Epistasis Blog

From the Computational Genetics Laboratory at the University of Pennsylvania (www.epistasis.org)

Tuesday, December 20, 2016

Complex systems analysis of bladder cancer susceptibility reveals a role for decarboxylase activity in two genome-wide association studies

An example of combining epistasis analysis and pathway analysis to get more value out of GWAS

Cheng S, Andrew AS, Andrews PC, Moore JH. Complex systems analysis of bladder cancer susceptibility reveals a role for decarboxylase activity in two genome-wide association studies. BioData Min. 2016 Dec 12;9:40. [PDF]

Abstract

BACKGROUND:
Bladder cancer is common disease with a complex etiology that is likely due to many different genetic and environmental factors. The goal of this study was to embrace this complexity using a bioinformatics analysis pipeline designed to use machine learning to measure synergistic interactions between single nucleotide polymorphisms (SNPs) in two genome-wide association studies (GWAS) and then to assess their enrichment within functional groups defined by Gene Ontology. The significance of the results was evaluated using permutation testing and those results that replicated between the two GWAS data sets were reported.

RESULTS:
In the first step of our bioinformatics pipeline, we estimated the pairwise synergistic effects of SNPs on bladder cancer risk in both GWAS data sets using Multifactor Dimensionality Reduction (MDR) machine learning method that is designed specifically for this purpose. Statistical significance was assessed using a 1000-fold permutation test. Each single SNP was assigned a p-value based on its strongest pairwise association. Each SNP was then mapped to one or more genes using a window of 500 kb upstream and downstream from each gene boundary. This window was chosen to capture as many regulatory variants as possible. Using Exploratory Visual Analysis (EVA), we then carried out a gene set enrichment analysis at the gene level to identify those genes with an overabundance of significant SNPs relative to the size of their mapped regions. Each gene was assigned to a biological functional group defined by Gene Ontology (GO). We next used EVA to evaluate the overabundance of significant genes in biological functional groups. Our study yielded one GO category, carboxy-lysase activity (GO:0016831), that was significant in analyses from both GWAS data sets. Interestingly, only the gamma-glutamyl carboxylase (GGCX) gene from this GO group was significant in both the detection and replication data, highlighting the complexity of the pathway-level effects on risk. The GGCX gene is expressed in the bladder, but has not been previously associated with bladder cancer in univariate GWAS. However, there is some experimental evidence that carboxy-lysase activity might play a role in cancer and that genes in this pathway should be explored as drug targets. This study provides a genetic basis for that observation.

CONCLUSIONS:
Our machine learning analysis of genetic associations in two GWAS for bladder cancer identified numerous associations with pairs of SNPs. Gene set enrichment analysis found aggregation of risk-associated SNPs in genes and significant genes in GO functional groups. This study supports a role for decarboxylase protein complexes in bladder cancer susceptibility. Previous research has implicated decarboxylases in bladder cancer etiology; however, the genes that we found to be significant in the detection and replication data are not known to have direct influence on bladder cancer, suggesting some novel hypotheses. This study highlights the need for a complex systems approach to the genetic and genomic analysis of common diseases such as cancer.

Wednesday, December 14, 2016

A global test for gene-gene interactions based on random matrix theory

Frost HR, Amos CI, Moore JH. A global test for gene-gene interactions based on random matrix theory. Genet Epidemiol. 2016 Dec;40(8):689-701. [PubMed]

Abstract


Statistical interactions between markers of genetic variation, or gene-gene interactions, are believed to play an important role in the etiology of many multifactorial diseases and other complex phenotypes. Unfortunately, detecting gene-gene interactions is extremely challenging due to the large number of potential interactions and ambiguity regarding marker coding and interaction scale. For many data sets, there is insufficient statistical power to evaluate all candidate gene-gene interactions. In these cases, a global test for gene-gene interactions may be the best option. Global tests have much greater power relative to multiple individual interaction tests and can be used on subsets of the markers as an initial filter prior to testing for specific interactions. In this paper, we describe a novel global test for gene-gene interactions, the global epistasis test (GET), that is based on results from random matrix theory. As we show via simulation studies based on previously proposed models for common diseases including rheumatoid arthritis, type 2 diabetes, and breast cancer, our proposed GET method has superior performance characteristics relative to existing global gene-gene interaction tests. A glaucoma GWAS data set is used to demonstrate the practical utility of the GET method.