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Original Article
GWAS on prolonged gestation (post-term birth): analysis of successive Finnish birth cohorts
  1. William Schierding1,2,
  2. Jisha Antony3,
  3. Ville Karhunen4,5,6,7,
  4. Marja Vääräsmäki4,5,6,7,8,
  5. Steve Franks4,5,6,7,
  6. Paul Elliott6,
  7. Eero Kajantie8,9,10,
  8. Sylvain Sebert4,5,11,
  9. Alex Blakemore4,5,6,7,
  10. Julia A Horsfield2,3,
  11. Marjo-Riitta Järvelin4,5,6,7,
  12. Justin M O’Sullivan1,2,
  13. Wayne S Cutfield1,2
  1. 1University of Auckland, Auckland, New Zealand
  2. 2Gravida: National Centre for Growth and Development, University of Auckland, Auckland, Auckland, New Zealand
  3. 3Department of Pathology, Dunedin School of Medicine, The University of Otago, Dunedin, New Zealand
  4. 4Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland
  5. 5Biocenter Oulu, University of Oulu, Oulu, Finland
  6. 6Department of Epidemiology and Biostatistics, MRC–PHE Centre for Environment & Health, School of Public Health, Imperial College London, London, UK
  7. 7Unit of Primary Care, Oulu University Hospital, Oulu, Finland
  8. 8PEDEGO Research Unit, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
  9. 9Chronic Disease Prevention Unit, National Institute for Health and Welfare, Oulu, Finland
  10. 10Children’s Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
  11. 11Department of Genomics of Complex Diseases School of Public Health, Imperial College London, London, UK
  1. Correspondence to Dr Justin M O’Sullivan, Liggins Institute, University of Auckland, Private Bag 92019, Auckland, New Zealand; justin.osullivan{at}auckland.ac.nz

Abstract

Background Gestation is a crucial timepoint in human development. Deviation from a term gestational age correlates with both acute and long-term adverse health effects for the child. Both being born preterm and post-term, that is, having short and long gestational ages, are heritable and influenced by the prenatal and perinatal environment. Despite the obvious heritable component, specific genetic influences underlying differences in gestational age are poorly understood.

Methods We investigated the genetic architecture of gestational age in 9141 individuals, including 1167 born post-term, across two Northern Finland cohorts born in 1966 or 1986.

Results Here we identify one globally significant intronic genetic variant within the ADAMTS13 gene that is associated with prolonged gestation (p=4.85×10−8). Additional variants that reached suggestive levels of significance were identified within introns at the ARGHAP42 and TKT genes, and in the upstream (5’) intergenic regions of the B3GALT5 and SSBP2 genes. The variants near the ADAMTS13, B3GALT5, SSBP2 and TKT loci are linked to alterations in gene expression levels (cis-eQTLs). Luciferase assays confirmed the allele specific enhancer activity for the BGALT5 and TKT loci.

Conclusions Our findings provide the first evidence of a specific genetic influence associated with prolonged gestation. This study forms a foundation for a better understanding of the genetic and long-term health risks faced by induced and post-term individuals. The long-term risks for induced individuals who have a previously overlooked post-term potential may be a major issue for current health providers.

  • gwas
  • post-term
  • prolonged gestation
  • adamts13
  • b3galt5

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Footnotes

  • Contributors WS, JMO and WSC contributed to the first draft of the manuscript. All authors critically reviewed the manuscript. JA and JAH performed the molecular analyses. WS contributed to bioinformatic analyses. VK, MV, SF, PE, EK, SS, AB and M-RJ generated and reviewed clinical data. WS, JMO and WSC contributed to interpretation of molecular and bioinformatic data. WSC, M-RJ and JMO conceptualised the study.

  • Competing interests None declared.

  • Ethics approval Signed, informed consent and written permission to use their data for scientific research was obtained from the NFBC 1966 study participants at age 31. For the 1986 cohort, adolescents and parents received written and oral information and gave their written informed consent. The studies were approved by the ethics committees of each of the participating medical university study sites in Finland. The research protocols for both the 1966 and 1986 studies were approved by the Ethics Committee of Northern Ostrobotnia Hospital District, Finland.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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