Abstract
Bipolar disorder (BPD) is a complex psychiatric trait with high heritability. Despite efforts through conducting genome-wide association (GWA) studies, the success of identifying susceptibility loci for BPD has been limited, which is partially attributed to the complex nature of its pathogenesis. Pathway-based analytic strategy is a powerful tool to explore joint effects of gene sets within specific biological pathways. Additionally, to incorporate other aspects of genomic data into pathway analysis may further enhance our understanding for the underlying mechanisms for BPD. Patterns of DNA methylation play important roles in regulating gene expression and function. A commonly observed phenomenon, allele-specific methylation (ASM) describes the associations between genetic variants and DNA methylation patterns. The present study aimed to identify biological pathways that are involve in the pathogenesis of BPD while incorporating brain specific ASM information in pathway analysis using two large-scale GWA datasets in Caucasian populations. A weighting scheme was adopted to take ASM information into consideration for each pathway. After multiple testing corrections, we identified 88 and 15 enriched pathways for their biological relevance for BPD in the Genetic Association Information Network (GAIN) and the Wellcome Trust Case Control Consortium dataset, respectively. Many of these pathways were significant only when applying the weighting scheme. Three ion channel related pathways were consistently identified in both datasets. Results in the GAIN dataset also suggest for the roles of extracellular matrix in brain for BPD. Findings from Gene Ontology (GO) analysis exhibited functional enrichment among genes of non-GO pathways in activity of gated channel, transporter, and neurotransmitter receptor. We demonstrated that integrating different data sources with pathway analysis provides an avenue to identify promising and novel biological pathways for exploring the underlying molecular mechanisms for bipolar disorder. Further basic research can be conducted to target the biological mechanisms for the identified genes and pathways.
Highlights
Bipolar disorder (BPD) is a severe and complex psychiatric disorder, with high heritability around 0.6 to 0.7 [1,2]
The MsigDB consists of several available online sources of pathway databases and manually curated pathways from the literature, including Kyoto Encyclopedia of Genes and Genomes (KEGG), BioCarta, Reactome, Gene Ontology (GO) terms, and gene sets compiled from published biomedical literature [24], which listed 4,726 pathways and 22,429 genes
We identified 15 pathways (11 of them were identified only when weighting procedure is applied for the allele-specific methylation (ASM) set) in the Wellcome Trust Case Control Consortium (WTCCC) dataset with p-value less than 0.01 after Benjamini and Hochberg (BH) correction (Table S2)
Summary
Bipolar disorder (BPD) is a severe and complex psychiatric disorder, with high heritability around 0.6 to 0.7 [1,2]. Prior individual linkage studies and meta-analyses suggested a number of susceptible regions in human genome for the risk of developing BPD. Most of these findings are inconsistent and rarely pointed to specific chromosomal locations for replication [3]. The GWA studies were anticipated to provide comprehensive genetic information for complex traits, previous GWA studies for BPD reported limited numbers of susceptible loci with small effect size. The reported associated variants from GWA studies often explain a small proportion of heritability for complex traits, a so called ‘missing heritability’ phenomenon [9]. Missing heritability may be owing to lack of power to detect common variants with very small effect, not including rare variants for their effects in whole-genomic array, or not considering other genomic mechanisms, such as complex gene-gene interaction and epigenetic influences [10]
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