Sex-Based Genetic Association Study Identifies CELSR1 as a Possible Chronic Obstructive Pulmonary Disease Risk Locus among Women

Am J Respir Cell Mol Biol. 2017 Mar;56(3):332-341. doi: 10.1165/rcmb.2016-0172OC.

Abstract

Chronic obstructive pulmonary disease (COPD) is a complex disease with strong environmental and genetic influences and sexually dimorphic features. Although genetic risk factors for COPD have been identified, much of the heritability remains unexplained. Sex-based genetic association studies may uncover additional COPD genetic risk factors. We studied current and former smokers from COPD case-control cohorts (COPDGene non-Hispanic whites and African Americans, Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points, and Genetics of Chronic Obstructive Lung Disease). COPD was defined as post-bronchodilator forced expiratory volume in 1 second/forced vital capacity less than 0.70 and forced expiratory volume in 1 second percent predicted less than 80. Testing was performed across all cohorts and combined in a meta-analysis adjusted for age, pack-years, and genetic ancestry. We first performed genome-wide single-nucleotide polymorphism (SNP)-by-sex interaction testing on the outcome of COPD affection status. We performed sex-stratified association testing for SNPs with interaction P less than 10-6. We examined over 8 million SNPs in four populations, including 6,260 subjects with COPD (40.6% female) and 5,269 smoking control subjects (47.3% female). The SNP rs9615358 in the cadherin gene CELSR1 approached genome-wide significance for an interaction with sex (P = 1.24 × 10-7). In the sex-stratified meta-analysis, this SNP was associated with COPD among females (odds ratio, 1.37 [95% confidence interval, 1.25-1.49]; P = 3.32 × 10-7) but not males (odds ratio, 0.90 [95% confidence interval, 0.79-1.01]; P = 0.06). CELSR1 is involved in fetal lung development. In a human fetal lung tissue dataset, we observed greater CELSR1 expression in female compared with male samples. This SNP-by-sex genome-wide association analysis identified the fetal lung development gene, CELSR1, as a potential sex-specific risk factor for COPD. Identifying sex-specific genetic risk factors may reveal new insights into sexually dimorphic features of COPD.

Keywords: chronic obstructive pulmonary disease; genetics; genome-wide association study; growth and development; sex.

Publication types

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

MeSH terms

  • Aged
  • Alleles
  • Cadherins / genetics*
  • Demography
  • Female
  • Gene Expression Regulation
  • Genetic Loci*
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study*
  • Humans
  • Lung / metabolism
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide / genetics
  • Pulmonary Disease, Chronic Obstructive / genetics*
  • Risk Factors

Substances

  • CELSR1 cadherin, human
  • Cadherins