Our results suggest the importance of brain maturation timing in which exposure to cannabis occurs. The COMT Val158Met genotype seems to modulate the association between cannabis and age at onset of psychotic disorders. These results are consistent with previous studies.

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Objectives: Neuritin 1 gene (NRN1) is involved in neurodevelopment processes and synaptic plasticity and its expression is regulated by brain-derived neurotrophic factor (BDNF). We aimed to investigate the association of NRN1 with schizophrenia-spectrum disorders (SSD) and bipolar disorders (BPD), to explore its role in age at onset and cognitive functioning, and to test the epistasis between NRN1 and BDNF. Methods: The study was developed in a sample of 954 SSD/BPD patients and 668 healthy subjects. Genotyping analyses included 11 SNPs in NRN1 and one functional SNP in BDNF. Results: The frequency of the haplotype C-C (rs645649-rs582262) was significantly increased in patients compared to controls (P ¼ 0.0043), while the haplotype T-C-C-T-C-A (rs3763180-rs10484320-rs4960155-rs9379002-rs9405890-rs1475157) was more frequent in controls (P ¼ 3.1 Â 10 À5). The variability at NRN1 was nominally related to changes in age at onset and to differences in intelligence quotient, in SSD patients. Epistasis between NRN1 and BDNF was significantly associated with the risk for SSD/BPD (P ¼ 0.005). Conclusions: Results suggest that: (i) NRN1 variability is a shared risk factor for both SSD and BPD, (ii) NRN1 may have a selective impact on age at onset and intelligence in SSD, and (iii) the role of NRN1 seems to be not independent of BDNF. ARTICLE HISTORY

Dysbindin-1 is a relatively ubiquitous protein in the brain which is involved in the modulation of synaptic homeostasis. The dysbindin-1 gene (DTNBP1) has been associated with schizophrenia and bipolar disorder diagnoses. However, its contribution to the severity of the clinical and neurocognitive expression of these disorders remains controversial. We aimed to explore the association between DTNBP1 and the phenotypes which are more directly linked with the underlying biology, such as age at onset and neurocognitive impairment. The present family sample comprised 894 Caucasian individuals: 268 patients affected by functional psychosis [58% with illness onset before 18 years, mean age at onset (SD): 14.71 (2.10)], 483 parents and 143 siblings. Ten DTNBP1 single nucleotide polymorphisms were genotyped in all individuals and their transmission disequilibrium was tested in relation to: (i) the risk for psychosis; (ii) patients' age at onset; and (iii) familial neurocognitive performance (including IQ estimation and executive functioning). In early-onset families a 5-marker haplotype encompassing exons 2-4 and the surrounding introns was significantly over-transmitted to cases, while in adult-onset families two haplotypes corresponding to the region between introns 4 and 7 were over-transmitted to cases. Estimated IQ was associated with the rs760666 marker in the whole sample, whereas a significant association between executive functioning and the rs2619522 marker appeared in early-onset families. Our findings confirm the role of the dysbindin-1 gene in the risk for functional psychosis and show a differential haplotypic risk pattern in families with early as opposed to adult onset in the affected offspring.

IntroductionDifferent studies have confirmed the association between cannabis use and psychosis and, also, the relationship between age at first cannabis use and age at onset of psychosis (Henquet et al 2005, Barnes et al 2006). In a young psychiatric sample, we aimed to investigate the correlation between cannabis use and the age at onset of psychotic and non-psychotic symptoms and whether this relationship is modulated by the genetic variability at COMT, CNR1 and CHRNA7genes.MethodsThe sample comprised 157 Caucasian patients (mean age: 17.01 (3.6)) diagnosed following DSM-IV-TR criteria: 80 patients with schizophrenia-spectrum disorders, 77 patients with affective or conduct disorders. Cannabis use was assessed with UNICA-A and DIGS scales (Nurnberger 1994) and 49% individuals were classified as consumers. SNPs were genotyped using Taqman 5′-exonuclease assays.ResultsWe observed a positive relationship between age at first cannabis use and age at onset in, both, schizophrenia-spectrum (β = 1.44 p < 0.001) and other psychiatric disorders (β = 0.56 p < 0.002). An interaction was observed between COMT Val158Met polymorphism and cannabis use specifically within schizophrenia-spectrum disorders’ group (β = −2.72 p = 0.04), with Val/Val genotype carriers showing an earlier age of onset than Val/Met carriers, and these, lower than the Met/Met carriers. No modulation effect of CNR1 or CHRNA7 polymorphisms was observed.ConclusionsOur results seem to indicate the importance of maturation timing and brain development in which exposition to cannabis occurs. We provide new evidence about the COMT modulation effect on the association between cannabis use and age at onset of symptoms, specifically in individuals affected by schizophrenia-spectrum disorders.