {\O}yvind Helgeland and Stefan Johansson and Nj{\o}lstad, {P{\aa}l R.} and Jo{\~a}o Fadista and Schork, {Andrew J.} and Ron Nudel and Miller, {Daniel E.} and Xiaoting Chen and Weirauch, {Matthew T.} and Mortensen, {Preben Bo} and B{\o}rglum, {Anders D.} and Merete Nordentoft and Ole Mors and Ke Hao and Ryckman, {Kelli K.} and Hougaard, {David M.} and Kottyan, {Leah C.} and Pennell, {Craig E.} and Lyytikainen, {Leo Pekka} and Klaus B{\o}nnelykke and Martine Vrijheid and Felix, {Janine F.} and Lowe, {William L.} and Grant, {Struan F.A.} and Elina Hypp{\"o}nen and Bo Jacobsson and Jarvelin, {Marjo Riitta} and Muglia, {Louis J.} and Murray, {Jeffrey C.} and Freathy, {Rachel M.} and Werge, {Thomas M.} and Mads Melbye and Alfonso Buil and Bjarke Feenstra",
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Liu, X, Helenius, D, Skotte, L, Beaumont, RN, Wielscher, M, Geller, F, Juodakis, J, Mahajan, A, Bradfield, JP, Lin, FTJ, Vogelezang, S, Bustamante, M, Ahluwalia, TS, Pitkänen, N, Wang, CA, Bacelis, J, Borges, MC, Zhang, G, Bedell, BA, Rossi, RM, Skogstrand, K, Peng, S, Thompson, WK, Appadurai, V, Lawlor, DA, Kalliala, I, Power, C, McCarthy, MI, Boyd, HA, Marazita, ML, Hakonarson, H, Hayes, MG, Scholtens, DM, Rivadeneira, F, Jaddoe, VWV, Vinding, RK, Bisgaard, H, Knight, BA, Pahkala, K, Raitakari, O, Helgeland, Ø, Johansson, S, Njølstad, PR, Fadista, J, Schork, AJ, Nudel, R, Miller, DE, Chen, X, Weirauch, MT, Mortensen, PB, Børglum, AD, Nordentoft, M, Mors, O, Hao, K, Ryckman, KK, Hougaard, DM, Kottyan, LC, Pennell, CE, Lyytikainen, LP, Bønnelykke, K, Vrijheid, M, Felix, JF, Lowe, WL, Grant, SFA, Hyppönen, E, Jacobsson, B, Jarvelin, MR, Muglia, LJ, Murray, JC, Freathy, RM, Werge, TM, Melbye, M, Buil, A & Feenstra, B 2019, 'Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration', Nature communications, vol. 10, no. 1, 3927. https://doi.org/10.1038/s41467-019-11881-8

Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration. / Liu, Xueping; Helenius, Dorte; Skotte, Line; Beaumont, Robin N.; Wielscher, Matthias; Geller, Frank; Juodakis, Julius; Mahajan, Anubha; Bradfield, Jonathan P.; Lin, Frederick T.J.; Vogelezang, Suzanne; Bustamante, Mariona; Ahluwalia, Tarunveer S.; Pitkänen, Niina; Wang, Carol A.; Bacelis, Jonas; Borges, Maria C.; Zhang, Ge; Bedell, Bruce A.; Rossi, Robert M.; Skogstrand, Kristin; Peng, Shouneng; Thompson, Wesley K.; Appadurai, Vivek; Lawlor, Debbie A.; Kalliala, Ilkka; Power, Christine; McCarthy, Mark I.; Boyd, Heather A.; Marazita, Mary L.; Hakonarson, Hakon; Hayes, M. Geoffrey; Scholtens, Denise M.; Rivadeneira, Fernando; Jaddoe, Vincent W.V.; Vinding, Rebecca K.; Bisgaard, Hans; Knight, Bridget A.; Pahkala, Katja; Raitakari, Olli; Helgeland, Øyvind; Johansson, Stefan; Njølstad, Pål R.; Fadista, João; Schork, Andrew J.; Nudel, Ron; Miller, Daniel E.; Chen, Xiaoting; Weirauch, Matthew T.; Mortensen, Preben Bo; Børglum, Anders D.; Nordentoft, Merete; Mors, Ole; Hao, Ke; Ryckman, Kelli K.; Hougaard, David M.; Kottyan, Leah C.; Pennell, Craig E.; Lyytikainen, Leo Pekka; Bønnelykke, Klaus; Vrijheid, Martine; Felix, Janine F.; Lowe, William L.; Grant, Struan F.A.; Hyppönen, Elina; Jacobsson, Bo; Jarvelin, Marjo Riitta; Muglia, Louis J.; Murray, Jeffrey C.; Freathy, Rachel M.; Werge, Thomas M.; Melbye, Mads; Buil, Alfonso; Feenstra, Bjarke.

In: Nature communications, Vol. 10, No. 1, 3927, 01.12.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration

AU - Liu, Xueping

AU - Helenius, Dorte

AU - Skotte, Line

AU - Beaumont, Robin N.

AU - Wielscher, Matthias

AU - Geller, Frank

AU - Juodakis, Julius

AU - Mahajan, Anubha

AU - Bradfield, Jonathan P.

AU - Lin, Frederick T.J.

AU - Vogelezang, Suzanne

AU - Bustamante, Mariona

AU - Ahluwalia, Tarunveer S.

AU - Pitkänen, Niina

AU - Wang, Carol A.

AU - Bacelis, Jonas

AU - Borges, Maria C.

AU - Zhang, Ge

AU - Bedell, Bruce A.

AU - Rossi, Robert M.

AU - Skogstrand, Kristin

AU - Peng, Shouneng

AU - Thompson, Wesley K.

AU - Appadurai, Vivek

AU - Lawlor, Debbie A.

AU - Kalliala, Ilkka

AU - Power, Christine

AU - McCarthy, Mark I.

AU - Boyd, Heather A.

AU - Marazita, Mary L.

AU - Hakonarson, Hakon

AU - Hayes, M. Geoffrey

AU - Scholtens, Denise M.

AU - Rivadeneira, Fernando

AU - Jaddoe, Vincent W.V.

AU - Vinding, Rebecca K.

AU - Bisgaard, Hans

AU - Knight, Bridget A.

AU - Pahkala, Katja

AU - Raitakari, Olli

AU - Helgeland, Øyvind

AU - Johansson, Stefan

AU - Njølstad, Pål R.

AU - Fadista, João

AU - Schork, Andrew J.

AU - Nudel, Ron

AU - Miller, Daniel E.

AU - Chen, Xiaoting

AU - Weirauch, Matthew T.

AU - Mortensen, Preben Bo

AU - Børglum, Anders D.

AU - Nordentoft, Merete

AU - Mors, Ole

AU - Hao, Ke

AU - Ryckman, Kelli K.

AU - Hougaard, David M.

AU - Kottyan, Leah C.

AU - Pennell, Craig E.

AU - Lyytikainen, Leo Pekka

AU - Bønnelykke, Klaus

AU - Vrijheid, Martine

AU - Felix, Janine F.

AU - Lowe, William L.

AU - Grant, Struan F.A.

AU - Hyppönen, Elina

AU - Jacobsson, Bo

AU - Jarvelin, Marjo Riitta

AU - Muglia, Louis J.

AU - Murray, Jeffrey C.

AU - Freathy, Rachel M.

AU - Werge, Thomas M.

AU - Melbye, Mads

AU - Buil, Alfonso

AU - Feenstra, Bjarke

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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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U2 - 10.1038/s41467-019-11881-8

DO - 10.1038/s41467-019-11881-8

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