Association of Genetic Liability to Psychotic Experiences With Neuropsychotic Disorders and Traits

Abstract

IMPORTANCE Psychotic experiences, such as hallucinations and delusions, are reported by approximately 5% to 10% of the general population, although only a small proportion develop psychotic disorders such as schizophrenia. Studying the genetic causes of psychotic experiences in the general population, and its association with the genetic causes of other disorders, may increase the understanding of their pathologic significance. OBJECTIVES To determine whether genetic liability to psychotic experiences is shared with schizophrenia and/or other neuropsychiatric disorders and traits and to identify genetic loci associated with psychotic experiences. DESIGN, SETTING AND PARTICIPANTS Analyses of genetic correlation, polygenic risk scores, and copy number variation were performed using data from participants in the UK Biobank from April 1, 2018, to March 20, 2019, to assess whether genetic liability to psychotic experiences is shared with schizophrenia and/or other neuropsychiatric disorders and traits. Genome-wide association studies of psychotic experience phenotypes were conducted to identify novel genetic loci. Participants in the final analyses after exclusions included 6123 individuals reporting any psychotic experience, 2143 individuals reporting distressing psychotic experiences, and 3337 individuals reporting multiple occurrences of psychotic experiences. A total of 121 843 individuals who did not report a psychotic experience formed the comparator group. Individuals with a psychotic disorder were excluded from all analyses. MAIN OUTCOMES AND MEASURES Genetic associations with psychotic experience phenotypes. RESULTS The study included a total of 127 966 participants (56.0% women and 44.0% men; mean [SD] age, 64.0 [7.6] years). Psychotic experiences were genetically correlated with major depressive disorder, schizophrenia, autism spectrum disorder, and attention-deficit/ hyperactivity disorder. Analyses of polygenic risk scores identified associations between psychotic experiences and genetic liability for major depressive disorder, schizophrenia, bipolar disorder, autism spectrum disorder, and attention-deficit/hyperactivity disorder. Individuals reporting psychotic experiences had an increased burden of copy number variations previously associated with schizophrenia (odds ratio [OR], 2.04; 95% CI, 1.39-2.98; P = 2.49 × 10 −4) and neurodevelopmental disorders more widely (OR, 1.75; 95% CI, 1.24-2.48; P = 1.41 × 10 −3). Genome-wide association studies identified 4 significantly associated loci, including a locus in Ankyrin-3 (ANK3 [GenBank NM_020987]) (OR, 1.16; 95% CI, 1.10-1.23; P = 3.06 × 10 −8) with any psychotic experience, and a locus in cannabinoid receptor 2 gene (CNR2 [GenBank NM_001841]) (OR, 0.66; 95% CI, 0.56-0.78; P = 3.78 × 10 −8) with distressing psychotic experiences. The genome-wide association study of any psychotic experience had a low single-nucleotide polymorphism-based heritability estimate (h 2 = 1.71%; 95% CI, 1.02%-2.40%). CONCLUSIONS AND RELEVANCE A large genetic association study of ...

Psychotic-like experiences, polygenic risk scores for schizophrenia and structural properties of the salience, default mode and central-executive networks in healthy participants from UK Biobank

“…We did not find any significant association between PRSSZ and total number of PLEs in the entire UKBiobank sample (N = 308,693), consistent with previous studies investigating this relationship in adolescence [65,66]. A recent UKBiobank study found a weak association between the presence of any PLEs and PRSSZ at a threshold of P ≤ 0.05 (OR, 1.09; 95% CI, 1.06-1.12; adjusted R2 = 0.001; P = 2.96x10 −11 , N = 500,000); however, as the authors noted, this association may be biased by the possibility that their analysis included sample overlap between UKBiobank and the training sets [9].…”

“…Psychotic-like experiences (PLEs) of lesser severity are present not only in patients but also in 5-8% of the general population [5], and to some extent predict transition to psychiatric disorders among those with higher PLEs [6]; with cohort studies supporting a continuity between subclinical and clinically significant psychotic symptoms [7,8]. A recent study found shared genetic aetiology between PLEs and several psychiatric and neurodevelopmental disorders, indicating that PLEs may be related to a general risk for mental health disorders [9]. Studies of the relationship between PLEs and brain imaging metrics have, however, been scarce and characterised by small sample sizes (with N ranging from 25 for auditory hallucinations to 76 for any PLEs [10][11][12][13]).…”

Subthreshold psychosis symptoms associated with molecular genetic risk in a population-based cohort: Findings from Generation Scotland

“…One well-powered molecular genetic analysis has recently detected shared genetic covariance of psychotic experiences (e.g., auditory/visual hallucinations and delusions) with schizophrenia and with four other psychiatric disorders using interview data from UK Biobank. 4 These results are promising for genetic studies of subthreshold psychosis symptoms, since schizotypy measures provide increased variation and sensitivity with respect to risk-a key empirical finding from the literature on subthreshold negative symptoms. [11][12][13] The availability of symptom and common variant genetic data in a large population-based cohort, the Generation Scotland Scottish Family Health Study (N = 9,105 individuals aged 18-65 years), yields the unique opportunity to examine associations of these symptoms with polygenic risk for schizophrenia.…”

“…Because of potential for clinically significant overlap of items with other psychiatric symptoms, we followed up with additional analyses of polygenic risk for the four other psychiatric disorders examined in analyses of UK Biobank-major depression, bipolar disorder, autism spectrum disorder, and ADHD. 4 Recent data from the World Health Organization have suggested that psychotic experiences may be much less specific to schizophrenia than previously thought. 1 Indeed, psychotic experiences appear to lie on the continuum of neuroticism, and have been observed to either precede or follow the onset of a range of non-psychotic psychiatric disorders.…”

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

“…Genome-wide association studies (GWAS) indicate modest single-nucleotide polymorphism heritability (SNP-h 2 ) for some PENS in mid-adolescence (3%-9%) and for schizotypy in adults (20%-27%) [20][21][22] . Psychotic experiences share genome-wide genetic influences with schizophrenia and major depression 20,[23][24][25][26] , although not all studies found this, particularly those that used comparatively smaller samples or polygenic scores (PGS) from less well-powered GWAS 23,24,[27][28][29][30][31] . Schizophrenia PGS has been associated with schizotypy in adults assessed using semi-structured interviews, but not with self-rated PENS 32 .…”