title: Integrated genomic analyses in bronchopulmonary dysplasia.
abstract: OBJECTIVE
  To identify single-nucleotide polymorphisms (SNPs) and pathways associated with bronchopulmonary dysplasia (BPD) because O2 requirement at 36 weeks' postmenstrual age risk is strongly influenced by heritable factors.
  
  
  METHODS
  A genome-wide scan was conducted on 1.2 million genotyped SNPs, and an additional 7 million imputed SNPs, using a DNA repository of extremely low birth weight infants. Genome-wide association and gene set analysis was performed for BPD or death, severe BPD or death, and severe BPD in survivors. Specific targets were validated via the use of gene expression in BPD lung tissue and in mouse models.
  
  
  RESULTS
  Of 751 infants analyzed, 428 developed BPD or died. No SNPs achieved genome-wide significance (P < 10(-8)), although multiple SNPs in adenosine deaminase, CD44, and other genes were just below P < 10(-6). Of approximately 8000 pathways, 75 were significant at false discovery rate (FDR) <0.1 and P < .001 for BPD/death, 95 for severe BPD/death, and 90 for severe BPD in survivors. The pathway with lowest FDR was miR-219 targets (P = 1.41E-08, FDR 9.5E-05) for BPD/death and phosphorous oxygen lyase activity (includes adenylate and guanylate cyclases) for both severe BPD/death (P = 5.68E-08, FDR 0.00019) and severe BPD in survivors (P = 3.91E-08, FDR 0.00013). Gene expression analysis confirmed significantly increased miR-219 and CD44 in BPD.
  
  
  CONCLUSIONS
  Pathway analyses confirmed involvement of known pathways of lung development and repair (CD44, phosphorus oxygen lyase activity) and indicated novel molecules and pathways (adenosine deaminase, targets of miR-219) involved in genetic predisposition to BPD.
authors.affiliation: Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL. Electronic address: nambalavanan@peds.uab.edu.
authors.forename: Namasivayam
authors.initials: N
authors.lastname: Ambalavanan
authors.affiliation: Department of Pediatrics, Duke University, Durham, NC.
authors.forename: C Michael
authors.initials: CM
authors.lastname: Cotten
authors.affiliation: RTI International, Atlanta, GA.
authors.forename: Grier P
authors.initials: GP
authors.lastname: Page
authors.affiliation: Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Waldemar A
authors.initials: WA
authors.lastname: Carlo
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa City, IA.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Murray
authors.affiliation: Division of Neonatology and Program in Pediatric Molecular and Personalized Medicine, University of Rochester, Rochester, NY.
authors.forename: Soumyaroop
authors.initials: S
authors.lastname: Bhattacharya
authors.affiliation: Division of Neonatology and Program in Pediatric Molecular and Personalized Medicine, University of Rochester, Rochester, NY.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Mariani
authors.affiliation: Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, MO.
authors.forename: Alain C
authors.initials: AC
authors.lastname: Cuna
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Ona M
authors.initials: OM
authors.lastname: Faye-Petersen
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: David
authors.initials: D
authors.lastname: Kelly
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.
authors.forename: Rosemary D
authors.initials: RD
authors.lastname: Higgins
mesh_terms: D000818:Animals; D001997:Bronchopulmonary Dysplasia / Q000453:epidemiology / Q000235:genetics*; D004247:DNA / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D005865:Gestational Age; D006801:Humans; D015994:Incidence; D007223:Infant; D052577:Infant, Extremely Low Birth Weight; D007231:Infant, Newborn; D007234:Infant, Premature; D051379:Mice; D020641:Polymorphism, Single Nucleotide; D015996:Survival Rate / Q000639:trends; D014481:United States / Q000453:epidemiology
chemical_list: D004247:DNA