Do mood symptoms subdivide the schizophrenia phenotype? Association of the GMP6A gene with a depression subgroup
Genetic studies of clinically defined subgroups of schizophrenia patients may reduce the phenotypic heterogeneity of schizophrenia and thus facilitate the identification of genes that confer risk to this disorder. Several latent class analyses have provided subgroups of psychotic disorders that show considerable consistency over these studies. The presence or absence of mood symptoms was found to contribute most to the delineations of these subgroups. In this study we used six previously published subtypes of psychosis derived from latent class analysis of a large sample of psychosis patients. In 280 schizophrenia patients and 525 healthy controls we investigated the associations of these subgroups with myelin related genes. After bonferroni correction we found an association of the glycoprotein M6A gene (GPM6A) with the subgroup of schizophrenia patients with high levels of depression (P-corrected = 0.006). Borderline association of the microtubulin associated protein tau (MAPT) with a primarily non-affective group of schizophrenia patients (P-corrected = 0.052) was also observed. GPM6A modulates the influence of stress on the hippocampus in animals. Thus our findings could suggest that GMP6A plays a role in the stress-induced hippocampal alterations that are found in psychiatric disorders in general and schizophrenia in particular. Overall, these finding suggests that investigating subgroups of schizophrenia based symptoms profile and particularly mood symptoms can facilitate genetic studies of schizophrenia.
[Show abstract] [Hide abstract] ABSTRACT: There is increasing evidence that depression derives from the impact of environmental pressure on genetically susceptible individuals. We analyzed the effects of chronic mild stress (CMS) on prefrontal cortex transcriptome of two strains of mice bred for high (HA)and low (LA) swim stress-induced analgesia that differ in basal transcriptomic profiles and depression-like behaviors. We found that CMS affected 96 and 92 genes in HA and LA mice, respectively. Among genes with the same expression pattern in both strains after CMS, we observed robust upregulation of Ttr gene coding transthyretin involved in amyloidosis, seizures, stroke-like episodes, or dementia. Strain-specific HA transcriptome affected by CMS was associated with deregulation of genes involved in insulin secretion (Acvr1c, Nnat, and Pfkm), neuropeptide hormone activity (Nts and Trh), and dopamine receptor mediated signaling pathway (Clic6, Drd1a, and Ppp1r1b). LA transcriptome affected by CMS was associated with genes involved in behavioral response to stimulus (Fcer1g, Rasd2, S100a8, S100a9, Crhr1, Grm5, and Prkcc), immune effector processes (Fcer1g, Mpo, and Igh-VJ558), diacylglycerol binding (Rasgrp1, Dgke, Dgkg, and Prkcc), and long-term depression (Crhr1, Grm5, and Prkcc) and/or coding elements of dendrites (Crmp1, Cntnap4, and Prkcc) and myelin proteins (Gpm6a, Mal, and Mog). The results indicate significant contribution of genetic background to differences in stress response gene expression in the mouse prefrontal cortex. Electronic supplementary material The online version of this article (doi:10.1007/s12031-012-9850-1) contains supplementary material, which is available to authorized users.0Comments 15Citations
- "In our previous study, we found downregulation of Gpm6a in hippocampus of LA mice after CMS (Lisowski et al. 2011). GMP6A may play a role in the stress-induced hippocampal alterations that are found in psychiatric disorders (Boks et al. 2008). Mal encodes integral membrane protein belonging to the MAL family of proteolipids involved in myelin biogenesis and function. "
