title: Genome-wide interrogation of longitudinal FEV1 in children with asthma.
abstract: BACKGROUND
  Most genomic studies of lung function have used phenotypic data derived from a single time-point (e.g., presence/absence of disease) without considering the dynamic progression of a chronic disease.
  
  
  OBJECTIVE
  To characterize lung function change over time in subjects with asthma and identify genetic contributors to a longitudinal phenotype.
  
  
  METHODS
  We present a method that models longitudinal FEV1 data, collected from 1,041 children with asthma who participated in the Childhood Asthma Management Program. This longitudinal progression model was built using population-based nonlinear mixed-effects modeling with an exponential structure and the determinants of age and height.
  
  
  RESULTS
  We found ethnicity was a key covariate for FEV1 level. Budesonide-treated children with asthma had a slight but significant effect on FEV1 when compared with those treated with placebo or nedocromil (P < 0.001). A genome-wide association study identified seven single-nucleotide polymorphisms nominally associated with longitudinal lung function phenotypes in 581 white Childhood Asthma Management Program subjects (P < 10(-4) in the placebo ["discovery"] and P < 0.05 in the nedocromil treatment ["replication"] group). Using ChIP-seq and RNA-seq data, we found that some of the associated variants were in strong enhancer regions in human lung fibroblasts and may affect gene expression in human lung tissue. Genetic mapping restricted to genome-wide enhancer single-nucleotide polymorphisms in lung fibroblasts revealed a highly significant variant (rs6763931; P = 4 × 10(-6); false discovery rate < 0.05).
  
  
  CONCLUSIONS
  This study offers a strategy to explore the genetic determinants of longitudinal phenotypes, provide a comprehensive picture of disease pathophysiology, and suggest potential treatment targets.
authors.affiliation: 1 Department of Medicine and.
authors.forename: Kehua
authors.initials: K
authors.lastname: Wu
authors.forename: Eric R
authors.initials: ER
authors.lastname: Gamazon
authors.forename: Hae Kyung
authors.initials: HK
authors.lastname: Im
authors.forename: Paul
authors.initials: P
authors.lastname: Geeleher
authors.forename: Steven R
authors.initials: SR
authors.lastname: White
authors.forename: Julian
authors.initials: J
authors.lastname: Solway
authors.forename: George L
authors.initials: GL
authors.lastname: Clemmer
authors.forename: Scott T
authors.initials: ST
authors.lastname: Weiss
authors.forename: Kelan G
authors.initials: KG
authors.lastname: Tantisira
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Cox
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
authors.forename: R Stephanie
authors.initials: RS
authors.lastname: Huang
mesh_terms: D000367:Age Factors; D018927:Anti-Asthmatic Agents / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D019819:Budesonide / Q000627:therapeutic use; D002648:Child; D005260:Female; D005347:Fibroblasts / Q000187:drug effects*; D005541:Forced Expiratory Volume / Q000187:drug effects* / Q000235:genetics*; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008137:Longitudinal Studies; D008168:Lung / Q000187:drug effects; D008297:Male; D008962:Models, Theoretical; D017835:Nedocromil / Q000627:therapeutic use*; D010641:Phenotype; D011110:Polymorphism, Genetic; D013997:Time Factors
chemical_list: D018927:Anti-Asthmatic Agents; D017835:Nedocromil; D019819:Budesonide
keywords: FEV1; NONMEM; asthma; longitudinal model