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Word count: 3166Number of figures: 3Number of tables: 2Title: Genetic association study of psychotic experiences in UK BiobankSubtitle: Psychotic experiences in UK BiobankSophie E. Legge1 PhD, Hannah J. Jones2,3,4 PhD, Kimberley M. Kendall1 MRCPsych, Antonio F. Pardi?as1 PhD, Georgina Menzies5 PhD, Matthew Bracher-Smith1 BSc, Valentina Escott-Price1,5 PhD, Elliott Rees1 PhD, Katrina A.S. Davis6 MRCPsych, Matthew Hotopf6 MRCPsych PhD, Jeanne E. Savage8 PhD, Danielle Posthuma8 PhD, Peter Holmans1 PhD, George Kirov1 MRCPsych PhD, Michael J. Owen1 FRCPsych PhD, Michael C. O’Donovan1 FRCPsych PhD, Stanley Zammit1,2,4* MRCPsych PhD, James T.R. Walters1* MRCPsych PhD* Both authors contributed equally to this projectCorresponding authorProfessor James WaltersEmail: WaltersJT@Cardiff.ac.ukTel: 02920 688434MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UKAffiliations1 MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK2 Centre for Academic Mental Health, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK3 Medical Research Centre, Integrative Epidemiology Unit, University of Bristol, Bristol, UK4 National Institute for Health Research Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust, University of Bristol, Bristol, UK5 UK-Dementia Research Institute at Cardiff, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK6 Institute of Psychiatry Psychology and Neuroscience, King's College London, South London and Maudsley NHS Foundation Trust and NIHR Biomedical Research Centre, London, UK7 South London and Maudsley NHS Foundation Trust, UK8 Department of Complex Trait Genetics, Centre for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University, Amsterdam, The NetherlandsKeywordsPsychotic experiences; UK Biobank; ALSPAC; GWASKey pointsQuestionIs the genetic liability to psychotic experiences shared with schizophrenia and/or other neuropsychiatric disorders and traits?FindingsGenetic correlation, polygenic risk score, and copy number variation analyses indicated a shared genetic aetiology between psychotic experiences and major depressive disorder, schizophrenia, bipolar disorder, and neurodevelopmental disorders. GWAS analyses identified four genetic loci associated with psychotic experiences including loci in ANK3 and CNR2.MeaningFindings suggest the genetic aetiology of psychotic experiences is shared with several psychiatric disorders, which include, but is not specific to, schizophrenia. Suggested TweetPsychotic experiences in UK Biobank have shared genetic aetiology with schizophrenia, depression, bipolar disorder and neurodevelopmental disorders.@sophlegge @drjameswalters AbstractImportancePsychotic 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.ObjectiveTo 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.DesignAnalyses 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.ParticipantsParticipants 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 MeasuresGenetic associations with psychotic experience phenotypes.ResultsThe 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 RelevanceIn 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.IntroductionPsychotic experiences, such as hallucinations and delusions, are features of psychiatric disorders, for example schizophrenia, but they are also reported by approximately 5%-10% of the general populationPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NY0dyYXRoPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48

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ADDIN EN.CITE.DATA 1,2. Psychotic experiences are only considered to be symptoms of psychiatric illness if they co-occur with other features of that disorder, including some aspect of psychosocial impairment. It is currently unclear whether psychotic experiences in the general population are (i) on a spectrum that at the extreme relates specifically to schizophrenia, (ii) largely unrelated to the psychotic symptoms experienced in schizophrenia and other major mental disorders, or (iii) related to liability to major mental disorders more generally. Twin studies and genome-wide association studies (GWAS) have provided evidence that psychotic experiences are heritable (30-50% from twin studiesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aYXZvczwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl

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ZT5=

ADDIN EN.CITE.DATA 7,8,11-13. Although many individuals with a lifetime history of psychotic experiences have their first experience in adolescence, nearly a quarter of first onset psychotic experiences occur after 40 years of agePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NY0dyYXRoPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

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ADDIN EN.CITE.DATA 14. Our aims were to use the UK Biobank to (i) identify genetic loci associated with psychotic experiences reported by adults in a population-based study, and (ii) to determine whether genetic liability to psychotic experiences is shared with schizophrenia and/or other neuropsychiatric disorders and traits.MethodsSampleStudy individuals were from the UK Biobank, a large prospective population-based cohort study of approximately 500,000 individuals aged between 40-69 who were recruited from across the UK between 2006-2010PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdWRsb3c8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 15. The North West Multi-Centre Ethics Committee granted ethical approval to UK Biobank and all participants provided informed consent. This study was conducted under UK Biobank project numbers 13310 and 14421.Psychotic experiences phenotypesA Mental Health Questionnaire (MHQ) was sent to all participants in 2016-2017 who provided an email address and was completed by a total of 157,397 individuals (46% of those emailed, 31% of the total UK Biobank sample). For psychotic experiences, participants