title: Targeted Sequencing and Meta-Analysis of Preterm Birth.
abstract: Understanding the genetic contribution(s) to the risk of preterm birth may lead to the development of interventions for treatment, prediction and prevention. Twin studies suggest heritability of preterm birth is 36-40%. Large epidemiological analyses support a primary maternal origin for recurrence of preterm birth, with little effect of paternal or fetal genetic factors. We exploited an "extreme phenotype" of preterm birth to leverage the likelihood of genetic discovery. We compared variants identified by targeted sequencing of women with 2-3 generations of preterm birth with term controls without history of preterm birth. We used a meta-genomic, bi-clustering algorithm to identify gene sets coordinately associated with preterm birth. We identified 33 genes including 217 variants from 5 modules that were significantly different between cases and controls. The most frequently identified and connected genes in the exome library were IGF1, ATM and IQGAP2. Likewise, SOS1, RAF1 and AKT3 were most frequent in the haplotype library. Additionally, SERPINB8, AZU1 and WASF3 showed significant differences in abundance of variants in the univariate comparison of cases and controls. The biological processes impacted by these gene sets included: cell motility, migration and locomotion; response to glucocorticoid stimulus; signal transduction; metabolic regulation and control of apoptosis.
authors.affiliation: Department of Pediatrics, Women & Infants Hospital of Rhode Island, Providence, Rhode Island, United States of America.|Brown Alpert Medical School, Providence, Rhode Island, United States of America.
authors.forename: Alper
authors.identifier: 0000-0001-6489-8591
authors.initials: A
authors.lastname: Uzun
authors.affiliation: Department of Pediatrics, Women & Infants Hospital of Rhode Island, Providence, Rhode Island, United States of America.
authors.forename: Jessica
authors.initials: J
authors.lastname: Schuster
authors.affiliation: Department of Pediatrics, Women & Infants Hospital of Rhode Island, Providence, Rhode Island, United States of America.
authors.forename: Bethany
authors.initials: B
authors.lastname: McGonnigal
authors.affiliation: Molecular Biology, Cell Biology & Biochemistry, Brown University, Providence, Rhode Island, United States of America.
authors.forename: Christoph
authors.identifier: 0000-0001-6132-3581
authors.initials: C
authors.lastname: Schorl
authors.affiliation: Department of Epidemiology and Public Health, Yale University, New Haven, Connecticut, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Dewan
authors.affiliation: Department of Pediatrics, Women & Infants Hospital of Rhode Island, Providence, Rhode Island, United States of America.|Brown Alpert Medical School, Providence, Rhode Island, United States of America.|Center for Computational Molecular Biology, Brown University, Providence, Rhode Island, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Padbury
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics*; D016022:Case-Control Studies; D059472:Exome; D005260:Female; D015723:Gene Library; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D007231:Infant, Newborn; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D000072741:Maternal Inheritance; D011247:Pregnancy; D047928:Premature Birth / Q000175:diagnosis / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics; D020837:SOS1 Protein / Q000235:genetics; D017422:Sequence Analysis, DNA; D020703:ras GTPase-Activating Proteins / Q000235:genetics*
chemical_list: C583557:IGF1 protein, human; C101002:IQGAP2 protein, human; D020837:SOS1 Protein; D020703:ras GTPase-Activating Proteins; D007334:Insulin-Like Growth Factor I; C491754:AKT3 protein, human; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf