Integrated genome-wide association, coexpression network, and expression single nucleotide polymorphism analysis identifies novel pathway in allergic rhinitis

Abstract

BackgroundAllergic rhinitis is a common disease whose genetic basis is incompletely explained. We report an integrated genomic analysis of allergic rhinitis.MethodsWe performed genome wide association studies (GWAS) of allergic rhinitis in 5633 ethnically diverse North American subjects. Next, we profiled gene expression in disease-relevant tissue (peripheral blood CD4+ lymphocytes) collected from subjects who had been genotyped. We then integrated the GWAS and gene expression data using expression single nucleotide (eSNP), coexpression network, and pathway approaches to identify the biologic relevance of our GWAS.ResultsGWAS revealed ethnicity-specific findings, with 4 genome-wide significant loci among Latinos and 1 genome-wide significant locus in the GWAS meta-analysis across ethnic groups. To identify biologic context for these results, we constructed a coexpression network to define modules of genes with similar patterns of CD4+ gene expression (coexpression modules) that could serve as constructs of broader gene expression. 6 of the 22 GWAS loci with P-value ≤ 1x10−6 tagged one particular coexpression module (4.0-fold enrichment, P-value 0.0029), and this module also had the greatest enrichment (3.4-fold enrichment, P-value 2.6 × 10−24) for allergic rhinitis-associated eSNPs (genetic variants associated with both gene expression and allergic rhinitis). The integrated GWAS, coexpression network, and eSNP results therefore supported this coexpression module as an allergic rhinitis module. Pathway analysis revealed that the module was enriched for mitochondrial pathways (8.6-fold enrichment, P-value 4.5 × 10−72).ConclusionsOur results highlight mitochondrial pathways as a target for further investigation of allergic rhinitis mechanism and treatment. Our integrated approach can be applied to provide biologic context for GWAS of other diseases.

Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease

“…This type of probabilistic causal network structure has previously been demonstrated to represent biologically functional pathways across a broad range of diseases including obesity and diabetes (20, 51–53), asthma and COPD (54, 55), and Alzheimer’s disease (56). We next excluded genes previously associated with PD (23), including LRRK2 , as well as genes within 1 Mb of LRRK2 to see whether either LRRK2 or other genes could be “recovered” by the network as being co-expressed with the IBD-associated genes.…”

Systems biology of asthma and allergic diseases: A multiscale approach

“…27 GWAS of ethnically diverse North American subjects identified distinct genome-wide significant loci among Latinos, with integrative genomic analyses showing enrichment of the identified GWAS loci for mitochondrial pathways. 28 …”

Linking childhood allergic asthma phenotypes with endotype through integrated systems biology: current evidence and research needs

“…Gene-based coexpression network analyses together with expression single nucleotide polymorphism (eSNP) provide a powerful framework by pinpointing GWAS loci for eSNPs and mapping these GWAS hit genes to relevant modules/interactome representing disease-driven functional pathways (13,70). Bunyavanich et al (70) report mitochondria module from CD41+ lymphocytes gene expression data, showing an effect of the GWAS hits. In the absence of such genotype data, coexpression network analyses alone can further provide meaningful interactomes of genes associated to asthma symptoms.…”

“…To date, there are several GWAS on allergic rhinitis (70): National Human Genome Research Institute catalogs one GWAS of allergic rhinitis comparing 33 for asthma and 61 diabetes (71), Andiappan et al report no significant GWAS loci for 942 Chinese subject, Ramasamy et al report one genome-wide significant locus in a GWAS meta-analysis of 12,898 Europeans (71), and Hinds et al report 16 genome-wide significant loci for self-reported allergy in a GWAS meta-analysis of subjects of European ancestry (72). To a broader context, Torgerson et al (73) report five asthma-susceptible loci from 5416 individuals in diverse North American population, replicated in additional 12,649 individuals from the same ethnic groups.…”

“…GSEA does limit the discovery of critical regulators within the context of known pathways only. It is often accompanied by coexpression network analyses to perform unsupervised module detection and to identify enriched pathways in these modules to further guide the data inference (12,13,70).…”