were asked about previous experience of visual hallucinations, auditory hallucinations, delusions of reference, delusions of persecution, how often these experiences occurred and how distressing they found them (see eAppendix 1). Individuals with a diagnosis of schizophrenia, bipolar disorder or any other psychotic disorder were identified using all available sources (hospital records, death records, self-report at the interview or from the MHQ) and were excluded from all analyses (full details in eMethods 1). We selected three primary phenotypes for GWAS (eFigure 1): (i) any psychotic experience defined as a positive response to any of the four symptom questions (UKB field IDs: 20471, 20463, 20474, 20468), (ii) a distressing psychotic experience, defined as any psychotic experience that was rated as ‘a bit’, ‘quite’ or ‘very’ distressing (UKB field ID: 20462), (iii) multiple occurrence psychotic experiences defined as any psychotic experience that occurred on more than one occasion (UKB field IDs: 20473, 20465, 20476, 20470). As a comparator group, we included individuals who provided a negative response to all four psychotic experience symptom questions. In addition, we investigated each individual psychotic experience symptom for association with PRS. Genetic dataGenetic data for the study participants was provided by UK Biobank and the imputation and quality control procedures are fully described elsewhere ADDIN EN.CITE <EndNote><Cite><Author>Bycroft</Author><Year>2017</Year><RecNum>4778</RecNum><DisplayText><style face="superscript">16</style></DisplayText><record><rec-number>4778</rec-number><foreign-keys><key app="EN" db-id="vfrazzdppe9w9ueee5x5ew0g005r90epvwfs" timestamp="1534153956">4778</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bycroft, Clare</author><author>Freeman, Colin</author><author>Petkova, Desislava</author><author>Band, Gavin</author><author>Elliott, Lloyd T</author><author>Sharp, Kevin</author><author>Motyer, Allan</author><author>Vukcevic, Damjan</author><author>Delaneau, Olivier</author><author>O&apos;Connell, Jared</author><author>Cortes, Adrian</author><author>Welsh, Samantha</author><author>McVean, Gil</author><author>Leslie, Stephen</author><author>Donnelly, Peter</author><author>Marchini, Jonathan</author></authors></contributors><titles><title>Genome-wide genetic data on ~500,000 UK Biobank participants</title><secondary-title>bioRxiv</secondary-title><alt-title>bioRxiv</alt-title></titles><periodical><full-title>bioRxiv</full-title></periodical><alt-periodical><full-title>bioRxiv</full-title></alt-periodical><dates><year>2017</year></dates><urls><related-urls><url>. The data release contained 488,377 participants assayed on either the UK Biobank Axiom or the UK BiLEVE Axiom purpose-built arrays at the Affymetrix Research Services Laboratory. Standard quality control procedures were applied prior to imputation using Haplotype Reference Consortium (HRC)PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NY0NhcnRoeTwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+

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ADDIN EN.CITE.DATA 18 panels. We applied additional quality control filters to select high quality SNPsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TbWl0aDwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 19; minor allele frequency (MAF) > 0.01, imputation score (INFO) > 0.8, missingness < 0.05, Hardy-Weinberg equilibrium (HWE) < 1 x 10-6, and removed SNPs imputed by the UK10K haplotype referencePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IdWFuZzwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 18 dataset in accordance with guidance from the UK Biobank (URL: ). One member from each related pair with a kinship coefficient > 0.15 was excluded from analyses, preferentially retaining individuals that had experienced a psychotic experience, and were otherwise removed at random. Analyses were restricted to individuals with a self-reported British and Irish background (UKB field ID: 21000) and principal components supplied by UK Biobank ADDIN EN.CITE <EndNote><Cite><Author>Bycroft</Author><Year>2017</Year><RecNum>4778</RecNum><DisplayText><style face="superscript">16</style></DisplayText><record><rec-number>4778</rec-number><foreign-keys><key app="EN" db-id="vfrazzdppe9w9ueee5x5ew0g005r90epvwfs" timestamp="1534153956">4778</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bycroft, Clare</author><author>Freeman, Colin</author><author>Petkova, Desislava</author><author>Band, Gavin</author><author>Elliott, Lloyd T</author><author>Sharp, Kevin</author><author>Motyer, Allan</author><author>Vukcevic, Damjan</author><author>Delaneau, Olivier</author><author>O&apos;Connell, Jared</author><author>Cortes, Adrian</author><author>Welsh, Samantha</author><author>McVean, Gil</author><author>Leslie, Stephen</author><author>Donnelly, Peter</author><author>Marchini, Jonathan</author></authors></contributors><titles><title>Genome-wide genetic data on ~500,000 UK Biobank participants</title><secondary-title>bioRxiv</secondary-title><alt-title>bioRxiv</alt-title></titles><periodical><full-title>bioRxiv</full-title></periodical><alt-periodical><full-title>bioRxiv</full-title></alt-periodical><dates><year>2017</year></dates><urls><related-urls><url> (UKB field ID: 22009) were used to make additional exclusions and control for population structure (described in eMethods 2, eFigures 2-3). GWAS analysisTo identify genetic risk variants for psychotic experiences, association analysis was performed in SNPTEST (v2.5.4) ADDIN EN.CITE <EndNote><Cite><Author>Marchini</Author><Year>2007</Year><RecNum>4782</RecNum><DisplayText><style face="superscript">22</style></DisplayText><record><rec-number>4782</rec-number><foreign-keys><key app="EN" db-id="vfrazzdppe9w9ueee5x5ew0g005r90epvwfs" timestamp="1534171192">4782</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Marchini, J.</author><author>Howie, B.</author><author>Myers, S.