Genetic overlap between psychotic experiences in the community across age and with psychiatric disorders

Abstract

BackgroundThis study explores the degree to which genetic influences on psychotic experiences are stable across adolescence and adulthood, and their overlap with psychiatric disorders.MethodsGenome-wide association results were obtained for adolescent psychotic experiences and negative symptom traits (N = 6,297-10,098), schizotypy (N = 3,967-4,057) and positive psychotic experiences in adulthood (N = 116,787-117,794), schizophrenia (N = 150,064), bipolar disorder (N = 41,653) and depression (N = 173,005). Linkage disequilibrium score regression was used to estimate genetic correlations. Implicated genes from functional and gene-based analyses were compared. Mendelian Randomization was performed on trait pairs with significant genetic correlations.ResultsSubclinical auditory and visual hallucinations and believing in conspiracies during adulthood were significantly genetically correlated with schizophrenia (rg = .27-.67) and major depression (rg = .41-.96) after correction for multiple testing. Auditory and visual subclinical hallucinations were highly genetically correlated (rg = .95). Cross-age genetic correlations for psychotic experiences were not significant. Gene mapping and gene association analyses revealed 14 possible genes associated with psychotic experiences that overlapped across age for psychotic experiences or between psychotic experiences and psychiatric disorders. Mendelian Randomization indicated bidirectional associations between auditory and visual hallucinations in adults but did not support causal relationships between psychotic experiences and psychiatric disorders.ConclusionsPsychotic experiences in adulthood may be more linked genetically to schizophrenia and major depression than psychotic experiences in adolescence. Our study implicated specific genes that are associated with psychotic experiences across development as well as genes shared between psychotic experiences and psychiatric disorders.

A scoping review and comparison of approaches for measuring genetic heterogeneity in psychiatric disorders

“…Three of these evaluated departure from Hardy-Weinberg equilibrium at one or more individual loci (Mant et al, 1994;Neale et al, 2008;Rietschel et al, 1996). Eightyseven studies quantified genetic correlation (Abdellaoui et al, 2021(Abdellaoui et al, , 2019Adams et al, 2020;Amare et al, 2020;Andersson et al, 2020;Anttila et al, 2018;Bahrami et al, 2020;Barkhuizen et al, 2020;Brick et al, 2019;Cabana-Domínguez et al, 2019;Campbell et al, 2021;Charney et al, 2017;Cheng et al, 2020;Clifton et al, 2018;Coleman et al, 2020;Coombes et al, 2020;Cross-Disorder Group of the Psychiatric Genomics Consortium, 2013;Direk et al, 2017;Duncan et al, 2017;Duncan L.E. et al, 2018aDuncan L.E.…”

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

“…Although the PRS-Sz has been used to reliably predict PLEs (Jones et al, 2016(Jones et al, , 2018bPain et al, 2018;Taylor et al, 2019), the most discriminant SNPs for PLE may have not been captured by our PRS. However, considering the genetic overlap between schizophrenia and PLE (Barkhuizen et al, 2020), our significant result remains informative. Although our results consistently show that PRS-Sz is associated with lifetime cannabis use, we cannot make any conclusions about the effects of recent or current cannabis use.…”

“…those who have already manifested positive symptoms. Some have argued that the previously reported associations between PLE-Sz and the positive symptom domain in young adult populations can be explained by the fact that the genetic overlap between positive and negative psychotic experiences and schizophrenia might be stronger in adulthood than in adolescence (Barkhuizen et al, 2020). As previously suggested by Jones et al (2016), this would imply that genetic risk for schizophrenia is in fact associated with positive PLE, but that this risk may be expressed in young adulthood rather than adolescence.…”

“…Through our longitudinal design, our analyses did not find any evidence to support mediation nor moderation hypotheses that explain the relationship between lifetime cannabis use and PLE. Consequently, these null findings suggest that despite the common genetic vulnerability of psychotic experiences, cannabis use and schizophrenia (Barkhuizen, Pain, Dudbridge, & Ronald, 2020;Pasman et al, 2018), both PRS-Sz and cannabis use independently increase one's risk for PLE, leaving room for alternative explanations of the cannabis-psychosis relationship. We report the results of the path analysis examining the link between PRS-Sz and PLE, and whether there is a significant indirect effect (mediation) through cannabis use.…”

Role for Positive Schizotypy and Hallucination Proneness in Semantic Processing

“…While other components of positive schizotypy remain stable over adolescence, unusual perceptual experiences decline ( Debbané et al, 2013 ). Indeed, psychotic-like experiences in adulthood, but not adolescence, are genetically linked with psychotic and mood disorders ( Barkhuizen et al, 2020 ). Hallucinations and schizotypy are identified as separate factors in middle-aged adults ( Rössler et al, 2013 ).…”