Genetic Pathways and Functional Subnetworks for the Complex Nature of Bipolar Disorder in Genome-Wide Association Study

Abstract

Bipolar disorder is a complex psychiatric trait that is also recognized as a high substantial heritability from a worldwide distribution. The success in identifying susceptibility loci for bipolar disorder (BPD) has been limited due to its complex genetic architecture. Growing evidence from association studies including genome-wide association (GWA) studies points to the need of improved analytic strategies to pinpoint the missing heritability for BPD. More importantly, many studies indicate that BPD has a strong association with dementia. We conducted advanced pathway analytics strategies to investigate synergistic effects of multilocus within biologically functional pathways, and further demonstrated functional effects among proteins in subnetworks to examine mechanisms underlying the complex nature of bipolarity using a GWA dataset for BPD. We allowed bipolar susceptible loci to play a role that takes larger weights in pathway-based analytic approaches. Having significantly informative genes identified from enriched pathways, we further built function-specific subnetworks of protein interactions using MetaCore. The gene-wise scores (i.e., minimum p-value) were corrected for the gene-length, and the results were corrected for multiple tests using Benjamini and Hochberg’s method. We found 87 enriched pathways that are significant for BPD; of which 36 pathways were reported. Most of them are involved with several metabolic processes, neural systems, immune system, molecular transport, cellular communication, and signal transduction. Three significant and function-related subnetworks with multiple hotspots were reported to link with several Gene Ontology processes for BPD. Our comprehensive pathway-network frameworks demonstrated that the use of prior knowledge is promising to facilitate our understanding between complex psychiatric disorders (e.g., BPD) and dementia for the access to the connection and clinical implications, along with the development and progression of dementia.

Immunoglobulin genes expressed in lymphoblastoid cell lines discern and predict lithium response in bipolar disorder patients

“…Apart from the immunoglobulin genes, we found the HLA-U, ZNF300, and TRAT1 genes to be significantly downregulated in NR subtypes. Interestingly, previous GWAS studies have reported the association of these genes with BD and other psychiatric disorders [ 73 – 75 ]. HLA-U is a pseudogene found on the MHC complex [ 76 ].…”

Bipolar spectrum disorders in neurologic disorders

“…A recent GWAS analysis has found 87 enriched pathways that are relevant for BSD. Most are involved in cellular processes, signal transduction, metabolic processes, neuronal activities, immune system, and inflammation-related processes ( 143 ). Six of these metabolic pathways (drug metabolism, retinol metabolism, pentose and glucuronate interconversions, porphyrin and chlorophyll metabolism, starch and sucrose metabolism, ascorbate, and aldarate metabolism) were connected to dementia-related mechanisms, thereby suggesting links between BSD and the risk of dementia ( 143 ).…”