Avaliação de polimorfismos dos genes de receptores endocanabinóides (CNR1 e CNR2) e sua relação com o desempenho cognitivo em pacientes com esquizofrenia e controles

Abstract

Schizophrenia is a chronic, complex and inheritable psychiatric syndrome characterized by generalized cognitive deficits that account for most of the socio-occupational dysfunctions associated with the disease. Although cognitive deficits are currently recognized as central to the psychopathology of the disorder, little is known about its pathophysiological determinants. In this perspective, the study of the endocannabinoid system (EcS) can aid in the advancement of knowledge regarding its pathophysiological mechanisms. Several EcS alterations have been described in patients with schizophrenia and point to their involvement in the pathophysiology of the disorder, and particularly in the deficits of cognitive abilities. In the central nervous system (CNS), endocannabinoids, mainly via CB1R, act in the modulation of other neurotransmitter systems and are important for fine-tuning the information flow in neural networks. In addition, EcS plays an important role in crucial stages of brain development. Cognitive abilities are considered complex traits, ie, multifactorial, with the participation of environmental and genetic factors, and one of the strategies to understand the etiological factors of the cognitive deficits of schizophrenia is the study of genes involved with these impairments. Association studies found a relationship between schizophrenia and CNR1 polymorphisms, but the results were not consistent, and the relation of genetic variations of EcS elements with the cognitive impairments of these patients was little studied. Therefore, our hypothesis is that genetic variations of endocannabinoid receptor genes will be associated with cognitive performance in patients, but not in controls. The main objective of the present work is to test if two polymorphisms of the CNR1 gene (rs1049353 and rs12720071) and a polymorphism of the CNR2 gene (rs2229579) of the endocannabinoid receptors are associated with the cognitive impairments evaluated by the BACS in a sample of 69 patients with schizophrenia and 45 controls. The secondary endpoint was also to assess whether the same polymorphisms would be associated with the risk for the syndrome. We found a consistent association of CNR1 polymorphism rs12720071 (T> C) genotypes with the cognitive performance of patients in several domains. Patients C / C, presented significantly worse performance in the domains of motor speed, verbal fluency, working memory (significant even after correction for multiple tests), attention / processing speed and reasoning / problem solving (nominally significant). This same polymorphism was also associated with the risk for the development of schizophrenia. In addition to the patients presenting a higher proportion of the C allele, patients with the C allele (T/C or C/C) were more likely to have schizophrenia (3.86 times in the dominant model and 1.73 times in the additive model) than T/T subjects (p <0.001, significant even after correction for multiple tests). For polymorphism rs2229579 (G> A), there was no association of the genotypes with the syndrome, but the A allele was nominally correlated with the risk for schizophrenia. Although limited by methodological issues, our data support the general hypothesis that CNR1 variations may be associated with the pathophysiology of the syndrome. In particular, polymorphism rs12720071 (T> C) of CNR1 may be involved in the pathogenesis of cognitive deficits of schizophrenia.