</author><author>McVean, G.</author><author>Donnelly, P.</author></authors></contributors><auth-address>Department of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG, UK.</auth-address><titles><title>A new multipoint method for genome-wide association studies by imputation of genotypes</title><secondary-title>Nature Genetics</secondary-title><alt-title>Nat Genet</alt-title></titles><periodical><full-title>Nat Genet</full-title><abbr-1>Nature genetics</abbr-1></periodical><alt-periodical><full-title>Nat Genet</full-title><abbr-1>Nature genetics</abbr-1></alt-periodical><pages>906-13</pages><volume>39</volume><number>7</number><keywords><keyword>Case-Control Studies</keyword><keyword>Genetic Markers</keyword><keyword>Genetics, Population</keyword><keyword>*Genome, Human</keyword><keyword>Genomics/*statistics &amp; numerical data</keyword><keyword>Genotype</keyword><keyword>Humans</keyword><keyword>Models, Genetic</keyword><keyword>Polymorphism, Single Nucleotide</keyword></keywords><dates><year>2007</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1061-4036 (Print)&#xD;1061-4036 (Linking)</isbn><accession-num>17572673</accession-num><urls><related-urls><url> using bgen v1.2 imputed dosage data ADDIN EN.CITE <EndNote><Cite><Author>Band</Author><Year>2018</Year><RecNum>4793</RecNum><DisplayText><style face="superscript">23</style></DisplayText><record><rec-number>4793</rec-number><foreign-keys><key app="EN" db-id="vfrazzdppe9w9ueee5x5ew0g005r90epvwfs" timestamp="1534836580">4793</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Band, Gavin</author><author>Marchini, Jonathan</author></authors></contributors><titles><title>BGEN: a binary file format for imputed genotype and haplotype data</title><secondary-title>bioRxiv</secondary-title></titles><periodical><full-title>bioRxiv</full-title></periodical><dates><year>2018</year></dates><urls><related-urls><url>. Over 7.5 million SNPs were included in each GWAS. An additive logistic regression model was used including as covariates genotyping array, the top five principal components (as recommended for most GWAS approachesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UdWNrZXI8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 25 (r2 < 0.1, p < 1x10-4, window size < 3MB) for each GWAS using a reference panel of 1000 randomly selected UK Biobank individuals with confirmed European ancestry. Functional annotation was conducted using FUMAPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXRhbmFiZTwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+

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ADDIN EN.CITE.DATA 27 was used to calculate the LD score intercept and heritability on the observed scale using the summary statistics from each psychotic experience GWAS. Validation analyses in ALSPAC cohortTo assess the reproducibility of the psychotic experience GWAS, we used the summary statistics from the any psychotic experience GWAS to target psychotic experiences in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohortPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb3lkPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA 11,30. The psychotic experience PRS was generated for each ALSPAC participant using the widely used method ADDIN EN.CITE <EndNote><Cite><Author>Schizophrenia Working Group of the Psychiatric Genomics Consortium</Author><Year>2014</Year><RecNum>4226</RecNum><DisplayText><style face="superscript">31</style></DisplayText><record><rec-number>4226</rec-number><foreign-keys><key app="EN" db-id="vfrazzdppe9w9ueee5x5ew0g005r90epvwfs" timestamp="1435143642">4226</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Schizophrenia Working Group of the Psychiatric Genomics Consortium,</author></authors></contributors><titles><title>Biological insights from 108 schizophrenia-associated genetic loci</title><secondary-title>Nature</secondary-title><alt-title>Nature</alt-title></titles><periodical><full-title>Nature</full-title><abbr-1>Nature</abbr-1></periodical><alt-periodical><full-title>Nature</full-title><abbr-1>Nature</abbr-1></alt-periodical><pages>421-7</pages><volume>511</volume><number>7510</number><keywords><keyword>Alleles</keyword><keyword>Brain/metabolism/physiology</keyword><keyword>Enhancer Elements, Genetic/genetics</keyword><keyword>*Genetic Loci</keyword><keyword>Genetic Predisposition to Disease/*genetics</keyword><keyword>*Genome-Wide Association Study</keyword><keyword>Glutamic Acid/metabolism</keyword><keyword>Humans</keyword><keyword>Immunity/genetics/physiology</keyword><keyword>Multifactorial Inheritance/genetics</keyword><keyword>Mutation/genetics</keyword><keyword>Odds Ratio</keyword><keyword>Polymorphism, Single Nucleotide/genetics</keyword><keyword>Schizophrenia/*genetics/immunology</keyword><keyword>Synaptic Transmission/genetics</keyword></keywords><dates><year>2014</year><pub-dates><date>Jul 24</date></pub-dates></dates><isbn>1476-4687 (Electronic)&#xD;0028-0836 (Linking)</isbn><accession-num>25056061</accession-num><urls><related-urls><url> and logistic regression was used to test for association between PRS and psychotic experiences reported at age 12 and 18 years (eMethods 3). Genetic correlationsLDSCPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdWxpay1TdWxsaXZhbjwvQXV0aG9yPjxZZWFyPjIwMTU8

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ADDIN EN.CITE.DATA 35, attention deficit/hyperactivity disorder (ADHD)PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZW1vbnRpczwvQXV0aG9yPjxZZWFyPjIwMTk8L1llYXI+

