Interaction between COMT haplotypes and cannabis in schizophrenia: A case-only study in two samples from Spain

Costas, Javier; Sanjuán, Julio; Ramos-Ríos, Ramón; Paz, Eduardo; Agra, Santiago; Tolosa, A.; Páramo, Mario; Brenlla, Julio; Arrojo, Manuel

doi:10.1016/j.schres.2011.01.014

Cited by 55 publications

(32 citation statements)

References 51 publications

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“…Polymorphisms in COMT have repeatedly been linked with prefrontal cortical dysfunction (Roffman et al, 2008). Cannabis use is thought to interact with COMT in the development of schizophrenia (Costas et al, 2011), and cannabinoid function in the PFC is essential for emotional regulation and sustained attention (Arguello and Jentsch, 2004;McLaughlin et al, 2014). This evidence strongly indicates these three genes in mental disorders associated with PFC dysfunction, and the current data indicate that COMT and OPRD1, in particular, may have opposing roles in mediating executive function.…”

Section: Discussionsupporting

confidence: 50%

Dissociable Deficits of Executive Function Caused by Gestational Adversity are Linked to Specific Transcriptional Changes in the Prefrontal Cortex

Grissom

Herdt

Desilets

et al. 2014

Neuropsychopharmacol

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Poor-quality maternal diet during pregnancy, and subsequent gestational growth disturbances in the offspring, have been implicated in the etiology of multiple neurodevelopmental disorders, including ADHD, schizophrenia, and autism. These disorders are characterized, in part, by abnormalities in responses to reward and errors of executive function. Here, we demonstrate dissociable deficits in reward processing and executive function in male and female mice, solely due to maternal malnutrition via high-fat or low-protein diets. Gestational exposure to a high-fat diet delayed acquisition of a fixed ratio response, and decreased motivation as assessed by progressive ratio. In contrast, offspring of a low-protein diet displayed no deficits in operant learning, but were more prone to assign salience to a cue that predicts reward (sign-tracking) in a Pavlovian-conditioned approach task. In the 5-choice serial reaction time task (5-CSRTT), gestational exposure to a high-fat diet promoted impulsivity, whereas exposure to a low-protein diet led to marked inattention. These dissociable executive function deficits are known to be mediated by the medial prefrontal cortex (PFC), which displays markers of epigenetic dysregulation in neurodevelopmental disorders. Following behavioral characterization, we assayed PFC gene expression using a targeted PCR array and found that both maternal diets increased overall transcription in PFC. Cluster analysis of the relationships between individual transcripts and behavioral outcomes revealed a cluster of primarily epigenetic modulators, whose overexpression was linked to executive function deficits. The overexpression of four genes, DNA methyltransferase 1 (DNMT1), d-opioid receptor (OPRD1), cannabinoid receptor 1 (CNR1), and catechol-o-methyltransferase (COMT), was strongly associated with overall poor performance. All 5-CSRTT deficits were associated with DNMT1 upregulation, whereas impulsive behavior could be dissociated from inattention by overexpression of OPRD1 or COMT, respectively, as well as a distinct cluster of epigenetic regulators. These data provide molecular support for dissociable domains of executive function.

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Section: Discussionsupporting

confidence: 50%

Dissociable Deficits of Executive Function Caused by Gestational Adversity are Linked to Specific Transcriptional Changes in the Prefrontal Cortex

Grissom

Herdt

Desilets

et al. 2014

Neuropsychopharmacol

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“…Sub-analyses based on race (African American and Caucasian) did not yield significant findings (289). In contrast to the original Caspi et al study (200), a case-only study from Spain (155 out of 748 total schizophrenia subjects who used cannabis) actually found an association between the low-activity Met allele of COMT and cannabis use in psychotic disorder (283). Estrada et al (290) showed a dose-effect of COMT polymorphism on the age of onset of psychosis among cannabis users: individuals who were homozygous for the Val allele of COMT had the earliest age of onset of psychotic disorders at 15.4 years; homozygotes for the Met allele had the latest age of onset at 18.8 years; heterozygotes with intermediate enzymatic activity, had an age of onset of 17.1 years.…”

