Genome-wide analysis of adolescent psychotic experiences shows genetic overlap with psychiatric disorders

Abstract

This study aimed to test for overlap in genetic influences between psychotic experience traits shown by adolescents in the community, and clinically-recognized psychiatric disorders in adulthood, specifically schizophrenia, bipolar disorder, and major depression. The full spectra of psychotic experience domains, both in terms of their severity and type (positive, cognitive, and negative), were assessed using self-and parent-ratings in three European community samples aged [15][16][17][18][19]098). A megagenome-wide association study (mega-GWAS) for each psychotic experience domain was performed. SNP-heritability of each psychotic experience domain was estimated using genomic-relatedness-based restricted maximum-likelihood (GREML) and linkage disequilibrium-(LD-) score regression. Genetic overlap between specific psychotic experience domains and schizophrenia, bipolar disorder, and major depression was assessed using polygenic risk scoring (PRS) and LD-score regression. GREML returned SNPheritability estimates of 3-9% for psychotic experience trait domains, with higher estimates for less skewed traits (Anhedonia, Cognitive Disorganization) than for more skewed traits (Paranoia and Hallucinations, Parent-rated Negative Symptoms). Mega-GWAS analysis identified one genome-wide significant association for Anhedonia within IDO2 but which did not replicate in an independent sample. PRS analysis revealed that the schizophrenia PRS significantly predicted all adolescent psychotic experience trait domains (Paranoia and Hallucinations only in non-zero scorers). The major depression PRS significantly predicted Anhedonia and Parent-rated Negative Symptoms in adolescence. Psychotic experiences during adolescence in the community show additive genetic effects and partly share genetic influences with clinically-recognized psychiatric disorders, specifically schizophrenia and major depression.Oliver Pain et al.3

A systematic review of genome-wide research on psychotic experiences and negative symptom traits: new revelations and implications for psychiatry

“…Heritability estimates of schizophrenia are considerably higher than of PENS in the community (80% versus 30-50%, respectively) (23,41) but it is not a like for like comparison because the schizophrenia estimate assumes an underlying liability. While the question of a qualitative cut off is not settled, as discussed below in our systematic review, genome-wide studies have considerably advanced our understanding of the link between psychiatric conditions and PENS through estimating shared genetic variance using measured DNA variants (1,3,4,(42)(43)(44)(45)(46)(47).…”

“…The number of papers identified by looking through reference lists was 0. Three other studies were identified by the authors through reading unpublished manuscripts on Biorxiv or from being involved in the work or citing the studies (1,48,49), making a total of 13 studies. Results were summarized in a table form.…”

“…The review revealed that three studies to date have estimated the SNP heritability of PENS (1,2,50) (see Table 1). Figure 1 shows the twin and SNP heritability estimates for specific PENS from the largest respective studies (1,23). SNP heritability estimates of PENS are modest with non-significant differences in estimates across types of PENS.…”

“…While some groups focus solely on positive psychotic experiences, several independent groups now include a range of positive psychotic experiences, cognitive psychotic experiences and negative symptom trait measures in their studies, e.g. (1)(2)(3)(4). As with all trait measures, this definition does not mean that PENS are equivalent to schizophrenia.…”

Psychotic experiences as a health indicator: A provisional framework

“…In agreement with models of developmental etiology and pathogenesis of diseases, our framework first acknowledges the associations between psychotic experiences and chronic conditions may be explained by shared underlying genetic liabilities. Psychotic experiences are moderately heritable (Ronald et al, 2014;Sieradzka et al, 2015) and overlap partly with chronic health conditions (Legge et al, 2019;Pain et al, 2018; and health behaviors (Taylor et al, 2015). The persistence of psychotic experiences (which may be especially predictive of health problems) can be attributable to some common genetic factors as well (Wigman et al, 2011).…”