Accessing Gene Expression in Treatment-Resistant Schizophrenia

Author(s):Show less -

Moretti, Patricia N. ^{[1, 2]} ; Ota, Vanessa K. ^{[3, 1, 4]} ; Gouvea, Eduardo S. ^{[5, 1]} ; Pedrini, Mariana ^{[1, 6]} ; Santoro, Marcos L. ^{[3, 1, 4]} ; Talarico, Fernanda ^{[3, 1, 4]} ; Spindola, Leticia M. ^{[3, 1, 4]} ; Carvalho, Carolina Muniz ^{[3, 1, 4]} ; Noto, Cristiano ^{[1, 4]} ; Xavier, Gabriela ^{[3, 1, 4]} ; Brietzke, Elisa ^{[1, 6]} ; Gadelha, Ary ^{[1, 4]} ; Bressan, Rodrigo ^{[1, 4]} ; Mari, Jair ^{[1, 4]} ; Belangero, Sintia ^{[3, 4, 7]}

Affiliation

^[1] Univ Fed Sao Paulo UNIFESP, Psychiat Dept, Sao Paulo - Brazil

^[2] Univ Brasilia UNB, Dept Genet & Morphol, Brasilia, DF - Brazil

^[3] Univ Fed Sao Paulo UNIFESP, Dept Morphol & Genet, Sao Paulo - Brazil

^[4] Univ Fed Sao Paulo UNIFESP, Psychiat Dept, Interdisciplinary Lab Clin Neurosci LiNC, Sao Paulo - Brazil

^[5] Irmandade Santa Casa Misericordia Sao Paulo ISCMS, Dept Psychiat, Sao Paulo - Brazil

^[6] Univ Fed Sao Paulo UNIFESP, Res Grp Behav & Mol Neurosci Bipolar Disorder, Sao Paulo - Brazil

^[7] Univ Fed Sao Paulo, Disciplina Genet, Rua Botucatu, 740 Ed Leitao da Cunha, 1 Andar, BR-04023900 Sao Paulo - Brazil

• Document type: Journal article
• Source: Molecular Neurobiology; v. 55, n. 8, p. 7000-7008, AUG 2018.
• Web of Science Citations: 8

Abstract

Schizophrenia (SCZ) is a mental disorder arising from a complex interaction of genetic and environmental factors. It has been suggested that treatment-resistant schizophrenia (TRS) is a distinct, more severe, and homogenous subgroup of schizophrenia that could present specific biological markers. Our aim was to characterize expression of target genes in blood of TRS patients compared with non-TRS (NTRS) patients and healthy controls (HC). TRS has been defined using failure to respond to two previous antipsychotic trials. We hypothesized that genes involved in neurodevelopment, myelination, neuroplasticity, neurotransmission, and miRNA processing could be involved in treatment resistance; then, we investigated 13 genes related to those processes in 256 subjects, being 94 healthy controls and 162 schizophrenia patients treated with antipsychotics. Of those, 78 were TRS patients and 84 were NTRS patients. Peripheral blood samples were collected from all subjects and RNA was isolated. Gene expression analysis was performed using the TaqMan low-density array (TLDA) technology. To verify the influence of expression quantitative trait loci (eQTLs), we evaluated single-nucleotide polymorphism (SNP) of all genes using data from GTEx Project. SNP genotypes were obtained from HumanOmniExpress BeadChip. We did not detect gene expression differences between TRS and NTRS subjects, indicating candidate genes specific to treatment resistance. We detected an upregulation of CNR1 and UFD1L gene expression in patients (TRS and NTRS groups) when compared to controls, that may be associated with the release of neurotransmitters, which can influence neuronal plasticity, or with a stress response-activating protein degradation. DICER1 and AKT1 expression increased slightly across the groups and could differentiate only the extreme opposite groups, HC and TRS. Both genes act in heterogeneous pathways, such as cell signaling and miRNA processing, and seem to have an increased demand in the TRS group. We did not detect any eQTLs in our sample that could explain differences in mRNA levels, suggesting a possible regulation by other mechanism, not driven by genotypes. Our data strengthen the importance of several biological pathways involved in the schizophrenia refractoriness and severity, adding knowledge to develop more effective treatments in the future. (AU)

• FAPESP's process: 14/07280-1 - Search for genetic markers of risk, progression and response to treatment
• Grantee: Síntia Iole Nogueira Belangero
• Support Opportunities: Regular Research Grants
• FAPESP's process: 12/12669-0 - mRNA and miRNA expression analysis in treatment resistance in Schizophrenia
• Grantee: Patrícia Natália Silva Moretti
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 11/50740-5 - Prevention in schizophrenia and bipolar disorder from neuroscience to the community: a multiphase, multimodal and translational platform for research and intervention
• Grantee: Rodrigo Affonseca Bressan
• Support Opportunities: Research Projects - Thematic Grants