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Exploring the Wnt signaling pathway in schizophrenia and bipolar disorder.

ABSTRACT: The Wnt signaling pathway plays a crucial role in neurodevelopment and in regulating the function and structure of the adult nervous system. Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental disorders with evidence of subtle neurodevelopmental, structural and functional neuronal abnormalities. We aimed to elucidate the role of aberrant regulation of the Wnt system in these disorders by evaluating plasma levels of secreted Wnt modulators in patients (SCZ?=?551 and BD?=?246) and healthy controls (HCs?=?639) using enzyme immune-assay. We also investigated the expression of 141 Wnt-related genes in whole blood in a subsample (SCZ?=?338, BD?=?241, and HCs?=?263) using microarray analysis. Both SCZ and BD had dysregulated mRNA expression of Wnt-related genes favoring attenuated canonical (beta-catenin-dependent) signaling, and there were also indices of enhanced non-canonical Wnt signaling. In particular, FZD7, which may activate all Wnt pathways, but favors non-canonical signaling, and NFATc3, a downstream transcription factor and readout of the non-canonical Wnt/Ca2+ pathway, were significantly increased in SCZ and BD (p?

SUBMITTER: Hoseth EZ

PROVIDER: S-EPMC5838215 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Exploring the Wnt signaling pathway in schizophrenia and bipolar disorder.

Hoseth Eva Z EZ Krull Florian F Dieset Ingrid I Mørch Ragni H RH Hope Sigrun S Gardsjord Erlend S ES Steen Nils Eiel NE Melle Ingrid I Brattbakk Hans-Richard HR Steen Vidar M VM Aukrust Pål P Djurovic Srdjan S Andreassen Ole A OA Ueland Thor T

Translational psychiatry 20180306 1

The Wnt signaling pathway plays a crucial role in neurodevelopment and in regulating the function and structure of the adult nervous system. Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental disorders with evidence of subtle neurodevelopmental, structural and functional neuronal abnormalities. We aimed to elucidate the role of aberrant regulation of the Wnt system in these disorders by evaluating plasma levels of secreted Wnt modulators in patients (SCZ = 551 and BD = 246) and heal ...[more]

PMID: 29507296

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Project description:CONTEXT:The Wnt signaling pathways promote cell growth and are best known for their role in embryogenesis and cancer. Several lines of evidence suggest that these pathways might also be involved in bipolar disorder. OBJECTIVE:To test for an association between candidate genes in the Wnt signaling pathways and disease susceptibility in a family-based bipolar disorder study. DESIGN:Two hundred twenty-seven tagging single- nucleotide polymorphisms (SNPs) from 34 genes were successfully genotyped. Initial results led us to focus on the gene PPARD, in which we genotyped an additional 13 SNPs for follow-up. SETTING:Nine academic medical centers in the United States. PARTICIPANTS:Five hundred fifty-four offspring with bipolar disorder and their parents from 317 families. MAIN OUTCOME MEASURES:Family-based association using FBAT and HBAT (http://www.biostat.harvard.edu/~fbat/default.html; Harvard School of Public Health, Boston, Massachusetts). Exploratory analyses testing for interactions of PPARD SNPs with clinical covariates and with other Wnt genes were conducted with GENASSOC (Stata Corp, College Station, Texas). RESULTS:In the initial analysis, the most significantly associated SNP was rs2267665 in PPARD (nominal P < .001). This remained significant at P = .05 by permutation after accounting for all SNPs tested. Additional genotyping in PPARD yielded 4 SNPs in 1 haplotype block that were significantly associated with bipolar disorder (P < .01), the most significant being rs9462082 (P < .001). Exploratory analyses revealed significant evidence (P < .01) for interactions of rs9462082 with poor functioning on the Global Assessment Scale (odds ratio [OR], 3.36; 95% confidence interval [CI], 1.85-6.08) and with SNPs in WNT2B (rs3790606: OR, 2.56; 95% CI, 1.67-4.00) and WNT7A (rs4685048: OR, 1.79; 95% CI, 1.23-2.63). CONCLUSIONS:We found evidence for association of bipolar disorder with PPARD, a gene in the Wnt signaling pathway. The consistency of this result with one from the Wellcome Trust Case-Control Consortium encourages further study. If the finding can be confirmed in additional samples, it may illuminate a new avenue for understanding the pathogenesis of severe bipolar disorder and developing more effective treatments.

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Exploring the Wnt signaling pathway in schizophrenia and bipolar disorder.

Publications

Exploring the Wnt signaling pathway in schizophrenia and bipolar disorder.

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