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2016 ; 11
(9
): e0162910
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Pathway Analysis Incorporating Protein-Protein Interaction Networks Identified
Candidate Pathways for the Seven Common Diseases
#MMPMID27622767
Lin PL
; Yu YW
; Chung RH
PLoS One
2016[]; 11
(9
): e0162910
PMID27622767
show ga
Pathway analysis has become popular as a secondary analysis strategy for
genome-wide association studies (GWAS). Most of the current pathway analysis
methods aggregate signals from the main effects of single nucleotide
polymorphisms (SNPs) in genes within a pathway without considering the effects of
gene-gene interactions. However, gene-gene interactions can also have critical
effects on complex diseases. Protein-protein interaction (PPI) networks have been
used to define gene pairs for the gene-gene interaction tests. Incorporating the
PPI information to define gene pairs for interaction tests within pathways can
increase the power for pathway-based association tests. We propose a pathway
association test, which aggregates the interaction signals in PPI networks within
a pathway, for GWAS with case-control samples. Gene size is properly considered
in the test so that genes do not contribute more to the test statistic simply due
to their size. Simulation studies were performed to verify that the method is a
valid test and can have more power than other pathway association tests in the
presence of gene-gene interactions within a pathway under different scenarios. We
applied the test to the Wellcome Trust Case Control Consortium GWAS datasets for
seven common diseases. The most significant pathway is the chaperones modulate
interferon signaling pathway for Crohn's disease (p-value = 0.0003). The pathway
modulates interferon gamma, which induces the JAK/STAT pathway that is involved
in Crohn's disease. Several other pathways that have functional implications for
the seven diseases were also identified. The proposed test based on gene-gene
interaction signals in PPI networks can be used as a complementary tool to the
current existing pathway analysis methods focusing on main effects of genes. An
efficient software implementing the method is freely available at
http://puppi.sourceforge.net.