Pathways-based analyses of whole-genome association study data in bipolar disorder reveal genes mediating ion channel activity and synaptic neurotransmission

Abstract

Despite known heritability, the complex genetic architecture of bipolar disorder (likely including trait, locus and allelic heterogeneity, as well as genetic interactions) has confounded genetic discovery for many years. Even modern day whole genome association studies (WGAS) using over half a million common SNPs have implicated only a handful of genes at the genomewide level. Temporally coincident with this series of WGAS, a host of pathways-based analyses (PBAs) have emerged as novel computational approaches in the examination of large-scale datasets, but thus far rarely have been applied to WGAS data in psychiatric disorders. Here, we report a series of PBAs conducted using exploratory visual analysis, an analytic and visualization software tool for examining genomic data, to examine results from the National Institutes of Mental Health and Wellcome-Trust Case Control Consortium WGAS in bipolar disorder. Consistent with a host of prior linkage findings, some candidate gene association studies, and recent WGAS, our strongest findings suggest involvement of ion channel structural and regulatory genes, including voltage-gated ion channels and the broader ion channel group that comprises both voltage- and ligand-gated channels. Moreover, we found only modest overlap in the particular genes driving the significance of these gene sets across the analyses. This observation strongly suggests that variation in ion channel genes, as a class of genes, may contribute to the susceptibility of bipolar disorder and that heterogeneity may figure prominently in the genetic architecture of this susceptibility.

RETRACTED: Identification of gene ontologies linked to prefrontal–hippocampal functional coupling in the human brain

“…Increasing evidence suggests that common genetic risk variants for psychiatric disorders are not distributed randomly but rather lie among sets of genes with overlapping functions (19)(20)(21)(22). Gene set enrichment analysis (GSEA) is a data analytical approach that leverages a priori knowledge to gain insight into the biological functions of genes and pathways in the analysis of genetic data (23,24).…”

Neuronal cell adhesion genes

“…Many groups have been developing pathway-based approaches to analyzing genome-wide association datasets and our SNP-ratio test (SRT) is just one such approach. [7][8][9][10][11][12][13] The SRT can be applied flexibly to different pathway resources as a hypothesis-free test, which simply identifies whether there are more nominally significant SNPs in genes mapping to that pathway in cases in a GWAS dataset than to genes mapping to all other indicated pathways. 7 Applying this approach to the Kyoto Encyclopedia of Genes and Genomes (KEGG) database of 212 experimentally-derived pathways we captured information on 4,760 genes.…”

Molecular pathways involved in neuronal cell adhesion and membrane scaffolding contribute to schizophrenia and bipolar disorder susceptibility

“…A number of formal pathway-based analytical methods have been described previously [6][7][8][9][10][11] and are reviewed elsewhere. 9,12 In this study, we used the SNP ratio test (SRT) 10 for the following reasons.…”