Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function

PLoS Genet. 2012;8(12):e1003098. doi: 10.1371/journal.pgen.1003098. Epub 2012 Dec 20.

Abstract

Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV(1) and FEV(1)/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P(JMA = )5.00×10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA = )4.35×10(-9)), and KCNJ2 and SOX9 (smallest P(JMA = )1.28×10(-8)) were associated with FEV(1)/FVC or FEV(1) in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Forced Expiratory Volume / genetics*
  • Gene Expression
  • Genome, Human
  • Genome-Wide Association Study*
  • HLA-DQ Antigens / genetics
  • HLA-DQ beta-Chains / genetics
  • Humans
  • Lung / metabolism
  • Lung / physiopathology
  • Nerve Tissue Proteins / genetics
  • Polymorphism, Single Nucleotide
  • Potassium Channels, Inwardly Rectifying / genetics
  • Pulmonary Disease, Chronic Obstructive* / genetics
  • Pulmonary Disease, Chronic Obstructive* / physiopathology
  • Receptors, Cell Surface / genetics
  • SOX9 Transcription Factor / genetics
  • Smoking* / genetics
  • Smoking* / physiopathology
  • Vital Capacity / genetics*

Substances

  • DNER protein, human
  • HLA-DQ Antigens
  • HLA-DQ beta-Chains
  • HLA-DQA2 antigen
  • HLA-DQB1 antigen
  • KCNJ2 protein, human
  • Nerve Tissue Proteins
  • Potassium Channels, Inwardly Rectifying
  • Receptors, Cell Surface
  • SOX9 Transcription Factor
  • SOX9 protein, human

Grant support