Section: Moderators/mediators Of the Link Between Cannabis And Psychosismentioning

confidence: 72%

Gone to Pot â€“ A Review of the Association between Cannabis and Psychosis

2014

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Cannabis is the most commonly used illicit drug worldwide, with ~5 million daily users worldwide. Emerging evidence supports a number of associations between cannabis and psychosis/psychotic disorders, including schizophrenia. These associations-based on case-studies, surveys, epidemiological studies, and experimental studies indicate that cannabinoids can produce acute, transient effects; acute, persistent effects; and delayed, persistent effects that recapitulate the psychopathology and psychophysiology seen in schizophrenia. Acute exposure to both cannabis and synthetic cannabinoids (Spice/K2) can produce a full range of transient psychotomimetic symptoms, cognitive deficits, and psychophysiological abnormalities that bear a striking resemblance to symptoms of schizophrenia. In individuals with an established psychotic disorder, cannabinoids can exacerbate symptoms, trigger relapse, and have negative consequences on the course of the illness. Several factors appear to moderate these associations, including family history, genetic factors, history of childhood abuse, and the age at onset of cannabis use. Exposure to cannabinoids in adolescence confers a higher risk for psychosis outcomes in later life and the risk is dose-related. Individuals with polymorphisms of COMT and AKT1 genes may be at increased risk for psychotic disorders in association with cannabinoids, as are individuals with a family history of psychotic disorders or a history of childhood trauma. The relationship between cannabis and schizophrenia fulfills many but not all of the standard criteria for causality, including temporality, biological gradient, biological plausibility, experimental evidence, consistency, and coherence. At the present time, the evidence indicates that cannabis may be a component cause in the emergence of psychosis, and this warrants serious consideration from the point of view of public health policy.

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“…However, this finding proved difficult to replicate. While initial experimental data supported the interaction (94), several independent studies reported non-replications (83, 95–97) or even findings in the opposite direction (98). It appeared that this gene–environment interaction must have been a false-positive finding.…”

Section: Gene–environment Interactions Involving Specific Molecular Gmentioning

confidence: 99%

Geneâ€“Environment Interactions in Severe Mental Illness

2014

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Severe mental illness (SMI) is a broad category that includes schizophrenia, bipolar disorder, and severe depression. Both genetic disposition and environmental exposures play important roles in the development of SMI. Multiple lines of evidence suggest that the roles of genetic and environmental factors depend on each other. Gene–environment interactions may underlie the paradox of strong environmental factors for highly heritable disorders, the low estimates of shared environmental influences in twin studies of SMI, and the heritability gap between twin and molecular heritability estimates. Sons and daughters of parents with SMI are more vulnerable to the effects of prenatal and postnatal environmental exposures, suggesting that the expression of genetic liability depends on environment. In the last decade, gene–environment interactions involving specific molecular variants in candidate genes have been identified. Replicated findings include an interaction between a polymorphism in the AKT1 gene and cannabis use in the development of psychosis and an interaction between the length polymorphism of the serotonin transporter gene and childhood maltreatment in the development of persistent depressive disorder. Bipolar disorder has been underinvestigated, with only a single study showing an interaction between a functional polymorphism in the BDNF gene and stressful life events triggering bipolar depressive episodes. The first systematic search for gene–environment interactions has found that a polymorphism in CTNNA3 may sensitize the developing brain to the pathogenic effect of cytomegalovirus in utero, leading to schizophrenia in adulthood. Strategies for genome-wide investigations will likely include coordination between epidemiological and genetic research efforts, systematic assessment of multiple environmental factors in large samples, and prioritization of genetic variants.

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Interaction between COMT haplotypes and cannabis in schizophrenia: A case-only study in two samples from Spain

Cited by 55 publications

References 51 publications

Dissociable Deficits of Executive Function Caused by Gestational Adversity are Linked to Specific Transcriptional Changes in the Prefrontal Cortex

Dissociable Deficits of Executive Function Caused by Gestational Adversity are Linked to Specific Transcriptional Changes in the Prefrontal Cortex

Gone to Pot â€“ A Review of the Association between Cannabis and Psychosis

Geneâ€“Environment Interactions in Severe Mental Illness

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