A pathway analysis applied to Genetic Analysis Workshop 16 genome-wide rheumatoid arthritis data

Abstract

The identification of several hundred genomic regions affecting disease risk has proven the ability of genome-wide association studies have proven their ability to identify genetic contributors to disease. Currently, single-nucleotide polymorphism (SNP) association analysis is the most widely used method of genome-wide association data, but recent research shows that multi-marker tests of association may provide greater power, especially when more than one mutation is present within a gene and the mutations are in low linkage disequilibrium with each other. Here we use a multi-marker association test based on regression to SNPs located within known genes to obtain a gene-level score of association. We then perform pathway analysis using this score as a measure of gene importance. We use two tests of pathway enrichment - a binomial test and a random set method. By utilizing publicly available gene and pathway information, we identify B cell, cytokine and inflammation response, and antigen presentation pathways as being associated with rheumatoid arthritis. These results confirm known biological mechanisms for auto-immunity disorders, of which rheumatoid arthritis is one.

Breaking Free from the Chains of Pathway Annotation: de Novo Pathway Discovery for the Analysis of Disease Processes

“…Over the last few years pathway analysis has become an important tool in the analysis of GWAS and has successfully identified molecular pathways involved in human disease; for example, the identification of associations between immune-related pathways and Crohn's disease [28][29][30]36,37]. However, for other phenotypes, the results have been less reproducible.…”

Measles Contributes to Rheumatoid Arthritis: Evidence from Pathway and Network Analyses of Genome-Wide Association Studies

“…RA affects approximately 1% of the adult population worldwide [2]. According to the National Institute of Arthritis and Musculoskeletal and Skin Diseases, about 1.3 million adults in the U.S. suffer from RA [3]. RA is a complex disease caused by a combination of genetic susceptibility and environmental factors [4].…”

“…We consider that the strong association between both diseases may be caused by shared genetic pathways. Fortunately, pathway-based method to study existing GWAS datasets has been applied into RA [3], [14], [15], [16], [17], [18], [19], [20]. However, no study reported the involvement of measles in RA.…”

“…However, no study reported the involvement of measles in RA. We found that all the pathway analyses used the Wellcome Trust Case-Control Consortium (WTCCC) or North American Rheumatoid Arthritis Consortium (NARAC) dataset or both datasets [3], [14], [15], [16], [17], [18], [19], [20]. We think that the study power would benefit from examining large-scale GWAS datasets.…”

Pathway-based identification of SNPs predictive of survival

“…4 Ballard et al performed two pathway-based tests, a binomial test and a random set method to identify pathways associated with rheumatoid arthritis. 5 Wang et al utilized a modified gene set enrichment method for SNP data to identify pathways associated with Crohn's disease. 6 Both Wang et al and Dinu et al performed pathway-based analyses to study age-related macular degeneration.…”