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ADDIN EN.CITE.DATA 37. A Bonferroni correction was applied to control for multiple testing.Polygenic risk scoresPRSs were generated to investigate additional psychotic experience phenotypes that were not sufficiently powered for genetic correlation analyses. We selected the same summary statistics used for genetic correlations to create the risk scores for UK Biobank participants using the method described by the PGC ADDIN EN.CITE <EndNote><Cite><Author>Schizophrenia Working Group of the Psychiatric Genomics Consortium</Author><Year>2014</Year><RecNum>4226</RecNum><DisplayText><style face="superscript">31</style></DisplayText><record><rec-number>4226</rec-number><foreign-keys><key app="EN" db-id="vfrazzdppe9w9ueee5x5ew0g005r90epvwfs" timestamp="1435143642">4226</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Schizophrenia Working Group of the Psychiatric Genomics Consortium,</author></authors></contributors><titles><title>Biological insights from 108 schizophrenia-associated genetic loci</title><secondary-title>Nature</secondary-title><alt-title>Nature</alt-title></titles><periodical><full-title>Nature</full-title><abbr-1>Nature</abbr-1></periodical><alt-periodical><full-title>Nature</full-title><abbr-1>Nature</abbr-1></alt-periodical><pages>421-7</pages><volume>511</volume><number>7510</number><keywords><keyword>Alleles</keyword><keyword>Brain/metabolism/physiology</keyword><keyword>Enhancer Elements, Genetic/genetics</keyword><keyword>*Genetic Loci</keyword><keyword>Genetic Predisposition to Disease/*genetics</keyword><keyword>*Genome-Wide Association Study</keyword><keyword>Glutamic Acid/metabolism</keyword><keyword>Humans</keyword><keyword>Immunity/genetics/physiology</keyword><keyword>Multifactorial Inheritance/genetics</keyword><keyword>Mutation/genetics</keyword><keyword>Odds Ratio</keyword><keyword>Polymorphism, Single Nucleotide/genetics</keyword><keyword>Schizophrenia/*genetics/immunology</keyword><keyword>Synaptic Transmission/genetics</keyword></keywords><dates><year>2014</year><pub-dates><date>Jul 24</date></pub-dates></dates><isbn>1476-4687 (Electronic)&#xD;0028-0836 (Linking)</isbn><accession-num>25056061</accession-num><urls><related-urls><url> and detailed in eMethods 4. The intelligence GWAS summary statistics used in this study specifically excluded participants from UK Biobank (n=74,214 individuals remaining). None of the other training sets included UK Biobank as a contributing sample, although we were not able to test for duplicates at the genotype level and so cannot rule these out. Given this potential for sample overlap with the training sets, PRS results should be treated with a degree of caution and are used primarily to support and extend findings from genetic correlation analysis (which allows for overlapping samples). The primary analysis used standardised scores generated from SNPs with a discovery sample p-value threshold of p ≤ 0.05, but associations at 10 other p-value thresholds were also tested. A logistic regression model was used to test the association of each PRS with various psychotic experience phenotypes, covarying for the first five principal components and genotyping array. Copy number variationCNV calling for UK Biobank has been described in detail elsewherePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LZW5kYWxsPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48

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ADDIN EN.CITE.DATA 44 with the three primary psychotic experience phenotypes used for GWAS. Association analyses were carried out using logistic regression and included age, sex and genotyping array as covariates. Results A total of 7803 (5.0%, 60.0% female, mean age 63 (SD=7.7)) individuals from UK Biobank who completed the MHQ reported at least one psychotic experience, 3012 individuals rated the psychotic experience as distressing, and a total of 4388 reported multiple occurrences of at least one psychotic experience. A total of 147,461 individuals (56.0% female, mean age 64 (SD=7.6)) who reported no psychotic experiences constituted the comparison group for our association analyses. The mean age of the first psychotic experience was 31.6 years (SD=17.6) (eFigure 4) with 2341 (35.2%) first occurring before the age of 20 or for as long as the participant could remember, 2137 (32.1%) between the ages of 20-39, and 2176 (32.7%) between the ages of 40 and 76. We excluded 198 individuals who had a diagnosis of schizophrenia, 818 with bipolar disorder, and 346 with other psychotic disorders from all genetic analyses (detailed in eMethods 1). GWASThe GWAS of any psychotic experience in 6123 cases and 121,843 controls (following QC, exclusions detailed in eMethods 6) identified two variants that were associated at the genome-wide significance (GWS) level of p < 5x10-8 (Figure 1, Table 1, λGC=1.05, LD Score regression intercept=1.00); rs10994278, an intronic variant within Ankyrin-3 (ANK3, OR=1.16, 95% confidence intervals (CI)=1.10-1.23, p=3.06x10-8), and intergenic variant rs549656827 (OR=0.61, 95% CI=0.50-0.73, p=3.30x10-8). A second GWAS restricting the cases to 2143 individuals with distressing psychotic experiences identified two GWS variants (Table 1, λGC=1.03, LD Score intercept=1.01); rs75459873 intronic to cannabinoid receptor 2 (CNR2, OR=0.66, 95% CI=0.56-0.78, p=3.78x10-8) and intergenic variant rs3849810 (OR=1.22, 95% CI=1.13-1.31, p=4.55x10-8).The third GWAS restricting the cases to 3337 individuals who reported multiple occurrences of psychotic experiences did not identify any associated variants at GWS (λGC=1.03, LD Score intercept=1.00). QQ plots for each GWAS are displayed in eFigure 5 and LocusZoom plots for each GWS loci are provided in eFigure 6. SNP based heritability estimates calculated by LDSCPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdWxpay1TdWxsaXZhbjwvQXV0aG9yPjxZZWFyPjIwMTU8

