The association between reasons for first using cannabis, later pattern of use, and risk of first-episode psychosis: the EU-GEI case-control study.

BACKGROUND: While cannabis use is a well-established risk factor for psychosis, little is known about any association between reasons for first using cannabis (RFUC) and later patterns of use and risk of psychosis. METHODS: We used data from 11 sites of the multicentre European Gene-Environment Interaction (EU-GEI) case-control study. 558 first-episode psychosis patients (FEPp) and 567 population controls who had used cannabis and reported their RFUC.We ran logistic regressions to examine whether RFUC were associated with first-episode psychosis (FEP) case-control status. Path analysis then examined the relationship between RFUC, subsequent patterns of cannabis use, and case-control status. RESULTS: Controls (86.1%) and FEPp (75.63%) were most likely to report 'because of friends' as their most common RFUC. However, 20.1% of FEPp compared to 5.8% of controls reported: 'to feel better' as their RFUC (χ2 = 50.97; p < 0.001). RFUC 'to feel better' was associated with being a FEPp (OR 1.74; 95% CI 1.03-2.95) while RFUC 'with friends' was associated with being a control (OR 0.56; 95% CI 0.37-0.83). The path model indicated an association between RFUC 'to feel better' with heavy cannabis use and with FEPp-control status. CONCLUSIONS: Both FEPp and controls usually started using cannabis with their friends, but more patients than controls had begun to use 'to feel better'. People who reported their reason for first using cannabis to 'feel better' were more likely to progress to heavy use and develop a psychotic disorder than those reporting 'because of friends'.

DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia.

We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.

The androgen receptor gene polyglycine repeat polymorphism is associated with memory performance in healthy Chinese individuals.

Cognitive functions such as memory are quantitative traits in human, and have both genetic and environmental influences. Testosterone has been implicated in the modulation of memory function. Therefore, genetic variation which influences testosterone signaling may modulate memory function. The principal receptor for testosterone is the androgen receptor, the gene for which maps to the X chromosome. In the present study, we hypothesized that common variation in two functional polymorphisms in the androgen receptor gene, the polyglutamine (CAG) and/or polyglycine (GGN) repeats, would influence memory function in healthy subjects. Variation in length of either repeat modulates the function of the AR gene, either by changing the amount of protein produced, by altering transactivation of the receptor or by producing toxic polyglycine or polyglutamine fragments. In order to test this hypothesis, we analyzed 449 healthy Chinese individuals. CAG repeats were not associated with memory performance. However we observed a significant association between GGN repeats and Immediate Logical Memory (chi(2)=23.6, d.f.=7, p=0.001) and Delayed Logical Memory (chi(2)=16.3, d.f.=7, p=0.022). The association of GGN repeats with Immediate Logical Memory remained significant after 6000 permutation corrections (p=0.013). There was also a sex difference, as association between GGN repeats and memory was observed only in females (p=0.002 for Immediate and p=0.014 for Delayed Logical Memory), but not in males (p=0.31 and 0.83, respectively). We conclude that functional variation of the androgen receptor gene is able to modulate memory function in women.