Gene, pathway and network frameworks to identify epistatic interactions of single nucleotide polymorphisms derived from GWAS data.

Authors:
Yu Liu
Yu Liu
State Key Laboratory of Ophthalmology
Singapore
Sean Maxwell
Sean Maxwell
Case Western Reserve University
United States
Tao Feng
Tao Feng
Kunming Institute of Botany
China
Xiaofeng Zhu
Xiaofeng Zhu
School of Medicine
Baltimore | United States
Robert C Elston
Robert C Elston
Case Western Reserve University
United States
Mark R Chance
Mark R Chance
Case Western Reserve University
United States

BMC Syst Biol 2012 17;6 Suppl 3:S15. Epub 2012 Dec 17.

Center for Proteomics and Bioinformatics, Case Western Reserve University, Cleveland, OH, USA.

Background: Interactions among genomic loci (also known as epistasis) have been suggested as one of the potential sources of missing heritability in single locus analysis of genome-wide association studies (GWAS). The computational burden of searching for interactions is compounded by the extremely low threshold for identifying significant p-values due to multiple hypothesis testing corrections. Utilizing prior biological knowledge to restrict the set of candidate SNP pairs to be tested can alleviate this problem, but systematic studies that investigate the relative merits of integrating different biological frameworks and GWAS data have not been conducted.

Results: We developed four biologically based frameworks to identify pairwise interactions among candidate SNP pairs as follows: (1) for each human protein-coding gene, a set of SNPs associated with that gene was constructed providing a gene-based interaction model, (2) for each known biological pathway, a set of SNPs associated with the genes in the pathway was constructed providing a pathway-based interaction model, (3) a set of SNPs associated with genes in a disease-related subnetwork provides a network-based interaction model, and (4) a framework is based on the function of SNPs. The last approach uses expression SNPs (eSNPs or eQTLs), which are SNPs or loci that have defined effects on the abundance of transcripts of other genes. We constructed pairs of eSNPs and SNPs located in the target genes whose expression is regulated by eSNPs. For all four frameworks the SNP sets were exhaustively tested for pairwise interactions within the sets using a traditional logistic regression model after excluding genes that were previously identified to associate with the trait. Using previously published GWAS data for type 2 diabetes (T2D) and the biologically based pair-wise interaction modeling, we identify twelve genes not seen in the previous single locus analysis.

Conclusion: We present four approaches to detect interactions associated with complex diseases. The results show our approaches outperform the traditional single locus approaches in detecting genes that previously did not reach significance; the results also provide novel drug targets and biomarkers relevant to the underlying mechanisms of disease.

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http://dx.doi.org/10.1186/1752-0509-6-S3-S15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3524014PMC
June 2013
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