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ADDIN EN.CITE.DATA 35. Validation analyses in ALSPACThere was evidence of association between the PRS calculated using the any psychotic experience GWAS from UK Biobank at the p-value threshold of ≤0.5 and definite psychotic experiences between ages 12 and 18 years in ALSPAC (OR=1.13; 95% CI=1.02-1.25; R2=0.002; p=0.02). This finding was consistent for thresholds below p<0.05 and when using measures from age 18 years only (eFigure 7, eTable 1). However, the psychotic experiences PRS was also associated with the presence of major depressive disorder at age 18 (OR = 1.19; 95% CI=1.05-1.35; R2=0.004; p=0.01). Relationship between association at CNR2 and cannabis use We investigated, but found no evidence for, a mediating or moderating effect of cannabis use on the association between distressing psychotic experiences and rs75459873 at the cannabinoid receptor gene CNR2. Cannabis use itself (UKB field id: 20453) was significantly associated with distressing psychotic experiences (OR=1.36, 95% CI=1.32-1.40, p=9.16 x 10-88), but rs75459873 was not associated with cannabis use (OR=0.99, 95% CI=0.95-1.04, p=0.70). Furthermore, the association between rs75459873 and distressing psychotic experiences was unchanged in a model including cannabis use as a covariate (OR=0.62, 95% CI=0.52-0.75) or as an interaction term (OR=0.59, 95% CI=0.48-0.73, interaction p=0.31). Genetic correlations Significant genetic correlations (rg) were observed between any psychotic experience and major depressive disorder (rg=0.46, p=4.64x10-11), autism spectrum disorder (rg=0.39, p=1.68x10-4), ADHD (rg=0.24, p=4.61x10-3) and schizophrenia (rg=0.21, p=7.29x10-5). Figure 2 displays these genetic correlations and eTable 2 details the full results. The other psychotic experience GWAS analyses did not meet requirementsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaGVuZzwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 45 for genetic correlation analysis.Polygenic risk score analysisWe found evidence of a weak association between any psychotic experience and genetic liability indicated by PRS at a p<0.05 threshold for SNP inclusion for schizophrenia (OR=1.09; 95% CI=1.06-1.12; adjusted R2=0.001; p=2.96x10-11), major depressive disorder (OR=1.16; 95% CI=1.13-1.19; R2=0.003; p=1.48x10-30), bipolar disorder (OR=1.07; 95% CI=1.04-1.10; R2=0.001; p=5.11x10-7), ADHD (OR=1.06; 95% CI=1.03-1.09; R2=0.0005; p=5.73x10-6) and autism spectrum disorder (OR=1.07; 95% CI=1.04-1.10; R2=0.001; p=1.34x10-5). These associations were stronger for distressing psychotic experiences (Figure 3, eTable 2) and consistent across most p-value thresholds (eFigures 8-9). We also considered individual psychotic symptoms and found that PRSs for schizophrenia, bipolar disorder, depression and ADHD were more strongly associated with delusions of persecution than the other psychotic symptoms (eTable 3, eFigures 10-12). The association with psychotic experience phenotypes for bipolar disorder PRS and major depressive disorder PRS remained significant in analyses controlling for schizophrenia PRS (eTable 4). The association with major depressive disorder PRS remained significant when individuals with a diagnosis of depression were removed (eTable 5). Given the potential for sample overlap with the training sets, PRS findings should be treated with a degree of caution.Copy number variationIndividuals reporting distressing psychotic experiences in particular had an increased burden of CNVs previously associated with schizophrenia (OR=2.04; 95% CI=1.39-2.98; p=2.49x10-4) and neurodevelopmental disorders (OR=1.75; 95% CI=1.24-2.48; p=1.41x10-3). There was evidence of an increased burden of these CNVs in individuals reporting any psychotic experience but not multiple occurrence psychotic experiences (Table 2). DiscussionWe conducted the largest genetic-association study of psychotic experiences using the population-based UK Biobank sample and found evidence of a shared genetic aetiology between psychotic experiences and several psychiatric disorders, which included, but was not specific to, schizophrenia. Genetic correlation analysis identified significant genetic correlations between psychotic experiences and major depressive disorder (rg=0.46), autism spectrum disorder (rg=0.39), ADHD (rg=0.24) and schizophrenia (rg=0.21). PRS analyses identified associations between psychotic experiences and genetic liability for schizophrenia, major depressive disorder, bipolar disorder, ADHD and autism, and we found particular enrichment of these PRS scores in distressing psychotic experience and for delusions of persecution. However, given the possibility of sample overlap between UK Biobank and the training sets, the PRS findings should be treated with caution. The mechanisms underlying the high genetic correlation between depression and psychotic experiences cannot be discerned from our analysis but one possibility is that the psychotic experiences have arisen in the context of mood-related changes, consistent with the strong associations between psychotic experiences and depressive symptomatology observed in population-based studiesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gUm9zc3VtPC9BdXRob3I+PFllYXI+MjAxMTwvWWVh

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ADDIN EN.CITE.DATA 41,55 and depression ADDIN EN.CITE <EndNote><Cite><Author>Kendall</Author><Year>2019</Year><RecNum>4884</RecNum><DisplayText><style face="superscript">56</style></DisplayText><record><rec-number>4884</rec-number><foreign-keys><key app="EN" db-id="vfrazzdppe9w9ueee5x5ew0g005r90epvwfs" timestamp="1551343406">4884</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kendall, K. M.</author><author>Rees, E.</author><author>Bracher-Smith, M.</author><author>Legge, S. E.</author><author>Riglin, L.</author><author>Zammit, S.</author><author>O&apos;Donovan, M. C.</author><author>Owen, M. J.</author><author>Kirov, G.</author><author>Walters, J. T. R.