Genetic association study of psychotic experiences in UK Biobank

Abstract

Psychotic experiences, such as hallucinations and delusions, are reported by approximately 5%-10% of the general population, though only a small proportion of individuals develop psychotic disorders such as schizophrenia or bipolar disorder. Studying the genetic aetiology of psychotic experiences in the general population, and its relationship with the genetic aetiology of other disorders, may increase our understanding of their pathological significance. Using the population-based UK Biobank sample, we performed the largest genetic association study of psychotic experiences in individuals without a psychotic disorder. We conducted three genomewide association studies (GWAS) for (i) any psychotic experience (6123 cases vs. 121,843 controls), (ii) distressing psychotic experiences (2143 cases vs. 121,843 controls), and (iii) multiple occurrence psychotic experiences (3337 cases vs. 121,843 controls). Analyses of polygenic risk scores (PRS), genetic correlation, and copy number variation (CNV) were conducted to assess whether genetic liability to psychotic experiences is shared with schizophrenia and/or other neuropsychiatric disorders and traits. GWAS analyses identified four loci associated with psychotic experiences including a locus in Ankyrin-3 (ANK3, OR=1.16, p=3.06x 10 -8 ) with any psychotic experience and a locus in cannabinoid receptor 2 gene (CNR2, OR=0.66, p=3.78x10 -8 ) with distressing psychotic experiences. PRS analyses identified associations between psychotic experiences and genetic liability for schizophrenia, major depressive disorder, and bipolar disorder, and these associations were stronger for distressing psychotic experiences. Genetic correlation analysis identified significant genetic correlations between psychotic experiences and major depressive disorder, schizophrenia, autism spectrum disorder and a cross-disorder GWAS. Individuals reporting psychotic experiences had an increased burden of CNVs previously associated with schizophrenia (OR=2.04, p=2.49x10 -4 ) and of those associated with neurodevelopmental disorders more widely (OR=1.75, p=1.41x10 -3 ). In conclusion, we identified four genome-wide significant loci in the largest GWAS of psychotic experiences from the population-based UK Biobank sample and found support for a shared genetic aetiology between psychotic experiences and schizophrenia, but also major depressive disorder, bipolar disorder and neurodevelopmental disorders.

Genetic and clinical analyses of psychosis spectrum symptoms in a large multi-ethnic youth cohort reveal significant link with ADHD

“…Contrary to recent genetic evidence based on psychotic experiences in adulthood (21), psychosis spectrum symptoms in youth did not yield a general association with multiple psychiatric illnesses, but with ADHD specifically. While an association between schizophrenia genetic risk and psychosis symptoms has been reported in adults, the lack of such an association in our study is consistent with previous literature in adolescents (in a population sample of >5k genotyped youth aged 12-18, no such association was observed (22)).…”

“…The heritability of psychotic experiences has been estimated between 30-50% from twin studies (18,19) with the proportion of genetic variance explained by common variants (SNP-heritability) of 3-17% in adolescents (18,20). Adults with psychotic symptoms harbor increased genetic liability for a broad spectrum of psychiatric disorders, including schizophrenia and other neuropsychiatric disorders (21). While in adolescents some evidence suggests increased genetic risk for schizophrenia (and major depressive disorder) for specific features of psychosis (18), the reported effect sizes are very small, and these effects not very robust (22).…”

“…The method combines multiple summary statistics from different GWAS into a single predictive model, thus potentially increasing classification power. Given evidence suggesting PS increases risk for broader psychopathology (11,21) and the wide spectrum of genetic inter-correlations in adults with psychotic experiences (21), we include a range of heritable psychiatric and brain traits in our analyses, an analytic approach that has not been previously explored in this type of cohort. In addition to multi-variate classification, we perform univariate associations and also assess phenotypic overlap between traits.…”

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

“…It is also possible that non-additive genetic influences or rare variants are shared across psychotic experiences measures and age. In an independent report, genetic risk for psychotic experiences in adults did not predict psychotic experiences in 12 year olds or 16 year olds, in agreement with our findings of lack of genetic overlap across adolescent and adult psychotic experiences, although there was some evidence of genetic association with psychotic experiences at age 18 years (55). Because UK Biobank participants were asked to report on psychotic experiences across their lives, some may have referred to experiences such as hallucinations in later adulthood that can occur as part of conditions such as dementia, eye conditions, Charles Bonnet syndrome and medication side effects, which may have different etiologies to psychotic experiences in adolescence.…”

“…We found that positive psychotic experiences in the UK Biobank shared a moderate to substantial amount of common genetic variation with depression and schizophrenia, specifically experiences of auditory and visual hallucinations (un-real voices and un-real vision) and paranoid beliefs (believing in conspiracies) with schizophrenia (r g = 0.27 - 0.67) and with depression (r g = 0.41 - 0.96), consistent with an independent report (55). Our MR analyses indicated that liability to schizophrenia may be directionally associated with a propensity to believe in un-real conspiracies, and that liability to depression may be directionally associated with a propensity to report un-real voices and conspiracies.…”