| 1 | Schizophr. Res. 2011 Feb 125: 187-93 |
|---|---|
| PMID | 21050724 |
| Title | Clock genes and body composition in patients with schizophrenia under treatment with antipsychotic drugs. |
| Abstract | In the healthy population, several pathways are known to exert an effect on basal metabolic factors. Previous studies have found associations between single nucleotide polymorphisms in clock genes or downstream hormone receptors such as the leptin receptor (LEPR) or glucocorticoid receptor (NR3C1) and obesity in the healthy population, but this association remains to be examined in patients with schizophrenia treated with antipsychotics. To assess anthropomorphic parameters in patients taking second-generation antipsychotics (SGA) as a function of nine polymorphisms in three core genes of the clock pathway, and two genes of downstream hormone receptors. Clinical parameters were evaluated in 261 patients with schizophrenia spectrum disorder. Polymorphisms in LEPR, MC3R, NR3C1, PER2 and SDC3 were genotyped. In order to control for multiple testing, permutation tests were used to generate corrected empirical p-values using the Max(T) procedure in PLINK. A significant effect of the rs6196 polymorphism in the NR3C1 on weight (?=-4.18; SE=2.02; p=0.018), BMI (?=-1.88; SE=0.64; p=0.004), waist (?=-5.77; SE=1.75; p=0.001) and waist/hip ratio (?=-0.03; SE=0.012; p=0.009) was found. Permutation tests confirmed the findings for BMI (p=0.037) and waist (p=0.024). Carriers of the G allele consistently displayed better parameters than patients with the wild type allele. A weak effect of rs4949184 in SDC3 on BMI was found, but this did not sustain permutation testing (?=-1.27; SE=0.58; p=0.030, p=0.270 after permutations). Variations in genes implicated in circadian regulation or its related downstream pathways may be important in the regulation of antropomorphic parameters in patients with schizophrenia during long-term treatment with SGA. |
| SCZ Keywords | schizophrenia |
| 2 | Transl Psychiatry 2012 -1 2: e73 |
| PMID | 22832735 |
| Title | A promoter polymorphism in the Per3 gene is associated with alcohol and stress response. |
| Abstract | The period homolog genes Per1, PER2 and Per3 are important components of the circadian clock system. In addition to their role in maintaining circadian rhythm, these genes have been linked to mood disorders, stress response and vulnerability to addiction and alcoholism. In this study, we combined high-resolution sequence analysis and quantitative trait locus (QTL) mapping of gene expression and behavioral traits to identify Per3 as a compelling candidate for the interaction between circadian rhythm, alcohol and stress response. In the BXD family of mouse strains, sequence variants in Per3 have marked effects on steady-state mRNA and protein levels. As a result, the transcript maps as a cis-acting expression QTL (eQTL). We found that an insertion/deletion (indel) variant in a putative stress response element in the promoter region of Per3 causes local control of transcript abundance. This indel results in differences in protein binding affinities between the two alleles through the Nrf2 transcriptional activator. Variation in Per3 is also associated with downstream differences in the expression of genes involved in circadian rhythm, alcohol, stress response and schizophrenia. We found that the Per3 locus is linked to stress/anxiety traits, and that the basal expression of Per3 is also correlated with several anxiety and addiction-related phenotypes. Treatment with alcohol results in increased expression of Per3 in the hippocampus, and this effect interacts with acute restraint stress. Our data provide strong evidence that variation in the Per3 transcript is causally associated with and also responsive to stress and alcohol. |
| SCZ Keywords | schizophrenia |
| 3 | Front Behav Neurosci 2014 -1 8: 388 |
| PMID | 25414651 |
| Title | Addiction and reward-related genes show altered expression in the postpartum nucleus accumbens. |
| Abstract | Motherhood involves a switch in natural rewards, whereby offspring become highly rewarding. Nucleus accumbens (NAC) is a key CNS region for natural rewards and addictions, but to date no study has evaluated on a large scale the events in NAC that underlie the maternal change in natural rewards. In this study we utilized microarray and bioinformatics approaches to evaluate postpartum NAC gene expression changes in mice. Modular Single-set Enrichment Test (MSET) indicated that postpartum (relative to virgin) NAC gene expression profile was significantly enriched for genes related to addiction and reward in five of five independently curated databases (e.g., Malacards, Phenopedia). Over 100 addiction/reward related genes were identified and these included: Per1, PER2, Arc, Homer2, Creb1, Grm3, Fosb, Gabrb3, Adra2a, Ntrk2, Cry1, Penk, Cartpt, Adcy1, Npy1r, Htr1a, Drd1a, Gria1, and Pdyn. ToppCluster analysis found maternal NAC expression profile to be significantly enriched for genes related to the drug action of nicotine, ketamine, and