Gene-environment interaction between an endocannabinoid system genetic polymorphism and cannabis use in first episode of psychosis, Miquel Bioque et al., 2019

Gene-environment interaction between an endocannabinoid system genetic polymorphism and cannabis use in first episode of psychosis

Miquel Bioque, Sergi Mas, Maria Cristina Costanzo, Bibiana Cabrera, Antonio Lobo, Ana González-Pinto, Elisa Rodriguez-Toscano, Iluminada Corripio, Eduard Vieta, Immaculada Baeza, Ángela Ibáñez, Miguel Gutiérrez Fraile, Manuel J. Cuesta, Gisela Mezquida, Amalia Lafuente, Miguel Bernardo, PEPs GROUP

European Neuropsychopharmacology, 2019, 29, (6), 786-794



Alterations of the endocannabinoid system (ECS) may play an important role in the development of schizophrenia and other psychotic disorders. Cannabis use is one of the environmental fac- tors more repeatedly related to an increase the risk of developing a psychotic episode, while its use modifies the ECS normal function. In the present study we purposed to examine the gene by environment (GxE) interaction between 15 selected single nucleotide polymorphisms (SNPs) related to the ECS and cannabis use in a cohort of 321 patients with a first episode of psychosis (FEP) and 241 matched healthy controls. We found the fatty-acid amide hydrolase (FAAH) rs2295633 SNP genetic polymorphism was associated with a greater risk of presenting a FEP in subjects with relevant cannabis use, but not in subjects without a history of cannabis use. The probability of presenting a FEP was tenfold higher (OR: 10.69) in cannabis users who were homozygote carriers of the T allele of the FAAH rs2295633 SNP, compared to users of cannabis without this genotype. We also found that a higher a proportion of TT carriers of the FAAH rs2295633 SNP with a positive history of cannabis use was treated with high potency antipsychotic. This study has identified a GxE-environment interaction between a genetic poly- morphism from the ECS and cannabis use involved in the risk of presenting a FEP. Although this preliminary data should be replicated with independent samples, our results highlight the importance of the pro-psychotic effects of exogenous cannabis use over the ECS in certain subjects.

KEYWORDS : Cannabis; Endocannabinoid system; FAAH; Psychosis; rs2295633; Schizophrenia


1. Introduction

Biological foundations of psychotic disorders include an extensive genetic predisposition, with an estimated heritability around eighty percent (Schizophrenia Working Group of the Psychiatric Genomics, 2014). Genetic studies have linked many genetic variants with schizophrenia related dis- orders, but each variant is only associated with a small effect (Schizophrenia Working Group of the Psychiatric Genomics, 2014). Therefore, an increasing attention has re- cently shifted to the weight of environmental risk factors, such as infections during pregnancy, migration, cannabis use or urbanicity, which can carry on a two to four fold increase in risk (van Os et al., 2014). Gene-environment interaction (GxE) has been proposed as a causal mechanism where ge- netic variants and environmental factors contribute to the causation of a condition, in which the effect of environ- mental exposure depends on individual’s genotype (van Os et al., 2014).

The endocannabinoid system (ECS) may play an important role in FEP physiopathology. Cerebrospinal Fluid (CSF) levels of anandamide (AEA), one of the endogenous ligands of the ECS, were found elevated in subjects with acute schizophre- nia (Giuffrida et al., 2004). Higher levels of CSF AEA were also associated with a lower risk of psychotic symptoms fol- lowing cannabis use in volunteers ( Morgan et al., 2013 ). The remission of psychotic symptoms has been associated with a significant decrease AEA levels and cannabinoid recep- tor 2 (CB2) mRNA transcripts in peripheral blood mononu- clear cells (PBMC) (de Campos-Carli et al., 2017; De Marchi et al., 2003). The antipsychotic effect of cannabidiol has also been related to the inhibition of AEA deactivation (Leweke et al., 2012). Our group described a peripheral ECS dysregulation in subjects with a FEP compared to healthy controls (Bioque et al., 2013), associated to certain cogni- tive deficits (Bioque et al., 2016). Postmortem studies on brain tissues have shown a genetically predetermined relationship between lower functioning of CB2 receptors (poly- morphism Q63R) and increased risk of schizophrenia when combined with other risk factors (Ishiguro et al., 2010), to- gether with local specific alterations in some endocannabi- noids’ levels (Muguruza et al., 2013). Finally, neuroimaging studies have showed a reduced CB1 expression and activity in certain brain areas of patients with schizophrenia (Eggan et al., 2008; Wong et al., 2011).

Besides, it is well-known that cannabis use approximately doubles the risk of developing a FEP (McGrath et al., 2010), largely modifying the ECS normal function (Fakhoury, 2016).

The purpose of this study is to examine the interaction between cannabis use and fifteen selected SNPs from the ECS in our cohort of FEPs and matched healthy controls.