</author></authors></contributors><titles><title>The role of rare copy number variants in depression</title><secondary-title>JAMA Psychiatry</secondary-title><alt-title>JAMA Psych</alt-title></titles><periodical><full-title>JAMA Psychiatry</full-title><abbr-1>JAMA psychiatry</abbr-1></periodical><dates><year>2019</year></dates><urls></urls></record></Cite></EndNote>56, adding strength to our findings of a lack of specificity for psychotic experiences genetic risk. A number of studies have demonstrated that psychopathology in the population is best described by a bifactor model with a common latent trait as well as specific traits, and that psychotic experiences index the more severe end of the common or shared traitPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYWhleTwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 7,8,11,12. Nonetheless, despite lacking specificity, our results suggest that incorporating questions about distress to self-reported assessments of psychotic experiences may allow a more valid identification of experiences that index schizophrenia and major mental health disorder liability. In the largest GWAS analyses of psychotic experiences to date, we identified four genome-wide significant loci. However, consistent with other studiesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Kb25lczwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 7,11, the heritability estimate (1.7%) was low and given the variance explained in our PRS analysis was also low, the findings suggest that understanding the genetics of psychotic experiences is unlikely to have an important impact on understanding the genetics of schizophrenia specifically. The primary GWAS findings are related to intronic variants in ANK3 and CNR2. The GWAS of any psychotic experience identified two significant loci, the most significant of which was indexed by rs10994278, an intronic variant to ANK3 (OR=1.16, p=3.06x10-8). The ANK3 gene encodes ankyrin-G, a protein that has been shown to regulate the assembly of voltage-gated sodium channels and is essential for normal synaptic function ADDIN EN.CITE <EndNote><Cite><Author>Leussis</Author><Year>2012</Year><RecNum>4877</RecNum><DisplayText><style face="superscript">47</style></DisplayText><record><rec-number>4877</rec-number><foreign-keys><key app="EN" db-id="vfrazzdppe9w9ueee5x5ew0g005r90epvwfs" timestamp="1548771574">4877</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Leussis, M. P.</author><author>Madison, J. M.</author><author>Petryshen, T. L.</author></authors></contributors><auth-address>Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry and Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA. petryshen@chgr.mgh.harvard.edu.</auth-address><titles><title>Ankyrin 3: genetic association with bipolar disorder and relevance to disease pathophysiology</title><secondary-title>Biology of Mood &amp; Anxiety Disorders</secondary-title><alt-title>Biol Mood Anxiety Disord</alt-title></titles><alt-periodical><full-title>Biol Mood Anxiety Disord</full-title></alt-periodical><pages>18</pages><volume>2</volume><dates><year>2012</year><pub-dates><date>Oct 1</date></pub-dates></dates><isbn>2045-5380 (Electronic)&#xD;2045-5380 (Linking)</isbn><accession-num>23025490</accession-num><urls><related-urls><url>. ANK3 is one of strongest and most replicated genes for bipolar disorderPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdGFobDwvQXV0aG9yPjxZZWFyPjIwMTk8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 34, and variants within ANK3 have also been associated in the PGC cross-disorder GWAS ADDIN EN.CITE <EndNote><Cite><Author>Cross-Disorder Group of the Psychiatric Genomics Consortium</Author><Year>2013</Year><RecNum>4503</RecNum><DisplayText><style face="superscript">40</style></DisplayText><record><rec-number>4503</rec-number><foreign-keys><key app="EN" db-id="vfrazzdppe9w9ueee5x5ew0g005r90epvwfs" timestamp="1443003867">4503</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cross-Disorder Group of the Psychiatric Genomics Consortium,</author></authors></contributors><titles><title>Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis</title><secondary-title>The Lancet</secondary-title><alt-title>Lancet</alt-title></titles><periodical><full-title>The Lancet</full-title></periodical><alt-periodical><full-title>Lancet</full-title><abbr-1>Lancet</abbr-1></alt-periodical><pages>1371-1379</pages><volume>381</volume><number>9875</number><dates><year>2013</year></dates><isbn>0140-6736</isbn><urls></urls></record></Cite></EndNote>40, and in a rare variant analysis of autism spectrum disorder ADDIN EN.CITE <EndNote><Cite><Author>Bi</Author><Year>2012</Year><RecNum>4844</RecNum><DisplayText><style face="superscript">48</style></DisplayText><record><rec-number>4844</rec-number><foreign-keys><key app="EN" db-id="vfrazzdppe9w9ueee5x5ew0g005r90epvwfs" timestamp="1543323364">4844</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bi, C.</author><author>Wu, J.</author><author>Jiang, T.</author><author>Liu, Q.</author><author>Cai, W.</author><author>Yu, P.</author><author>Cai, T.</author><author>Zhao, M.</author><author>Jiang, Y. H.</author><author>Sun, Z. S.</author></authors></contributors><auth-address>Institute of Psychology, Chinese Academy of Sciences, Beijing, P. R. China.</auth-address><titles><title>Mutations of ANK3 identified by exome sequencing are associated with autism susceptibility</title><secondary-title>Hum Mutat</secondary-title></titles><periodical><full-title>Hum Mutat</full-title></periodical><pages>1635-8</pages><volume>33</volume><number>12</number><keywords><keyword>Amino Acid Sequence</keyword><keyword>Ankyrins/*genetics</keyword><keyword>Autistic Disorder/*genetics</keyword><keyword>Base Sequence</keyword><keyword>Conserved Sequence</keyword><keyword>*Exome</keyword><keyword>Female</keyword><keyword>Genetic Association Studies</keyword><keyword>Genetic Predisposition to Disease</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>*Mutation, Missense</keyword><keyword>Pedigree</keyword><keyword>*Point Mutation</keyword><keyword>Sequence Analysis, DNA</keyword></keywords><dates><year>2012</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1098-1004 (Electronic)&#xD;1059-7794 (Linking)</isbn><accession-num>22865819</accession-num><urls><related-urls><url> GWAS of distressing psychotic experiences also identified two significant loci, the most significant of which was indexed by rs75459873, an intronic variant to CNR2 (OR=0.66, p=3.78x10-8). CNR2 encodes for CB2, one of two well-characterised cannabinoid receptors (CB1 being the other). Several lines of evidence have implicated the endocannabinoid system in psychiatric disorders including schizophreniaPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MdTwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJlY051

