The independent and combined influence of schizophrenia polygenic risk score and heavy cannabis use on risk for psychotic disorder: A case-control analysis from the EUGEI study.

Abstract

Background Some recent studies have challenged the direction of causality for the association between cannabis use and psychotic disorder, suggesting that cannabis use initiation is explained by common genetic variants associated with risk of schizophrenia.We used data from the European Union Gene-Environment Interaction consortium (EUGEI) case-control study to test for the independent and combined effect of heavy cannabis use, and of Schizophrenia Polygenic risk score (SZ PRS), on risk for psychotic disorder.Methods Genome-wide data were obtained from 492 first episode psychosis patients (FEPp) and from 787 controls of European Ancestry, and used to generate SZ PRS from the summary results of an independent meta-analysis. Information on pattern of cannabis use was used to build a 7-level frequency-type composite cannabis use measure that we previously found was a strong predictor of psychotic disorder. Results: SZ PRS did not predict cannabis initiation (b=0.027; p=0.51) or how frequently controls (b=0.027; p=0.06) or FEPp (b=0.006; p=0.91) used it, or the type of cannabis they used (Controls: b = 0.032; p=0.31); FEPp: b= 0.005; p=0.89). The frequency-type composite cannabis use measure (OR=1.32; 95% CI 1.22-1.44) and SZ PRS (OR=2.29; 95%CI 1.71-3.05) showed independent effects from each other on the OR for psychotic disorder.Conclusion SZ PRS does not predict an individual's propensity to try cannabis, frequency of use, or the potency of the cannabis used. Our findings provide the first evidence that SZ PRS and heavy cannabis use exert effects independent from each other on the risk for psychotic disorder.

Genetic and psychosocial stressors have independent effects on the level of subclinical psychosis: findings from the multinational EU-GEI study

“…Blood samples of the control sample were genotyped by the Medical Research Council Centre for Neuropsychiatric Genetics and Genomics (Cardiff, United Kingdom) using a custom ‘ Illumina HumanCoreExome-24 BeadChip ’ genotyping array, covering 570 038 genetic variants. As described elsewhere (Di Forti et al ., 2019 b ), the PRS-SZ were generated using PRSice from the summary results of the Psychiatric Genomics Consortium (PGC), wave 2 (Schizophrenia Working Group of the PGC, 2014 ). Clumping was performed to obtain SNPs in approximate linkage disequilibrium with an r 2 < 0.25 within a 250 kb window.…”

“…The genome-wide effects of disease-associated common genetic variants can be summarised in a polygenic risk score (PRS) (Anderson et al ., 2019 ), which offers new opportunities to characterise the complex genetic aetiology of psychotic disorders. In subjects included through the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI), the PRS for schizophrenia (PRS-SZ) explained between 7 and 9% of the variance of the case-control status (Di Forti et al ., 2019 b ; Tripoli et al ., 2020 ), consistently with other studies (Vassos et al ., 2017 ). Of note, among patients with psychotic disorders, the PRS-SZ is also associated with antipsychotic treatment response, the level of quality of life, or, in the general population, to the intelligence quotient (IQ), and the risk of attention-deficit/hyperactivity disorder (ADHD) (Mistry et al ., 2018 ; Legge et al ., 2019 ; Zhang et al ., 2019 ; Pries et al ., 2020 c ).…”

Adverse effects of heavy cannabis use: even plants can harm the brain

“…For instance, daily users of high-potency cannabis (THC = >10%) had a 5-fold increase (OR = 5.4; 95% CI 3.21-10.63) in their risk for psychotic disorders, even after controlling for the schizophrenia PRS. 32 …”

“… 68 Furthermore, individuals who have a high schizophrenia PRS and use cannabis heavily are at higher risk for psychosis than those who either carry a high schizophrenia PRS or smoke cannabis heavily. 32 A recent study described an additive interaction between schizophrenia PRS and cannabis use, 32 , 49 with no evidence that genetic liability increases the risk for cannabis use.…”

Genetic and psychosocial stressors have independent effects on the level of subclinical psychosis: findings from the multinational EU-GEI study

“…The genome-wide effects of disease-associated common genetic variants can be summarised in a polygenic risk score (PRS) (Anderson et al, 2019), which offers new opportunities to characterise the complex genetic aetiology of psychotic disorders. In subjects included through the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI), the PRS for schizophrenia (PRS-SZ) explained between 7 and 9% of the variance of the case-control status (Di Forti et al, 2019b;Tripoli et al, 2020), consistently with other studies (Vassos et al, 2017). Of note, among patients with psychotic disorders, the PRS-SZ is also associated with antipsychotic treatment response, the level of quality of life, or, in the general population, to the intelligence quotient (IQ), and the risk of attention-deficit/hyperactivity disorder (ADHD) (Mistry et al, 2018;Legge et al, 2019;Zhang et al, 2019;Pries et al, 2020c).…”