[Show abstract] [Hide abstract] ABSTRACT: The presence of a psychosis continuum is suggested by studies showing that schizophrenia and non-clinical psychotic symptoms in the general population share the same risk factors. However, to our knowledge no large-scale studies have been conducted which examine the specificity of these risk factors in the general population. To investigate whether socio-demographic characteristics associated with non-clinical psychotic symptoms are also associated with other psychiatric symptoms. And secondly, to examine to what extent concomitant psychiatric symptoms explain the relationship between socio-demographic characteristics and non-clinical psychotic symptoms. In a general population sample of 4894 subjects (mean age 39 years, 45% men) from the Utrecht Health Project we investigated the associations of socio-demographical characteristics with non-clinical psychotic symptoms and other psychiatric symptoms by using the SCL-90. We examined these associations using multivariable logistic regression analyses with and without controlling for the presence of other psychiatric symptoms. Participants with non-clinical psychotic symptoms had an 89% probability of concomitant depressive, anxiety or phobic anxiety symptoms, compared to 11% in participants without psychotic symptoms. The risk profiles for non-clinical psychotic symptoms and other psychiatric symptoms were largely similar. Non-Dutch ethnicity was most strongly associated with non-clinical psychotic symptoms. Adjusting for other psychiatric symptoms did not increase the specificity of the risk factors. Socio-demographic risk factors for non-clinical psychotic symptoms in the general population are also risk factors for other psychiatric symptoms. The relationship between these risk factors and psychotic symptoms are for a substantial part explained by an increase in other psychiatric symptoms.0Comments 29Citations
- "Our findings support those of other studies (Hanssen et al., 2003; Johns et al., 2004; Johns, 2005; Tien, 1991) in which subjects with non-clinical psychotic symptoms show a high prevalence of other psychiatric symptoms, specifically depressive symptoms. Some studies suggest that depressive symptoms are part of the ongoing psychotic process (Stefanis et al., 2002) and that controlling for these symptoms, as we did in this study, facilitates the study of risk factors in genetic and epidemiological studies (Boks et al., 2007; Boks et al., 2008). However, it is also possible that depressive symptoms are risk factors for developing psychotic symptoms (Maric et al., 2003; Krabbendam et al., 2005). "
[Show abstract] [Hide abstract] ABSTRACT: Histone methyltransferases specific for the histone H3-lysine 9 residue, including Setdb1 (Set domain, bifurcated 1)/Eset/Kmt1e are associated with repressive chromatin remodeling and expressed in adult brain, but potential effects on neuronal function and behavior remain unexplored. Here, we report that transgenic mice with increased Setdb1 expression in adult forebrain neurons show antidepressant-like phenotypes in behavioral paradigms for anhedonia, despair, and learned helplessness. Chromatin immunoprecipitation in conjunction with DNA tiling arrays (ChIP-chip) revealed that genomic occupancies of neuronal Setdb1 are limited to <1% of annotated genes, which include the NMDA receptor subunit NR2B/Grin2B and other ionotropic glutamate receptor genes. Chromatin conformation capture and Setdb1-ChIP revealed a loop formation tethering the NR2B/Grin2b promoter to the Setdb1 target site positioned 30 kb downstream of the transcription start site. In hippocampus and ventral striatum, two key structures in the neuronal circuitry regulating mood-related behaviors, Setdb1-mediated repressive histone methylation at NR2B/Grin2b was associated with decreased NR2B expression and EPSP insensitivity to pharmacological blockade of NR2B, and accelerated NMDA receptor desensitization consistent with a shift in NR2A/B subunit ratios. In wild-type mice, systemic treatment with the NR2B antagonist, Ro25-6981 [R-(R,S)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperidine propranol], and hippocampal small interfering RNA-mediated NR2B/Grin2b knockdown resulted in behavioral changes similar to those elicited by the Setdb1 transgene. Together, these findings point to a role for neuronal Setdb1 in the regulation of affective and motivational behaviors through repressive chromatin remodeling at a select set of target genes, resulting in altered NMDA receptor subunit composition and other molecular adaptations.0Comments 52Citations
- "For example, Gpm6a, is—like Grin2b and Grin2a— among the list of 29 Setdb1 gene targets on chromosomes 6/8/16 (Table 1). Gpm6a encodes a glycoprotein on neuronal membranes and genetic polymorphisms within GPM6A confer a significant risk for depression in subjects with psychosis (Boks et al., 2008). A more comprehensive assessment of Setdb1 target genes will require chromatin profiling across all murine chromosomes. "