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

Abstract

This study explores the degree to which genetic influences on psychotic experiences are stable across adolescence and adulthood, and their overlap with psychiatric disorders. Genome-wide association results were obtained for adolescent psychotic experiences and negative symptom traits (N = 6297-10,098), schizotypy (N = 3967-4057) 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. Results indicated that subclinical auditory and visual hallucinations and delusions of persecution during adulthood were significantly genetically correlated with schizophrenia (r_g = 0.27-0.67) and major depression (r_g = 0.41-96) after correction for multiple testing. Auditory and visual subclinical hallucinations were highly genetically correlated (r_g = 0.95). Cross-age genetic correlations for psychotic experiences were not significant. Gene mapping and 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. These findings indicate that psychotic 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.

Fig. 1. Heat map showing genetic correlations between psychotic experiences and psychiatric disorders.

PENS, Psychotic experiences (PE) and negative symptom traits; NA, genetic correlations could not be computed due to low SNP heritability or sample size (see Supplementary Table S1 for genetic covariance estimates). *Nominally statistically significant genetic correlations at p < .05; **genetic correlations that survived Benjamini–Hochberg correction for multiple testing for 105 pairwise correlations (at a FDR of 0.05); genetic correlations reported using unconstrained LD score regression intercept between phenotypes with sample overlap.

Fig. 2. Number of overlapping genes between psychotic experiences across age and psychiatric disorders.

PENS, Psychotic experiences (PE) and negative symptom traits. Genes identified using (a) genome-wide gene associations in MAGMA after Bonferroni correction for the number of gene associations tested, (b) positional mapping that prioritized genes based on variant functional annotations obtained using ANNOVAR, (c) eQTL (expressive quantitative trait) mapping, and (d) chromatin interaction mapping.