ADAM19 and HTR4 variants and pulmonary function cohorts for heart and aging research in genomic epidemiology (charge) consortium targeted sequencing study

Stephanie J. London, Wei Gao, Sina A. Gharib, Dana B. Hancock, Jemma B. Wilk, John S. House, Richard A. Gibbs, Donna M. Muzny, Thomas Lumley, Nora Franceschini, Kari E. North, Bruce M. Psaty, Christie L. Kovar, Josef Coresh, Yanhua Zhou, Susan R. Heckbert, Jennifer A. Brody, Alanna Cée Morrison

Research output: Contribution to journalArticlepeer-review

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. Methods and 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 singlenucleotide 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.

Original languageEnglish (US)
Pages (from-to)350-358
Number of pages9
JournalCirculation: Cardiovascular Genetics
Volume7
Issue number3
DOIs
StatePublished - Jun 2014

Keywords

  • Airway Obstruction
  • Chronic obstructive
  • DNA
  • Genome-wide association study
  • Lung
  • Polymorphism, genetic
  • Pulmonary disease
  • Respiratory function tests
  • Sequence analysis

ASJC Scopus subject areas

  • Genetics
  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'ADAM19 and HTR4 variants and pulmonary function cohorts for heart and aging research in genomic epidemiology (charge) consortium targeted sequencing study'. Together they form a unique fingerprint.

Cite this