Cannabinoid receptor 1 gene (CNR1) and susceptibility to a quantitative phenotype for hebephrenic schizophrenia

Abstract

Functional alterations of components of the endogenous cannabinoid system, in particular of the cannabinoid receptor 1 protein (CB1), are hypothetical contributors to many of the symptoms seen in schizophrenia. Variants within the cannabinoid receptor 1 gene (CNR1) have been shown to be directly associated with the hebephrenic form of schizophrenia in a Japanese population. This finding, however, has yet to be replicated. In the present study we sought to study the same (AAT)n-repeat microsatellite of the CNR1 gene which showed association to hebephrenic schizophrenia in Japan, and to investigate whether this microsatellite showed association to a hebephrenic type of schizophrenia in a family-based association study in a population of the Central Valley of Costa Rica. The Lifetime Dimensions of Psychosis Scale and a best estimate consensus process were utilized to identify subjects with schizophrenia who had an elevated lifetime dimensional score for negative and disorganized symptoms, which we used as a proxy for "hebephrenia." Using the Family Based Association Test we found association of these hebephrenic subjects and the (AAT)n-repeat marker of the CNR1 (multi-allelic P = 0.0368). Our hypothesis that an association with the (AAT)n-repeat marker of CNR1 would not be found with the more general type of schizophrenia was also confirmed. Schizophrenic subjects with prominent lifetime scores for disorganization and negative symptoms (dimension for hebephrenia) are associated with the CNR1 gene and present a type of symptomatology that resembles chronic cannabinoid-induced psychosis. The current finding points to the possibility of different genetic and pathophysiologic mechanisms underlying different types of schizophrenia.

The role of the CNR1 gene in schizophrenia: a systematic review including unpublished data

“…These findings support the hypothesis that variation in the CNR1 gene confers risk for a hebephrenic type of schizophrenia. 29 However, this study did not confirm the association between (AAT)n polymorphism and schizophrenia as a broad phenotype.…”

“…Chavarria-Siles et al 29 replicated the findings of Ujike et al 16 in a population of 244 subjects with a DSM-IV diagnosis of schizophrenia and 481 family members recruited from psychiatric hospitals and clinics in the Central Valley of Costa Rica. The study found a positive correlation of prominent lifetime scores for disorganization and negative symptoms (hebephrenia dimension) with the (AAT)n polymorphism (multiallelic p = 0.0368).…”

CNR1 Gene is Associated with High Neuroticism and Low Agreeableness and Interacts with Recent Negative Life Events to Predict Current Depressive Symptoms

“…We found a significant interaction to exist between the two haploblocks of this gene (epistasis), and this may have an impact on the expression of CB1 receptor (Zhang et al, 2004). Schizophrenia has also been associated with the CNR1 gene, although with conflicting results (Levinson et al, 2000;Leroy et al, 2001;Zhang et al, 2004;Chavarria-Siles et al, 2008;Hamdani et al, 2008). It is important to note that schizophrenic patients compared with depressed subjects, score just as high for neuroticism but even lower for agreeableness (Bagby et al, 1997), particularly if they have co-morbid substance abuse disorder (Reno, 2004).…”

“…This genetic region has been linked to schizophrenia (Levinson et al, 2000;Leroy et al, 2001), but this has not been replicated, although recently the CNR1 gene has been associated with specific symptoms or with non-responder status for antipsychotic drugs rather than with schizophrenia as a disorder (Chavarria-Siles et al, 2008;Hamdani et al, 2008). There are more convincing results on the association of the CNR1 gene and substance abuse disorders (Zhang et al, 2004;Zuo et al, 2007;Chen et al, 2008), although there is a negative replication study (Herman et al, 2006).…”

Functional Genetic Variation of the Cannabinoid Receptor 1 and Cannabis Use Interact on Prefrontal Connectivity and Related Working Memory Behavior

“…Furthermore, convergent findings suggest that CNR1 signaling may be abnormal in patients with this brain disorder, even if the functional specificity of these anomalies is unclear (Dalton et al, 2011). Moreover, CNR1 has been inconsistently associated with diagnoses of schizophrenia (Chavarría-Siles et al, 2008;Seifert et al, 2007), and genetic variability and cannabis use appear to interact in conferring risk for psychosis (Caspi et al, 2005;van Winkel et al, 2011b, Di Forti et al, 2012. Interestingly, CNR1 signaling has been implicated in dopamine signaling (Bloomfield et al, 2014), which is centrally linked with schizophrenia (Weinberger et al, 2001).…”