Genetic association study of psychotic experiences in UK Biobank: Psychotic experiences in UK Biobank, 2019, Hotopf et al

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Abstract
Importance
Psychotic experiences, such as hallucinations and delusions, are reported by approximately 5%-10% of the general population, though only a small proportion develop psychotic disorders such as schizophrenia. 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.

Objective
To determine whether genetic liability to psychotic experiences is shared with schizophrenia and/or other neuropsychiatric disorders and traits. To identify genetic loci associated with psychotic experiences.

Design
Analyses of genetic correlation, polygenic risk scores (PRS), and copy number variation (CNV) were used to assess whether genetic liability to psychotic experiences is shared with schizophrenia and/or other neuropsychiatric disorders and traits. GWAS analyses of psychotic experience phenotypes were conducted to identify novel genetic loci.

Setting
The population-based UK Biobank cohort.

Participants
Participants in the final analyses included 6123 individuals reporting any psychotic experience, 2143 individuals reporting distressing psychotic experiences, and 3337 individuals reporting multiple occurrence psychotic experiences. 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 with a mean age of 64 (sd =7.6) and of whom 56% were female. Psychotic experiences were genetically correlated with major depressive disorder, schizophrenia, autism spectrum disorder, and ADHD. PRS analyses identified associations between psychotic experiences and genetic liability for major depressive disorder, schizophrenia, bipolar disorder, autism spectrum disorder and ADHD. Individuals reporting psychotic experiences had an increased burden of CNVs previously associated with schizophrenia (OR=2.04, 95% CI=1.39-2.98, p=2.49x10-4) and of those associated with neurodevelopmental disorders more widely (OR=1.75, 95% CI=1.24-2.48, p=1.41x10-3). GWAS identified four significantly associated loci including a locus in Ankyrin-3 (ANK3, OR=1.16, 95% CI=1.10-1.23, p=3.06 x 10-8) with any psychotic experience and a locus in cannabinoid receptor 2 gene (CNR2, OR=0.66, 95% CI=0.56-0.78, p=3.78x10-8) with distressing psychotic experiences. The GWAS of any psychotic experience had a low SNP-based heritability (r2=1.71%).

Conclusions and Relevance
In the largest genetic-association study of psychotic experiences from the population-based UK Biobank sample, we found support for a shared genetic aetiology between psychotic experiences and schizophrenia, major depressive disorder, bipolar disorder and neurodevelopmental disorders."
https://kclpure.kcl.ac.uk/portal/en...nk(80878e44-5797-4f20-ba93-2ed86d637bf7).html