2019 Post-doctoral Clinical Fellowship
Genetic variation of the endocannabinoid system and risk of psychosis
Cannabis is used for recreational and medical purposes worldwide. Recreational cannabis misuse confers risk for developing psychotic disorders, which are severe mental health conditions mostly characterised by delusions, hallucinations, and thought disorder. The cannabis plant contains psychoactive exogenous cannabinoids, such as Δ9-tetrahydrocannabinol (THC), that target the endo(genous)-cannabinoid system (eCB) in our brain. Individuals vary in their genetic composition of eCB; whether this eCB genetic variation influences the expression of psychosis needs to be explored further.
Therefore, my fellowship aimed to determine 1) if the genetic variation of eCB places some individuals at higher risk to develop a first-episode psychotic disorder (FEP) independently from cannabis use; and 2) is this risk higher in those individuals regularly using cannabis.
I analysed a large international sample of FEP patients and general population controls. Based on individuals’ eCB genetic composition, I developed an eCB polygenic risk score (eCB-PRS) for each subject, based on how frequently eCB genetic variants are found in schizophrenia. Results showed compared with the rest of the sample, 1) individuals with a high eCB-PRS were more than two times likely to develop FEP (odds ratio[OR]=2.4); 2) individuals using cannabis on a daily basis were similarly at a higher risk of FEP (OR=2.6); 3) individuals having both high eCB-PRS and using cannabis on a daily basis were more than 10-times likely to develop FEP(OR=11.4).
These findings are relevant for public information and education on risks of cannabis misuse, and for developing both primary and secondary prevention strategies for cannabinoid-associated psychosis. There were other research questions raised during my fellowship, which I aim to investigate in the near future. These include: 1) possible genetic overlapping of eCB genetic risk variants with other disorders, including Parkinson’s Disease; 2) whether the increased use of more potent forms of cannabis over the last decade has resulted in an increased incidence of FEP; 3) whether genetic variation of eCB may impact epigenetic regulation of other systems in our brain, such as dopamine, in different neuropsychiatric disorders.
Position obtained after this fellowship:
I was able to secure a permanent clinical academic post as a psychiatrist at South London and Maudsley NHS Foundation Trust, which may include two research days per week. This post is now allowing me to contribute to the NHS efforts to fight the Covid19 pandemic. At the same time, I have developed international research collaborations, for example with the Psychiatric Genomic Consortium, which will help me to develop my plans to explore genetics and epigenetics of eCB in different neuropsychiatric disorders.
Genetic variation of the endocannabinoid system and risk of psychosis.
European Neuropsychopharmacology, 29, S152-S153.
Premorbid Adjustment and IQ in Patients with First Episode Psychosis: a multisite Case-Control Study of their Relationship with Cannabis Use.
Schizophrenia Bulletin, 2020 Apr 10;46(3):517-529. doi: 10.1093/schbul/sbz077. PMID: 31361020; PMCID: PMC7147569.
Do AKT1, COMT and FAAH influence reports of acute cannabis intoxication experiences in patients with first episode psychosis, controls and young adult cannabis users?
Translational psychiatry, 10(1), 1-13
Do Idiopathic Parkinson's Disease and Schizophrenia Lie on the Same Genetic Spectrum?
Commentary published in Biological Psychiatry, 2021 Feb 1;89(3):207-208. doi: 10.1016/j.biopsych.2020.11.011. PMID: 33357627.
1 February 2021
The continuity of effect of schizophrenia polygenic risk score and patterns of cannabis use on transdiagnostic symptom dimensions at first-episode psychosis: findings from the EU-GEI study
Translational Psychiatry 11, 423 (2021)