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    Original Investigation
    September 25, 2019

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

    Author Affiliations
    • 1MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom
    • 2Centre for Academic Mental Health, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
    • 3Medical Research Centre, Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
    • 4National Institute for Health Research Bristol Biomedical Research Centre, University Hospitals Bristol National Health Service Foundation Trust, University of Bristol, Bristol, United Kingdom
    • 5UK-Dementia Research Institute at Cardiff, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom
    • 6Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom
    • 7South London and Maudsley National Health Service Foundation Trust, London, United Kingdom
    • 8Department of Complex Trait Genetics, Centre for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit, Amsterdam, the Netherlands
    JAMA Psychiatry. Published online September 25, 2019. doi:https://doi.org/10.1001/jamapsychiatry.2019.2508
    Key Points

    Question  Is the genetic liability to psychotic experiences shared with schizophrenia and/or other neuropsychiatric disorders and traits?

    Findings  In this cohort study, genetic correlation, polygenic risk score, and copy number variation analyses indicated a shared genetic liability between psychotic experiences and major depressive disorder, schizophrenia, bipolar disorder, and neurodevelopmental disorders. Genome-wide association studies identified 4 genetic loci associated with psychotic experiences including loci in ANK3 and CNR2.

    Meaning  Findings suggest that the genetic liability of psychotic experiences is shared with several psychiatric disorders, which include, but is not specific to, schizophrenia.

    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 (h2 = 1.71%; 95% CI, 1.02%-2.40%).

    Conclusions and Relevance  A large genetic association study of psychotic experiences from the population-based UK Biobank sample found support for a shared genetic liability between psychotic experiences and schizophrenia, major depressive disorder, bipolar disorder, and neurodevelopmental disorders.

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