21 research outputs found
Integrative pathway genomics of lung function and airflow obstruction
Chronic respiratory disorders are important contributors to the global burden of disease. Genome-wide association studies (GWASs) of lung function measures have identified several trait-associated loci, but explain only a modest portion of the phenotypic variability. We postulated that integrating pathway-based methods with GWASs of pulmonary function and airflow obstruction would identify a broader repertoire of genes and processes influencing these traits. We performed two independent GWASs of lung function and applied gene set enrichment analysis to one of the studies and validated the results using the second GWAS. We identified 131 significantly enriched gene sets associated with lung function and clustered them into larger biological modules involved in diverse processes including development, immunity, cell signalling, proliferation and arachidonic acid. We found that enrichment of gene sets was not driven by GWAS-significant variants or loci, but instead by those with less stringent association P-values. Next, we applied pathway enrichment analysis to a meta-analysed GWAS of airflow obstruction. We identified several biologic modules that functionally overlapped with those associated with pulmonary function. However, differences were also noted, including enrichment of extracellular matrix (ECM) processes specifically in the airflow obstruction study. Network analysis of the ECM module implicated a candidate gene, matrix metalloproteinase 10 (MMP10), as a putative disease target. We used a knockout mouse model to functionally validate MMP10’s role in influencing lung’s susceptibility to cigarette smoke-induced emphysema. By integrating pathway analysis with population-based genomics, we unravelled biologic processes underlying pulmonary function traits and identified a candidate gene for obstructive lung disease
Study populations included in GWI study on active smoking and adult onset asthma.
<p>Study populations included in GWI study on active smoking and adult onset asthma.</p
Forest plots for the meta-analysis and replication study on the genetic effect of SNP rs5011804 on chromosome 12 in subjects exposed and non-exposed to ever active tobacco smoking (identified in second approach).
<p>The bottom forest plot presents the interaction meta-analysis and replication study for this SNP. ORs are calculated using a fixed effect model.</p
Forest plot for meta-analysis on the association between ever active tobacco smoking and adult onset asthma, without including the genetic effect.
<p>Forest plot for meta-analysis on the association between ever active tobacco smoking and adult onset asthma, without including the genetic effect.</p
Forest plots for the meta-analysis and replication study on the genetic effect of SNP rs9969775 on chromosome 9 in subjects exposed and non-exposed to ever active tobacco smoking (identified in first approach).
<p>The bottom forest plot presents the interaction meta-analysis and replication study for this SNP. ORs are calculated using a fixed effect model.</p
Top SNPs that interact with active tobacco smoking in adult onset asthma identified in first approach (overall interaction effect)<sup>#</sup>.
<p>Top SNPs that interact with active tobacco smoking in adult onset asthma identified in first approach (overall interaction effect)<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0172716#t002fn001" target="_blank"><sup>#</sup></a>.</p
Top SNPs that interact with active tobacco smoking in adult onset asthma identified in second approach (genetic effect in exposed)<sup>#</sup>.
<p>Top SNPs that interact with active tobacco smoking in adult onset asthma identified in second approach (genetic effect in exposed)<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0172716#t003fn001" target="_blank"><sup>#</sup></a>.</p
Top SNPs that interact with active tobacco smoking in adult onset asthma identified in both approaches<sup>#</sup>.
<p>Top SNPs that interact with active tobacco smoking in adult onset asthma identified in both approaches<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0172716#t004fn001" target="_blank"><sup>#</sup></a>.</p
Genetic effect of SNP rs5011804 following an additive model in the LifeLines cohort (N = 12,475), stratified by different tobacco smoke exposures.
<p>Genetic effect of SNP rs5011804 following an additive model in the LifeLines cohort (N = 12,475), stratified by different tobacco smoke exposures.</p