Investigation of manic and euthymic episodes identifies state- and trait-specific gene expression and STAB1 as a new candidate gene for bipolar disorder

Abstract

Bipolar disorder (BD) is a highly heritable psychiatric disease characterized by recurrent episodes of mania and depression. To identify new BD genes and pathways, the present study employed a three-step approach. First, gene-expression profiles of BD patients were assessed during both a manic and an euthymic phase. These profiles were compared intra-individually and with the gene-expression profiles of controls. Second, those differentially expressed genes that were considered potential trait markers of BD were validated using data from the Psychiatric Genomics Consortiums' genome-wide association study (GWAS) of BD. Third, the implicated molecular mechanisms were investigated using pathway analytical methods. In the present patients, this novel approach identified: (i) sets of differentially expressed genes specific to mania and euthymia; and (ii) a set of differentially expressed genes that were common to both mood states. In the GWAS data integration analysis, one gene (STAB1) remained significant (P=1.9 × 10−4) after adjustment for multiple testing. STAB1 is located in close proximity to PBMR1 and the NEK4-ITIH1-ITIH3-ITIH4 region, which are the top findings from GWAS meta-analyses of mood disorder, and a combined BD and schizophrenia data set. Pathway analyses in the mania versus control comparison revealed three distinct clusters of pathways tagging molecular mechanisms implicated in BD, for example, energy metabolism, inflammation and the ubiquitin proteasome system. The present findings suggest that STAB1 is a new and highly promising candidate gene in this region. The combining of gene expression and GWAS data may provide valuable insights into the biological mechanisms of BD.

Evaluation of European Schizophrenia GWAS Loci in Asian Populations via Comprehensive Meta-Analyses

“…Although showing strong associations with broader psychosis spectrum, the underlying molecular mechanism of these risk associations are yet to be determined. Previous studies have shown that the risk SNPs are associated with expression of GLT8D1, ITIH4, or STAB1 in different studies [20,22], and further investigations are needed.…”

“…Notably, rs2239547 is located in an extensive linkage disequilibrium (LD) block region that contained many genes and numerous high-linked SNPs [9]. In addition to schizophrenia, these risk loci also confer risk of bipolar disorder [19][20][21]. Although showing strong associations with broader psychosis spectrum, the underlying molecular mechanism of these risk associations are yet to be determined.…”

Novel genetic susceptibility loci identified by family based whole exome sequencing in Han Chinese schizophrenia patients

“…In this way, we found one gene stabilin 1 (STAB1) might contribute to schizophrenia susceptibility previously identified by pathway analysis 57 . Another study suggested that STAB1 is a new candidate gene for bipolar disorder combining of gene through expression and GWAS data 58 . Most noteworthy, we confirmed the importance of the NEK4-ITIH1-ITIH3-ITIH4 region locating in 3p21.1 (including PBRM1, STAB1) in the pathogenesis of psychiatric disease 41,42,59 .…”

Inter‐α‐inhibitor deficiency in the mouse is associated with alterations in anxiety‐like behavior, exploration and social approach

“…In the last few years, several gene‐wide association (GWA) studies have provided information on candidate genes that may predispose one to bipolar disorder and/or schizophrenia. Initial findings, that were subsequently replicated, suggested a candidate locus in chromosome 3p21, a region encompassing the genes NEK4‐ITIH1‐ITIH3‐ITIH4 . Inter‐α‐trypsin‐inhibitor (ITIH)1, ITIH3 and ITIH4 are members of the inter‐α‐inhibitor family, which has matrix stabilizing and anti‐inflammatory properties …”

“…Initial findings, that were subsequently replicated, suggested a candidate locus in chromosome 3p21, a region encompassing the genes NEK4-ITIH1-ITIH3-ITIH4. [3][4][5][6] Inter-α-trypsin-inhibitor (ITIH)1, ITIH3 and ITIH4 are members of the inter-α-inhibitor family, which has matrix stabilizing and anti-inflammatory properties. 7 Inter-α-inhibitor heavy chains ITIH1 and ITIH3 exist only in a complex with the light chain protein bikunin, which confers the trypsin-inhibitory activity that gives the protein its name.…”