Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function
Author(s)
Type
Journal Article
Abstract
Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function,
forced expiratory volume in one second (FEV1), and its ratio to forced vital capacity (FEV1/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 FEV1 and FEV1/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 PJMA = 5.00610211), HLA-DQB1 and HLA-DQA2 (smallest PJMA = 4.3561029
), and KCNJ2 and SOX9 (smallest
PJMA = 1.2861028
) were associated with FEV1/FVC or FEV1 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.
forced expiratory volume in one second (FEV1), and its ratio to forced vital capacity (FEV1/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 FEV1 and FEV1/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 PJMA = 5.00610211), HLA-DQB1 and HLA-DQA2 (smallest PJMA = 4.3561029
), and KCNJ2 and SOX9 (smallest
PJMA = 1.2861028
) were associated with FEV1/FVC or FEV1 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.
Date Issued
2012-12-01
Date Acceptance
2012-10-01
Citation
PLOS Genetics, 2012, 8 (12)
ISSN
1553-7390
Publisher
Public Library of Science
Journal / Book Title
PLOS Genetics
Volume
8
Issue
12
Copyright Statement
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for
any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
License URL
Sponsor
Medical Research Council (MRC)
Grant Number
G0801056B
Subjects
Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
GENETICS & HEREDITY
GENE-ENVIRONMENT INTERACTION
AIR-FLOW OBSTRUCTION
SMOOTH-MUSCLE-CELLS
CLASS-II ANTIGENS
BODY-MASS INDEX
LUNG-FUNCTION
FOLLOW-UP
RHEUMATOID-ARTHRITIS
SIGNALING CONTROLS
COMMON VARIANTS
Publication Status
Published
Article Number
e1003098