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

Sophie E. Legge; Hannah J. Jones; Kimberley M. Kendall; Antonio F. Pardiñas; Georgina Menzies; Matthew Bracher-Smith; Valentina Escott-Price; Elliott Rees; Katrina A.S. Davis; Matthew Hotopf; Jeanne E. Savage; Danielle Posthuma; Peter Holmans; George Kirov; Michael J. Owen; Michael C. O'Donovan; Stanley Zammit; James T.R. Walters

doi:10.1001/jamapsychiatry.2019.2508

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

Sophie E. Legge, Hannah J. Jones, Kimberley M. Kendall, Antonio F. Pardiñas, Georgina Menzies, Matthew Bracher-Smith, Valentina Escott-Price, Elliott Rees, Katrina A.S. Davis, Matthew Hotopf, Jeanne E. Savage, Danielle Posthuma, Peter Holmans, George Kirov, Michael J. Owen, Michael C. O'Donovan, Stanley Zammit, James T.R. Walters^*

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

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 121843 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 127966 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.

Original language	English
Pages (from-to)	1256-1265
Number of pages	10
Journal	JAMA Psychiatry
Volume	76
Issue number	12
DOIs	https://doi.org/10.1001/jamapsychiatry.2019.2508
Publication status	Published - 1 Dec 2019

Funding

Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom (Legge, Kendall, Pardiñas, Bracher-Smith, Escott-Price, Rees, Holmans, Kirov, Owen, O’Donovan, Zammit, Walters); Centre for Academic Mental Health, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom (Jones, Zammit); Medical Research Centre, Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom (Jones); National Institute for Health Research Bristol Biomedical Research Centre, University Hospitals Bristol National Health Service Foundation Trust, University of Bristol, Bristol, United Kingdom (Jones, Zammit); UK-Dementia Research Institute at Cardiff, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom (Menzies, Escott-Price); Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom (Davis, Hotopf); South London and Maudsley National Health Service Foundation Trust, London, United Kingdom (Davis, Hotopf); Department of Complex Trait Genetics, Centre for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit, Amsterdam, the Netherlands (Savage, Posthuma). O’Donovan, and Walters reported receiving a grant from Takeda Pharmaceuticals outside the submitted work. No other disclosures were reported. Research, Medical Research Council, and British Heart Foundation supplied funds to complete genotyping on all UK Biobank participants. This project was supported by the following grants: Medical Research Council Centre (MR/L010305/1), Program (G0800509), and Project (MR/L011794/1, MC_PC_17212) grants to Cardiff University, and The National Centre for Mental Health, funded by the Welsh Government through Health and Care Research Wales. Drs Jones and Zammit are supported by the National Institute for Health Research Biomedical Research Centre at University Hospitals Bristol National Health Service Foundation Trust and the University of Bristol. Dr Kendall is supported by a Wellcome Trust Clinical Research Training Fellowship. Drs Davis and Hotopf are supported by the National Institute for Health Research Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King’s College London. The UK Medical Research Council, the Wellcome Trust (102215/2/13/2) and the University of Bristol provide core support for the Avon Longitudinal Study of Parents and Children (ALSPAC). A comprehensive list of grants funding is available on the ALSPAC website. The collection of ALSPAC measures used was specifically funded by the Medical Research Council (G0701503/85179). ALSPAC GWAS data were generated by Sample Logistics and Genotyping Facilities at the Wellcome Trust Sanger Institute and the Laboratory Corporation of America using support from 23andMe.

Funders	Funder number
Medical Research Council Centre	MR/L011794/1, MC_PC_17212, G0800509
National Centre for Mental Health
National Institute for Health Research Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust
University Hospitals Bristol National Health Service Foundation Trust
Wellcome Trust Sanger Institute
King’s College London
Wellcome Trust
Health and Care Research Wales
Llywodraeth Cymru
Medical Research Council	MC_PC_17228, G0701503/85179, MR/M006727/1, MR/L010305/1
National Institute for Health Research
Cardiff University
University of Bristol

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Legge, S. E., Jones, H. J., Kendall, K. M., Pardiñas, A. F., Menzies, G., Bracher-Smith, M., Escott-Price, V., Rees, E., Davis, K. A. S., Hotopf, M., Savage, J. E., Posthuma, D., Holmans, P., Kirov, G., Owen, M. J., O'Donovan, M. C., Zammit, S., & Walters, J. T. R. (2019). Association of Genetic Liability to Psychotic Experiences with Neuropsychotic Disorders and Traits. JAMA Psychiatry, 76(12), 1256-1265. https://doi.org/10.1001/jamapsychiatry.2019.2508

@article{2d3b1fdf171c4b8185f433d69ab85878,

title = "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 121843 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 127966 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.",

author = "Legge, {Sophie E.} and Jones, {Hannah J.} and Kendall, {Kimberley M.} and Pardi{\~n}as, {Antonio F.} and Georgina Menzies and Matthew Bracher-Smith and Valentina Escott-Price and Elliott Rees and Davis, {Katrina A.S.} and Matthew Hotopf and Savage, {Jeanne E.} and Danielle Posthuma and Peter Holmans and George Kirov and Owen, {Michael J.} and O'Donovan, {Michael C.} and Stanley Zammit and Walters, {James T.R.}",

year = "2019",

month = dec,

day = "1",

doi = "10.1001/jamapsychiatry.2019.2508",

language = "English",

volume = "76",

pages = "1256--1265",

journal = "JAMA Psychiatry",

issn = "2168-622X",

publisher = "American Medical Association",

number = "12",

}

Legge, SE, Jones, HJ, Kendall, KM, Pardiñas, AF, Menzies, G, Bracher-Smith, M, Escott-Price, V, Rees, E, Davis, KAS, Hotopf, M, Savage, JE , Posthuma, D, Holmans, P, Kirov, G, Owen, MJ, O'Donovan, MC, Zammit, S & Walters, JTR 2019, 'Association of Genetic Liability to Psychotic Experiences with Neuropsychotic Disorders and Traits', JAMA Psychiatry, vol. 76, no. 12, pp. 1256-1265. https://doi.org/10.1001/jamapsychiatry.2019.2508

TY - JOUR

T1 - Association of Genetic Liability to Psychotic Experiences with Neuropsychotic Disorders and Traits

AU - Legge, Sophie E.

AU - Jones, Hannah J.

AU - Kendall, Kimberley M.

AU - Pardiñas, Antonio F.

AU - Menzies, Georgina

AU - Bracher-Smith, Matthew

AU - Escott-Price, Valentina

AU - Rees, Elliott

AU - Davis, Katrina A.S.

AU - Hotopf, Matthew

AU - Savage, Jeanne E.

AU - Posthuma, Danielle

AU - Holmans, Peter

AU - Kirov, George

AU - Owen, Michael J.

AU - O'Donovan, Michael C.

AU - Zammit, Stanley

AU - Walters, James T.R.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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 121843 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 127966 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.

AB - 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 121843 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 127966 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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Association of Genetic Liability to Psychotic Experiences with Neuropsychotic Disorders and Traits

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