title: Literature-Informed Analysis of a Genome-Wide Association Study of Gestational Age in Norwegian Women and Children Suggests Involvement of Inflammatory Pathways.
abstract: BACKGROUND
  Five-to-eighteen percent of pregnancies worldwide end in preterm birth, which is the major cause of neonatal death and morbidity. Approximately 30% of the variation in gestational age at birth can be attributed to genetic factors. Genome-wide association studies (GWAS) have not shown robust evidence of association with genomic loci yet.
  
  
  METHODS
  We separately investigated 1921 Norwegian mothers and 1199 children from pregnancies with spontaneous onset of delivery. Individuals were further divided based on the onset of delivery: initiated by labor or prelabor rupture of membranes. Genetic association with ultrasound-dated gestational age was evaluated using three genetic models and adaptive permutations. The top-ranked loci were tested for enrichment in 12 candidate gene-sets generated by text-mining PubMed abstracts containing pregnancy-related keywords.
  
  
  RESULTS
  The six GWAS did not reveal significant associations, with the most extreme empirical p = 5.1 × 10-7. The top loci from maternal GWAS with deliveries initiated by labor showed significant enrichment in 10 PubMed gene-sets, e.g., p = 0.001 and 0.005 for keywords "uterus" and "preterm" respectively. Enrichment signals were mainly caused by infection/inflammation-related genes TLR4, NFKB1, ABCA1, MMP9. Literature-informed analysis of top loci revealed further immunity genes: IL1A, IL1B, CAMP, TREM1, TFRC, NFKBIA, MEFV, IRF8, WNT5A.
  
  
  CONCLUSIONS
  Our analyses support the role of inflammatory pathways in determining pregnancy duration and provide a list of 32 candidate genes for a follow-up work. We observed that the top regions from GWAS in mothers with labor-initiated deliveries significantly more often overlap with pregnancy-related genes than would be expected by chance, suggesting that increased sample size would benefit similar studies.
authors.affiliation: Department of Obstetrics and Gynecology, Sahlgrenska University Hospital Östra, Gothenburg, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Bacelis
authors.affiliation: Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Julius
authors.initials: J
authors.lastname: Juodakis
authors.affiliation: Department of Obstetrics and Gynecology, Sahlgrenska University Hospital Östra, Gothenburg, Sweden.
authors.forename: Verena
authors.initials: V
authors.lastname: Sengpiel
authors.affiliation: Human Genetics Division, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.|Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children's Hospital Medical Center and March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati, Ohio, United States of America.
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Genetics and Bioinformatics, Area of Health Data and Digitalisation, Norwegian Institute of Public Health, Oslo, Norway.
authors.forename: Ronny
authors.initials: R
authors.lastname: Myhre
authors.affiliation: Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children's Hospital Medical Center and March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati, Ohio, United States of America.
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Muglia
authors.affiliation: Department of Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden.
authors.forename: Staffan
authors.initials: S
authors.lastname: Nilsson
authors.affiliation: Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.|Department of Genetics and Bioinformatics, Area of Health Data and Digitalisation, Norwegian Institute of Public Health, Oslo, Norway.
authors.forename: Bo
authors.initials: B
authors.lastname: Jacobsson
mesh_terms: D000328:Adult; D005260:Female; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D008957:Models, Genetic; D009664:Norway; D047928:Premature Birth / Q000235:genetics* / Q000276:immunology