title: ADAM19 and HTR4 variants and pulmonary function: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.
abstract: BACKGROUND
  The pulmonary function measures of forced expiratory volume in 1 second (FEV1) and its ratio to forced vital capacity (FVC) are used in the diagnosis and monitoring of lung diseases and predict cardiovascular mortality in the general population. Genome-wide association studies (GWASs) have identified numerous loci associated with FEV1 and FEV1/FVC, but the causal variants remain uncertain. We hypothesized that novel or rare variants poorly tagged by GWASs may explain the significant associations between FEV1/FVC and 2 genes: ADAM19 and HTR4.
  
  
  RESULTS
  We sequenced ADAM19 and its promoter region along with the ≈21-kb portion of HTR4 harboring GWAS single-nucleotide polymorphisms for pulmonary function and analyzed associations with FEV1/FVC among 3983 participants of European ancestry from Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Meta-analysis of common variants in each region identified statistically significant associations (316 tests; P<1.58×10(-4)) with FEV1/FVC for 14 ADAM19 single-nucleotide polymorphisms and 24 HTR4 single-nucleotide polymorphisms. After conditioning on the sentinel GWASs hit in each gene (ADAM19 rs1422795, minor allele frequency=0.33 and HTR4 rs11168048, minor allele frequency=0.40], 1 single-nucleotide polymorphism remained statistically significant (ADAM19 rs13155908, minor allele frequency=0.12; P=1.56×10(-4)). Analysis of rare variants (minor allele frequency <1%) using sequence kernel association test did not identify associations with either region.
  
  
  CONCLUSIONS
  Sequencing identified 1 common variant associated with FEV1/FVC independent of the sentinel ADAM19 GWAS hit and supports the original HTR4 GWAS findings. Rare variants do not seem to underlie GWAS associations with pulmonary function for common variants in ADAM19 and HTR4.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: London
authors.forename: Wei
authors.initials: W
authors.lastname: Gao
authors.forename: Sina A
authors.initials: SA
authors.lastname: Gharib
authors.forename: Dana B
authors.initials: DB
authors.lastname: Hancock
authors.forename: Jemma B
authors.initials: JB
authors.lastname: Wilk
authors.forename: John S
authors.initials: JS
authors.lastname: House
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.forename: Thomas
authors.initials: T
authors.lastname: Lumley
authors.forename: Nora
authors.initials: N
authors.lastname: Franceschini
authors.forename: Kari E
authors.initials: KE
authors.lastname: North
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
authors.forename: Christie L
authors.initials: CL
authors.lastname: Kovar
authors.forename: Josef
authors.initials: J
authors.lastname: Coresh
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Zhou
authors.forename: Susan R
authors.initials: SR
authors.lastname: Heckbert
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Brody
authors.forename: Alanna C
authors.initials: AC
authors.lastname: Morrison
authors.forename: Josée
authors.initials: J
authors.lastname: Dupuis
mesh_terms: D051722:ADAM Proteins / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D023281:Genomics; D006331:Heart Diseases / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D008168:Lung / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA
chemical_list: D051722:ADAM Proteins; C411902:ADAM19 protein, human
keywords: Airway Obstruction; genome-wide association study; lung; polymorphism, genetic; pulmonary disease, chronic obstructive; respiratory function tests; sequence analysis, DNA