Age at onset of psychotic disorder: Cannabis, BDNF Val66Met, and sex‐specific models of gene–environment interaction

Abstract

Discovering modifiable predictors for age at onset may help to identify predictors of transition to psychotic disorder in the "at-risk mental state." Inconsistent effects of sex, BDNF Val66Met (rs6265), and cannabis use on age of onset were previously reported. BDNF Val66Met and cannabis use before illness onset were retrospectively assessed in a sample of 585 patients with schizophrenia and their association with age at onset was evaluated. Cannabis use was significantly associated with earlier age at onset of psychotic disorder (AOP; average difference 2.7 years, P < 0.001), showing dose-response effects with higher frequency and earlier age at first use. There was a weak association between BDNF Val66Met genotype and AOP (difference 1.2 years; P = 0.050). No evidence was found for BDNF × cannabis interaction (interaction χ(2) (1) = 0.65, P = 0.420). However, a significant BDNF × cannabis × sex interaction was found (interaction χ(2) (1) = 4.99, P = 0.026). In female patients, cannabis use was associated with earlier AOP in BDNF Met-carriers (difference 7 years), but not in Val/Val-genotypes. In male patients, cannabis use was associated with earlier AOP irrespective of BDNF Val66Met genotype (difference 1.3 years). BDNF Val66Met genotype in the absence of cannabis use did not influence AOP, neither in female or male patients with psychotic disorder. Complex interactions between cannabis and BDNF may shape age at onset in female individuals at risk of psychotic disorder. No compelling evidence was found that BDNF genotype is associated with age at onset of psychotic disorder in the absence of cannabis use.

BDNF Val66Met Genotype Interacts With a History of Simulated Stress Exposure to Regulate Sensorimotor Gating and Startle Reactivity

“…Our study provides support for reports that the BDNF 66Met allele may play a role in the pathophysiology of schizophrenia, specifically stress-sensitive clinical aspects such as positive-related symptomology 12,13 neurocognitive function 58,59 and age of onset, [60][61][62][63] and that some of this involvement is likely to occur as a result of differential susceptibility to glucocorticoid signaling during critical periods such as adolescence/young adulthood. Clinical studies assessing a genomic role of BDNF in schizophrenia should therefore consider stratifying their analyses for all 3 Val66Met genotypes, as well as for an effect of adversity, early life stress, trauma or related measures of stress exposure, which may play a role in phenotype determination.…”

The BDNF gene Val66Met polymorphism as a modifier of psychiatric disorder susceptibility: progress and controversy

“…For instance, there have been several positive reports that the 66Met allele may be related to age of onset of schizophrenia, an effect that has been replicated in independent Armenian, 167 Asian 185 and AfricanAmerican 186 samples and appears to be compounded by cannabis use among females. 187 The Val66Met polymorphism has also been found to associate with the presence of depression-related symptoms 104,188,189 and with aspects of the positive symptom class of schizophrenia in patients, 190 as well as with psychosis-like experiences in healthy controls with a history of childhood abuse. 191 Therapeutic efficacy also appears to be gated by the Val66Met polymorphism, 192,193 with risperidone response being moderated by epistatic interactions with the BDNF (GT)n dinucleotide and C-270T variants.…”

Cannabinoids and Schizophrenia: Risks and Therapeutic Potential

“…A single nucleotide polymorphism (SNP) of the gene encoding brainderived neurotrophic factor, Val66Met (rs6265), has been shown to moderate the relationship between cannabis use and age of onset of psychosis. The interaction may be limited to females for unknown reasons; female cannabis users who carry the Val/Val polymorphism displayed psychotic symptoms on average 7 years earlier than female Met carriers [41]. CNR1 encodes the cannabinoid receptor 1 (CB 1 R), which is widespread throughout the central nervous system (CNS), including the brain.…”