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ADDIN EN.CITE.DATA 50,51 and depression ADDIN EN.CITE <EndNote><Cite><Author>Huang</Author><Year>2016</Year><RecNum>4882</RecNum><DisplayText><style face="superscript">52</style></DisplayText><record><rec-number>4882</rec-number><foreign-keys><key app="EN" db-id="vfrazzdppe9w9ueee5x5ew0g005r90epvwfs" timestamp="1551274430">4882</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Huang, W. J.</author><author>Chen, W. W.</author><author>Zhang, X.</author></authors></contributors><auth-address>Department of Neurology, Xuzhou Central Hospital, Xuzhou, Jiangsu 221009, P.R. China.</auth-address><titles><title>Endocannabinoid system: Role in depression, reward and pain control (Review)</title><secondary-title>Molecular Medicine Reports</secondary-title><alt-title>Mol Med Rep</alt-title></titles><alt-periodical><full-title>Mol Med Rep</full-title></alt-periodical><pages>2899-903</pages><volume>14</volume><number>4</number><keywords><keyword>Animals</keyword><keyword>Cannabinoids/*therapeutic use</keyword><keyword>Depression/complications/*drug therapy/*metabolism</keyword><keyword>Depressive Disorder/complications/drug therapy/metabolism</keyword><keyword>Drug Discovery</keyword><keyword>Endocannabinoids/*metabolism</keyword><keyword>Humans</keyword><keyword>Pain/complications/*drug therapy/*metabolism</keyword><keyword>Pain Management/methods</keyword></keywords><dates><year>2016</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1791-3004 (Electronic)&#xD;1791-2997 (Linking)</isbn><accession-num>27484193</accession-num><urls><related-urls><url>. The main psychoactive agent of cannabis, Δ9-tetrahydrocannabinol, can cause acute psychotic symptoms and cognitive impairment ADDIN EN.CITE <EndNote><Cite><Author>Manseau</Author><Year>2015</Year><RecNum>4811</RecNum><DisplayText><style face="superscript">53</style></DisplayText><record><rec-number>4811</rec-number><foreign-keys><key app="EN" db-id="vfrazzdppe9w9ueee5x5ew0g005r90epvwfs" timestamp="1536072597">4811</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Manseau, M. W.</author><author>Goff, D. C.</author></authors></contributors><auth-address>Department of Psychiatry, New York University Langone Medical Center, New York, NY, USA.&#xD;Department of Psychiatry, New York University Langone Medical Center, New York, NY, USA. Donald.Goff@.</auth-address><titles><title>Cannabinoids and Schizophrenia: Risks and Therapeutic Potential</title><secondary-title>Neurotherapeutics</secondary-title><alt-title>Neurotherapeutics</alt-title></titles><periodical><full-title>Neurotherapeutics</full-title></periodical><alt-periodical><full-title>Neurotherapeutics</full-title></alt-periodical><pages>816-24</pages><volume>12</volume><number>4</number><keywords><keyword>Animals</keyword><keyword>Antipsychotic Agents/*therapeutic use</keyword><keyword>Cannabinoids/*therapeutic use</keyword><keyword>Gene-Environment Interaction</keyword><keyword>Humans</keyword><keyword>Schizophrenia/*drug therapy</keyword><keyword>Cannabinoids</keyword><keyword>cannabidiol</keyword><keyword>cannabis</keyword><keyword>endocannabinoid</keyword><keyword>psychosis</keyword><keyword>schizophrenia</keyword></keywords><dates><year>2015</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1878-7479 (Electronic)&#xD;1878-7479 (Linking)</isbn><accession-num>26311150</accession-num><urls><related-urls><url>. Given that cannabis use is strongly associated with psychotic experiences, we tested, but found no evidence for, a mediating or moderating effect of cannabis use on the association of rs75459873 and distressing psychotic experiences. However, whilst no evidence was found in this study, a mediating effect of cannabis use cannot be ruled out given the relatively low power of such analyses and the potential measurement error in cannabis use assessed via lifetime self-report. Independent replication of genetic loci identified in this study will be required to further understand their role in sub-clinical psychotic experiences. Strengths and limitationsStrengths of this study include the large sample size (approximately 10x that of previous studies), the use of an adult cohort, and the use of multiple psychotic experience phenotypes, which increase confidence in our findings. Although we used all available information to identify and remove individuals with a psychotic disorder, it remains possible that some individuals were not identified and remained in the analysis. A further limitation of this study relates to the retrospective measurement of lifetime psychotic experiences by self-report from an online questionnaire, as this increases the likelihood of measurement error. A further limitation is the evidence of a ‘healthy volunteer’ selection bias for the participants recruited to UK Biobank and the sample cannot be therefore considered representative of the general populationPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Gcnk8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA 59. We also found that the participants that completed the MHQ had significantly higher intelligence and lower schizophrenia, depression and neuroticism PRS compared to UK Biobank participants who did not complete the MHQ (eTable 6). Lastly, we were not able to entirely de-duplicate the UK Biobank individuals from all of the external datasets used for the polygenic risk score analysis and thus these findings should be treated with caution. ConclusionsIn the largest GWAS of psychotic experiences from the population-based UK Biobank sample, we found support for a shared genetic aetiology between psychotic experiences and