dronabinol. Pathway analysis indicated postpartum NAC as enriched for RNA processing, CNS development/differentiation, and transcriptional regulation. Weighted Gene Coexpression Network Analysis (WGCNA) identified possible networks for transcription factors, including Nr1d1, PER2, Fosb, Egr1, and Nr4a1. The postpartum state involves increased risk for mental health disorders and MSET analysis indicated postpartum NAC to be enriched for genes related to depression, bipolar disorder (BPD), and schizophrenia. Mental health related genes included: Fabp7, Grm3, Penk, and Nr1d1. We confirmed via quantitative PCR Nr1d1, PER2, Grm3, Penk, Drd1a, and Pdyn. This study indicates for the first time that postpartum NAC involves large scale gene expression alterations linked to addiction and reward. Because the postpartum state also involves decreased response to drugs, the findings could provide insights into how to mitigate addictions. |
| SCZ Keywords | schizophrenia |
| 4 | Chronobiol. Int. 2015 May 32: 579-84 |
| PMID | 25799324 |
| Title | Depression-associated ARNTL and PER2 genetic variants in psychotic disorders. |
| Abstract | Circadian rhythm disturbances overlap between psychotic disorders, e.g. schizophrenia, and major depression. We hypothesized that circadian gene variants previously associated with unipolar depression would be overrepresented also in patients with psychotic disorder. Six genetic polymorphisms in ARNTL, PER2 and CRY2 were genotyped in 566 schizophrenia spectrum disorder patients and 926 controls. The rs2290036-C variant of ARNTL was over-represented in psychosis patients, and the variants rs934945-G and rs10462023-G of PER2 were associated with a more severe psychotic disorder. The directions of these genetic associations were in line with those previously identified for depression. |
| SCZ Keywords | schizophrenia |
| 5 | Schizophr. Res. 2016 Apr -1: -1 |
| PMID | 27132483 |
| Title | Altered circadian clock gene expression in patients with schizophrenia. |
| Abstract | Impaired circadian rhythmicity has been reported in several psychiatric disorders. schizophrenia is commonly associated with aberrant sleep-wake cycles and insomnia. It is not known if schizophrenia is associated with disturbances in molecular rhythmicity. We cultured fibroblasts from skin samples obtained from patients with chronic schizophrenia and from healthy controls, respectively, and analyzed the circadian expression during 48h of the clock genes CLOCK, BMAL1, PER1, PER2, CRY1, CRY2, REV-ERB? and DBP. In fibroblasts obtained from patients with chronic schizophrenia, we found a loss of rhythmic expression of CRY1 and PER2 compared to cells from healthy controls. We also estimated the sleep quality in these patients and found that most of them suffered from poor sleep in comparison with the healthy controls. In another patient sample, we analyzed mononuclear blood cells from patients with schizophrenia experiencing their first episode of psychosis, and found decreased expression of CLOCK, PER2 and CRY1 compared to blood cells from healthy controls. These novel findings show disturbances in the molecular clock in schizophrenia and have important implications in our understanding of the aberrant rhythms reported in this disease. |
| SCZ Keywords | schizophrenia |
| 6 | Psychoneuroendocrinology 2016 Feb 64: 108-16 |
| PMID | 26630391 |
| Title | Diurnal neurobiological alterations after exposure to clozapine in first-episode schizophrenia patients. |
| Abstract | Irregular circadian rhythm and some of its most characteristic symptoms are frequently observed in patients with schizophrenia. However, changes in the expression of clock genes or neuropeptides that are related to the regulation of circadian rhythm may influence the susceptibility to recurrence after antipsychotic treatment in schizophrenia, but this possibility has not been investigated. Blood samples were collected from 15 healthy male controls and 13 male schizophrenia patients at 4h intervals for 24h before and after treatment with clozapine for 8 weeks. The outcome measures included the relative expression of clock gene mRNA PERIOD1 (PER1), PERIOD2 (PER2), PERIOD3 (PER3) and the levels of plasma cortisol, orexin, and insulin. Compared with healthy controls, schizophrenia patients presented disruptions in diurnal rhythms of the expression of PER1, PER3, and NPAS2 and the release of orexin, accompanied by a delayed phase in the expression of PER2, decreases in PER3 and NPAS2 expression, and an increase in cortisol levels at baseline. Several of these disruptions (i.e., in PER1 and PER3 expression) persisted after 8 weeks of clozapine treatment, similar to the decreases in the 24-h expression of PER3 and NPAS2. Clozapine treatment for 8 weeks significantly decreased the 24-h levels of PER2 and increased the 24-h levels of insulin. These persistent neurobiological changes that occur after 8 weeks of clozapine treatment may contribute to the vulnerability to recurrence and efficacy of long-term maintenance treatment in schizophrenia. |
| SCZ Keywords | schizophrenia |