Background: Historically, gene X environment examinationsin psychotic disorders have employed candidate gene methods and environmental determinants impacting on similarbiological mechanisms. However, genome wide associationstudies (GWAS) show that many variants associated withschizophrenia have a modest effect size on risk. In this respect, it is unclear whether the effect of cannabis on psychosis phenotypes is modified by a few genes, e.g. thoseinvolved in dopamine signalling, or by the overall geneticsusceptibility to schizophrenia. Indeed, candidate gene approaches might be complementary to GWAS to test gene Xcannabis interaction. We aimed to investigate the interactive effects of cannabis use on variants in DRD2 gene on: 1)the risk of developing first episode psychosis (FEP); and 2)the frequency of positive symptoms at FEP.We undertook a replication study of previous Gene XCannabis interactions for DRD2 (rs1076560); further, wetested interactions between cannabis use and any SNP associated with schizophrenia within DRD2 gene in the lastPsychiatric Genomics Consortium (PGC) GWAS.Methods: We genotyped ∼830 FEP patients and ∼1200 controls recruited across six countries as part of the large EUGEIstudy. OPerational CRITeria system and Cannabis ExperienceQuestionnaire were used for evaluating psychopathologyand patterns of cannabis use. Dimensions of psychopathology, which included a specific dimension of positive symptoms, were estimated using multidimensional item responsemodelling in Mplus.We tested for an interaction between risk allele countand daily cannabis use on: 1) the risk of psychotic disorderin the case-control study; 2) the positive symptom dimension in the case-only sample. Only one SNP in DRD2 was significantly associated with schizophrenia in the PGC study,so we tested for interaction with rs2514218, in addition tors1076560.These regression models, conducted in STATA 14, wereadjusted for age, gender, ethnicity, 10 principal components(PC) for population stratification and SNP-environment andSNP-PC interaction terms. Results were corrected for multiple testing of four SNPs (p<0.0125 as significance threshold).Results: We found a significant interaction betweencannabis use and the rs2514218 in DRD2: daily cannabisusers with one risk allele showed a 2.5-fold increasedprobability to suffer a psychotic disorder (OR = 2.43; 95%confidence interval [CI]: 1.52–3.89). We did not replicate previous findings of an interaction between cannabisuse and rs1076560 in DRD2 for increasing psychosis risk(p=0.092). Higher levels of positive symptoms were seenin FEP who were daily cannabis users with either rs2514218(B=0.34; 95% CI: 0.04–0.64; p=0.024) or rs1076560 risk alleles (B=0.54; 95% CI: 0.15–0.93; p=0.006).Discussion: Our results suggest that dopamine signalingis implicated in cannabis associated psychosis, and, morespecifically, that variation within the DRD2 gene may modulate the effect of cannabis use on psychosis phenotypes.Such findings require a replication for rs2514218.
|Numero di pagine||1|
|Stato di pubblicazione||Published - 2019|