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; Bjarke Feenstra

doi:10.1038/s41467-019-11881-8

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

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 language	English
Journal	Nature Communications
Volume	10
Issue number	1
Pages (from-to)	3927
ISSN	2041-1722
DOIs	https://doi.org/10.1038/s41467-019-11881-8
Publication status	Published - 2 Sept 2019

Keywords

Chromosomes, Human, Pair 2/genetics
Cytokines/genetics
Female
Fetus/metabolism
Genome, Human/genetics
Genome-Wide Association Study
Gestational Age
Humans
Infant, Newborn
Polymorphism, Single Nucleotide
Pregnancy
Premature Birth/genetics

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10.1038/s41467-019-11881-8

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Liu, X., Helenius, D., Skotte, L., Beaumont, R. N., Wielscher, M., Geller, F., Juodakis, J., Mahajan, A., Bradfield, J. P., Lin, F. T. J., Vogelezang, S., Bustamante, M., Ahluwalia, T. S., Pitkänen, N., Wang, C. A., Bacelis, J., Borges, M. C., Zhang, G., Bedell, B. A., ... 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, 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, L-P, Bønnelykke, K, Vrijheid, M, Felix, JF, Lowe, WL, Grant, SFA, Hyppönen, E, Jacobsson, B, Jarvelin, M-R, 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, pp. 3927. https://doi.org/10.1038/s41467-019-11881-8

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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.",

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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 - 2019/9/2

Y1 - 2019/9/2

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.

KW - Chromosomes, Human, Pair 2/genetics

KW - Cytokines/genetics

KW - Female

KW - Fetus/metabolism

KW - Genome, Human/genetics

KW - Genome-Wide Association Study

KW - Gestational Age

KW - Humans

KW - Infant, Newborn

KW - Polymorphism, Single Nucleotide

KW - Pregnancy

KW - Premature Birth/genetics

U2 - 10.1038/s41467-019-11881-8

DO - 10.1038/s41467-019-11881-8

M3 - Journal article

C2 - 31477735

SN - 2041-1722

VL - 10

SP - 3927

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

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

Abstract

Keywords

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