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.
Available from: Marek Wieczorek
- "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. "
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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.
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The online version of this article (doi:10.1007/s12031-012-9850-1) contains supplementary material, which is available to authorized users.
Available from: Rahul Bharadwaj
- "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. "
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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.
Available from: Timothy J Crow
- "Heritability estimates for these new subtypes could test shared genetic origins and thus suitability as phenotypes in genetic research (McGrath et al., 2009; Boks et al., 2008). An alternative way to study the utility of these subtypes is to look at shared pathology – for example brain imaging findings – or etiology. "
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ABSTRACT: Patients grouped by latent class analysis of symptoms show some consensus between studies, and may be less etiologically heterogeneous than current diagnoses. If so, the effect size of 'neurodevelopmental' risk factors may be greater than in equivalent DSMIV diagnostic groups.
Two hundred fifty six individuals with neurodevelopmental risk factors recorded in the National Child Development Study (1958) UK birth cohort were grouped by data-driven illness subtypes, derived previously in over 1000 individuals. The effect sizes of these risks were compared between data-derived and DSMIV schizophrenia (295.x) groups.
Compared to DSMIV schizophrenia, the data-driven subtype broadly characterized by the presence of psychotic symptoms in the absence of affective symptoms showed significantly greater effect sizes in eight out of thirteen continuously-rated risk factors: birth weight, cognition, childhood behavioural problems, and neurological softsigns including handedness.
A data-driven subgroup of schizophrenia patients, characterized as lacking co-morbid depressive symptoms, is less heterogeneous with respect to neurodevelopmental etiology.
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