Dataset Information

Independent contribution of polygenic risk for schizophrenia and cannabis use in predicting psychotic-like experiences in young adulthood: testing gene × environment moderation and mediation.

ABSTRACT:

Background

It has not yet been determined if the commonly reported cannabis-psychosis association is limited to individuals with pre-existing genetic risk for psychotic disorders.

Methods

We examined whether the relationship between polygenic risk score for schizophrenia (PRS-Sz) and psychotic-like experiences (PLEs), as measured by the Community Assessment of Psychic Experiences-42 (CAPE-42) questionnaire, is mediated or moderated by lifetime cannabis use at 16 years of age in 1740 of the individuals of the European IMAGEN cohort. Secondary analysis examined the relationships between lifetime cannabis use, PRS-Sz and the various sub-scales of the CAPE-42. Sensitivity analyses including covariates, including a PRS for cannabis use, were conducted and results were replicated using data from 1223 individuals in the Dutch Utrecht cannabis cohort.

Results

PRS-Sz significantly predicted cannabis use (p = 0.027) and PLE (p = 0.004) in the IMAGEN cohort. In the full model, considering PRS-Sz and covariates, cannabis use was also significantly associated with PLE in IMAGEN (p = 0.007). Results remained consistent in the Utrecht cohort and through sensitivity analyses. Nevertheless, there was no evidence of a mediation or moderation effects.

Conclusions

These results suggest that cannabis use remains a risk factor for PLEs, over and above genetic vulnerability for schizophrenia. This research does not support the notion that the cannabis-psychosis link is limited to individuals who are genetically predisposed to psychosis and suggests a need for research focusing on cannabis-related processes in psychosis that cannot be explained by genetic vulnerability.

SUBMITTER: Elkrief L

PROVIDER: S-EPMC10106286 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Publications

Independent contribution of polygenic risk for schizophrenia and cannabis use in predicting psychotic-like experiences in young adulthood: testing gene × environment moderation and mediation.

Elkrief Laurent L Lin Bochao B Marchi Mattia M Afzali Mohammad H MH Banaschewski Tobias T Bokde Arun L W ALW Quinlan Erin Burke EB Desrivières Sylvane S Flor Herta H Garavan Hugh H Gowland Penny P Heinz Andreas A Ittermann Bernd B Martinot Jean-Luc JL Martinot Marie-Laure Paillère MP Nees Frauke F Orfanos Dimitri Papadopoulos DP Paus Tomáš T Poustka Luise L Hohmann Sarah S Fröhner Juliane H JH Smolka Michael N MN Walter Henrik H Whelan Robert R Schumann Gunter G Luykx Jurjen J Boks Marco P MP Conrod Patricia J PJ

Psychological medicine 20210923 5

<h4>Background</h4>It has not yet been determined if the commonly reported cannabis-psychosis association is limited to individuals with pre-existing genetic risk for psychotic disorders.<h4>Methods</h4>We examined whether the relationship between polygenic risk score for schizophrenia (PRS-Sz) and psychotic-like experiences (PLEs), as measured by the Community Assessment of Psychic Experiences-42 (CAPE-42) questionnaire, is mediated or moderated by lifetime cannabis use at 16 years of age in 17 ...[more]

PMID: 37310336

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Project description:BackgroundSchizophrenia is a heritable psychiatric disorder with a polygenic architecture. Genome-wide association studies have reported that an increasing number of risk-associated variants and polygenic risk scores (PRSs) explain 17% of the variance in the disorder. Substantial heterogeneity exists in the effect of these variants, and aggregating them based on biologically relevant functions may provide mechanistic insight into the disorder.MethodsUsing the largest schizophrenia genome-wide association study conducted to date, we associated PRSs based on 5 gene sets previously found to contribute to schizophrenia pathophysiology-postsynaptic density of excitatory synapses, postsynaptic membrane, dendritic spine, axon, and histone H3-K4 methylation-along with respective whole-genome PRSs, with neuroimaging (n > 29,000) and reported psychotic-like experiences (n > 119,000) variables in healthy UK Biobank subjects.ResultsSeveral variables were significantly associated with the axon gene-set (psychotic-like communications, parahippocampal gyrus volume, fractional anisotropy thalamic radiations, and fractional anisotropy posterior thalamic radiations (β range -0.016 to 0.0916, false discovery rate-corrected p [pFDR] ≤ .05), postsynaptic density gene-set (psychotic-like experiences distress, global surface area, and cingulate lobe surface area [β range -0.014 to 0.0588, pFDR ≤ .05]), and histone gene set (entorhinal surface area: β = -0.016, pFDR = .035). From these, whole-genome PRSs were significantly associated with psychotic-like communications (β = 0.2218, pFDR = 1.34 × 10-7), distress (β = 0.1943, pFDR = 7.28 × 10-16), and fractional anisotropy thalamic radiations (β = -0.0143, pFDR = .036). Permutation analysis revealed that these associations were not due to chance.ConclusionsOur results indicate that genetic variation in 3 gene sets relevant to schizophrenia may confer risk for the disorder through effects on previously implicated neuroimaging variables. Because associations were stronger overall for whole-genome PRSs, findings here highlight that selection of biologically relevant variants is not yet sufficient to address the heterogeneity of the disorder.

Project description:BackgroundChildhood psychotic-like experiences (PLEs) often precede the development of later severe psychopathology. This study examined whether childhood PLEs are associated with several psychopathology-related polygenic scores (PGSs) and additionally examined possible neural and behavioral mechanisms.MethodsAdolescent Brain Cognitive Development Study baseline data from children with European ancestry (n = 4650, ages 9-10 years, 46.8% female) were used to estimate associations between PLEs (i.e., both total and presence of significantly distressing) and PGSs for psychopathology (i.e., schizophrenia, psychiatric cross-disorder risk, PLEs) and related phenotypes (i.e., educational attainment [EDU], birth weight, inflammation). We also assessed whether variability in brain structure indices (i.e., volume, cortical thickness, surface area) and behaviors proximal to PGSs (e.g., cognition for EDU) indirectly linked PGSs to PLEs using mediational models.ResultsTotal and significantly distressing PLEs were associated with EDU and cross-disorder PGSs (all %ΔR2s = 0.202%-0.660%; false discovery rate-corrected ps < .006). Significantly distressing PLEs were also associated with higher schizophrenia and PLE PGSs (both %ΔR2 = 0.120%-0.216%; false discovery rate-corrected ps < .03). There was evidence that global brain volume metrics and cognitive performance indirectly linked EDU PGS to PLEs (estimated proportion mediated = 3.33%-32.22%).ConclusionsTotal and significantly distressing PLEs were associated with genomic risk indices of broad-spectrum psychopathology risk (i.e., EDU and cross-disorder PGSs). Significantly distressing PLEs were also associated with genomic risk for psychosis (i.e., schizophrenia, PLEs). Global brain volume metrics and PGS-proximal behaviors represent promising putative intermediary phenotypes that may indirectly link genomic risk to psychopathology. Broadly, polygenic scores derived from genome-wide association studies of adult samples generalize to indices of psychopathology risk among children.

Dataset Information

Independent contribution of polygenic risk for schizophrenia and cannabis use in predicting psychotic-like experiences in young adulthood: testing gene × environment moderation and mediation.

Background

Methods

Results

Conclusions

Publications

Independent contribution of polygenic risk for schizophrenia and cannabis use in predicting psychotic-like experiences in young adulthood: testing gene × environment moderation and mediation.

Similar Datasets

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