several psychiatric disorders including schizophrenia, major depressive disorder, bipolar disorder, and neurodevelopmental disorders indicating that psychotic experiences are not specifically related to schizophrenia, but rather to a general risk for mental health disorders. AcknowledgementsAuthor Contributions: Profs Zammit and Walters contributed equally to the work as senior authors. Dr Legge had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Legge, Jones, Kendall, Zammit, WaltersAcquisition, analysis or interpretation of data: All authors. Drafting of the manuscript: Legge, Jones, Kendall, Zammit, WaltersCritical revision of the manuscript for important intellectual content: All authors.Statistical analysis: Legge, Jones, KendallTechnical support: Pardi?as, Menzies, Bracher-Smith, Escott-PriceSupervision: Owen, O’Donovan, Zammit, WaltersConflict of Interest Disclosures: None of the authors report a conflict of interest.Funding/Support: The National Institute for Health Research, Medical Research Council and British Heart Foundation supplied funds to complete genotyping on all UK Biobank participants. The funding bodies had no experimental role in the comparison between DNA quantification methods used in the genotyping workflow. We thank UK Biobank participants for providing the samples for this project. This project was supported by the following grants: Medical Research Council (MRC) Centre (MR/L010305/1), Program (G0800509), Project (MR/L011794/1) grants to Cardiff University, and The National Centre for Mental Health (NCMH), funded by the Welsh Government through Health and Care Research Wales. HJJ and SZ are supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. KK is supported by a Wellcome Trust Clinical Research Training Fellowship. KD and MH are supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. The UK Medical Research Council, the Wellcome Trust (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for 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 (Grant ref: G0701503/85179). ALSPAC GWAS data was generated by Sample Logistics and Genotyping Facilities at the Wellcome Trust Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. 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The role of rare copy number variants in depression. JAMA Psychiatry. 2019.57.Lahey BB, Krueger RF, Rathouz PJ, Waldman ID, Zald DH. A hierarchical causal taxonomy of psychopathology across the life span. Psychological Bulletin. 2017;143(2):142-186.58.Stochl J, Khandaker GM, Lewis G, et al. Mood, anxiety and psychotic phenomena measure a common psychopathological factor. Psychological Medicine. 2015;45(7):1483-1493.59.Fry A, Littlejohns TJ, Sudlow C, et al. Comparison of Sociodemographic and Health-Related Characteristics of UK Biobank Participants With Those of the General Population. American Journal of Epidemiology. 2017;186(9):1026-1034.Figure 1Manhattan plot for GWAS analyses of any psychotic experience, distressing psychotic experiences and multiple occurrence psychotic experiences. Dashed line represent the genome-wide significance level of p < 5 x 10-8 and the dotted line represents p < 1 x 10-5. Figure 2Genetic correlation analysis. Colour corresponds to the strength of the correlation (rg) and stars correspond to the statistical significance of the correlation (* P < 6.25 x 10-3, ** P < 1.00 x 10-4, *** P < 1.00 x 10-5). Positive correlations are shown in blue and negative correlations in red. Figure 3Polygenic risk score (PRS) analysis. The y-axis refers to the PRS tested (schizophrenia, bipolar disorder, major depressive disorder, attention deficit/hyperactivity disorder (ADHD), autism spectrum disorder, neuroticism and intelligence) and x-axis represents the odds ratio (OR). Points display the OR and 95% confidence intervals (error bars) for each PRS (p < 0.05 SNP inclusion threshold) regressed against each psychotic experiences phenotype; any psychotic experience (dark blue), distressing psychotic experiences (orange) and multiple occurrence psychotic experiences (green). Plots displaying multiple p-value SNP inclusion thresholds are shown in eFigures 8-9.Table 1PhenotypeSNPCHRBPA1OR (95% CI)PPositionNearest geneAny PErs109942781062009219T1.16 (1.10-1.23)3.06 x 10-8IntronicANK3Any PErs549656827535349428G0.61 (0.50-0.73)3.30 x 10-8IntergenicPRLRDistressing PErs75459873124256312G0.66 (0.56-0.78)3.78 x 10-8IntronicCNR2Distressing PErs3849810853009606A1.22 (1.13-1.31)4.55 x 10-8IntergenicST18Genome-wide significant associations (p < 5 x 10-8) from GWAS analyses. Columns represent GWAS phenotype (PE = psychotic experience), variant (SNP), chromosome (CHR), base position (BP), risk allele (A1), odds ratio (OR) and 95% confidence intervals, p-value (P), position of risk variant (Position), and the nearest gene. Table 2Schizophrenia CNVsCase rate (n)Control rate (n)OR (95% CI)PAny PE0.010 (59/5829)0.006 (572/115807)1.54 (1.18-2.01)1.60 x 10-3Distressing PE0.014 (28/2046)0.006 (572/115807)2.04 (1.39-2.98)2.49 x 10-4Multiple occurrence PE0.009 (28/3177)0.006 (572/115807)1.34 (0.91-1.94)0.144Neurodevelopmental disorder CNVsCase rate (n)Control rate (n)OR (95% CI)PAny PE0.014 (83/5829)0.009 (1058/115807)1.54 (1.23-1.92)1.89 x 10-4Distressing PE0.017 (34/2046)0.009 (1058/115807)1.75 (1.24-2.48)1.41 x 10-3Multiple occurrence PE0.012 (38/3177)0.009 (1058/115807)1.30 (0.92-1.78)0.139Association of psychotic experience phenotypes with copy number variants (CNVs) previously associated with (i) schizophrenia and (ii) neurodevelopmental disorders (note all schizophrenia-associated CNVs are also included in neurodevelopmental disorders). Columns represent; phenotype (PE = psychotic experience), rate of CNVs in cases (those reporting a psychotic experience), rate of CNVs in controls (the comparator group, those who did not report a psychotic experience), odds ratio (OR) and 95% confidence intervals (CI), and p-value (P). ADDIN ................
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