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Gene expression over the course of schizophrenia: from clinical high-risk for psychosis to chronic stages.

ABSTRACT: The study of patients with schizophrenia (SZ) at different clinical stages may help clarify what effects could be due to the disease itself, to the pharmacological treatment, or to the disease progression. We compared expression levels of targeted genes in blood from individuals in different stages of SZ: clinical high risk for psychosis (CHR), first episode of psychosis (FEP), and chronic SZ (CSZ). Then, we further verified whether single-nucleotide polymorphisms (SNPs) could be related to gene expression differences. We investigated 12 genes in 394 individuals (27 individuals with CHR, 70 antipsychotic-naive individuals with FEP, 157 CSZ patients, and 140 healthy controls (HCs)). For a subsample, genotype data were also available, and we extracted SNPs that were previously associated with the expression of selected genes in whole blood or brain tissue. We generated a mediation model in which a putative cause (SNP) is related to a presumed effect (disorder) via an intermediate variable (gene expression). MBP and NDEL1 were upregulated in FEP compared to all other groups; DGCR8 was downregulated in FEP compared to HC and CHR; DGCR2 was downregulated in CSZ compared to FEP and HCs; DISC1 was upregulated in schizophrenia compared to controls or FEP, possibly induced by the rs3738398 and rs10864693 genotypes, which were associated with DISC1 expression; and UFD1 was upregulated in CSZ and CHR compared to FEP and HC. Our results indicated changes in gene expression profiles throughout the different clinical stages of SZ, reinforcing the need for staging approaches to better capture SZ heterogeneity.

SUBMITTER: Ota VK

PROVIDER: S-EPMC6438978 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Gene expression over the course of schizophrenia: from clinical high-risk for psychosis to chronic stages.

Ota Vanessa Kiyomi VK Moretti Patricia Natalia PN Santoro Marcos Leite ML Talarico Fernanda F Spindola Leticia Maria LM Xavier Gabriela G Carvalho Carolina Muniz CM Marques Diogo Ferri DF Costa Giovany Oliveira GO Pellegrino Renata R de Jong Simone S Cordeiro Quirino Q Hakonarson Hakon H Breen Gerome G Noto Cristiano C Bressan Rodrigo Affonseca RA Gadelha Ary A Jesus Mari Jair de J Belangero Sintia I SI

NPJ schizophrenia 20190328 1

The study of patients with schizophrenia (SZ) at different clinical stages may help clarify what effects could be due to the disease itself, to the pharmacological treatment, or to the disease progression. We compared expression levels of targeted genes in blood from individuals in different stages of SZ: clinical high risk for psychosis (CHR), first episode of psychosis (FEP), and chronic SZ (CSZ). Then, we further verified whether single-nucleotide polymorphisms (SNPs) could be related to gene ...[more]

PMID: 30923314

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Project description:BackgroundDisturbances in trait emotions are a predominant feature in schizophrenia. However, less is known about (a) differences in trait emotion across phases of the illness such as the clinical high-risk (CHR) phase and (b) whether abnormalities in trait emotion that are associated with negative symptoms are driven by primary (i.e. idiopathic) or secondary (e.g. depression, anxiety) factors.AimsTo examine profiles of trait affective disturbance and their clinical correlates in individuals with schizophrenia and individuals at CHR for psychosis.MethodIn two studies (sample 1: 56 out-patients diagnosed with schizophrenia and 34 demographically matched individuals without schizophrenia (controls); sample 2: 50 individuals at CHR and 56 individuals not at CHR (controls)), participants completed self-report trait positive affect and negative affect questionnaires, clinical symptom interviews (positive, negative, disorganised, depression, anxiety) and community-based functional outcome measures.ResultsBoth clinical groups reported lower levels of positive affect (specific to joy among individuals with schizophrenia) and higher levels of negative affect compared with controls. For individuals with schizophrenia, links were found between positive affect and negative symptoms (which remained after controlling for secondary factors) and between negative affect and positive symptoms. For individuals at CHR, links were found between both affect dimensions and both types of symptom (which were largely accounted for by secondary factors).ConclusionsBoth clinical groups showed some evidence of reduced trait positive affect and elevated trait negative affect, suggesting that increasing trait positive affect and reducing trait negative affect is an important treatment goal across both populations. Clinical correlates of these emotional abnormalities were more integrally linked to clinical symptoms in individuals with schizophrenia and more closely linked to secondary influences such as depression and anxiety in individuals at CHR.Declaration of interestNone.

Project description:While alterations in striatal dopamine in psychosis and stress have been well studied, the role of dopamine in prefrontal cortex is poorly understood. To date, no study has investigated the prefrontocortical dopamine response to stress in the psychosis spectrum, even though the dorsolateral and medial prefrontal cortices are key regions in cognitive and emotional regulation, respectively. The present study uses the high-affinity dopamine D2/3 receptor radiotracer 11C-FLB457 and PET together with a validated psychosocial stress challenge to investigate the dorsolateral and medial prefrontocortical dopamine response to stress in schizophrenia and clinical high risk for psychosis. Forty participants completed two 11C-FLB457 PET scans (14 antipsychotic-free schizophrenia, 14 clinical high risk for psychosis and 12 matched healthy volunteers), one while performing a Sensory Motor Control Task (control) and another while performing the Montreal Imaging Stress Task (stress). Binding potential (BPND) was estimated using Simplified Reference Tissue Model with cerebellar cortex as reference region. Dopamine release was defined as per cent change in BPND between control and stress scans (?BPND) using a novel correction for injected mass. Salivary cortisol response (?AUCI) was assessed throughout the tasks and its relationship with dopamine release examined. 11C-FLB457 binding at control conditions was significantly different between groups in medial [F(2,37) = 7.98, P = 0.0013] and dorsolateral [F(2,37) = 6.97, P = 0.0027] prefrontal cortex with schizophrenia patients having lower BPND than participants at clinical high risk for psychosis and healthy volunteers, but there was no difference in ?BPND among groups [dorsolateral prefrontal cortex: F(2,37) = 1.07, P = 0.35; medial prefrontal cortex: F(2,37) = 0.54, P = 0.59]. We report a positive relationship between ?AUCI and 11C-FLB457 ?BPND in dorsolateral and medial prefrontal cortex in healthy volunteers (r = 0.72, P = 0.026; r = 0.76, P = 0.014, respectively) and in participants at clinical high risk for psychosis (r = 0.76, P = 0.0075; r = 0.72, P = 0.018, respectively), which was absent in schizophrenia (r = 0.46, P = 1.00; r = 0.19, P = 1.00, respectively). Furthermore, exploratory associations between ?BPND or ?AUCI and stress or anxiety measures observed in clinical high risk for psychosis were absent in schizophrenia. These findings provide first direct evidence of a disrupted prefrontocortical dopamine-stress regulation in schizophrenia.

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Gene expression over the course of schizophrenia: from clinical high-risk for psychosis to chronic stages.

Publications

Gene expression over the course of schizophrenia: from clinical high-risk for psychosis to chronic stages.

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