{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T19:16:43Z","timestamp":1793906203591,"version":"4.8.0"},"reference-count":29,"publisher":"American Medical Association (AMA)","issue":"10","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Psychiatry"],"published-print":{"date-parts":[[2022,10,1]]},"abstract":"<jats:sec id=\"ab-yoi220055-4\"><jats:title>Importance<\/jats:title><jats:p>Understanding the origins of clinical heterogeneity in bipolar disorder (BD) will inform new approaches to stratification and studies of underlying mechanisms.<\/jats:p><\/jats:sec><jats:sec id=\"ab-yoi220055-5\"><jats:title>Objective<\/jats:title><jats:p>To identify components of genetic liability that are shared between BD, schizophrenia, and major depressive disorder (MDD) and those that differentiate each disorder from the others and to examine associations between heterogeneity for key BD symptoms and each component.<\/jats:p><\/jats:sec><jats:sec id=\"ab-yoi220055-6\"><jats:title>Design, Setting, and Participants<\/jats:title><jats:p>Using data from the Bipolar Disorder Research Network in the United Kingdom, components of liability were identified by applying genomic structural equation modeling to genome-wide association studies of schizophrenia, BD, and MDD. Polygenic risk scores (PRS) representing each component were tested for association with symptoms in an independent BD data set. Adults with <jats:italic>DSM<\/jats:italic>-<jats:italic>IV<\/jats:italic> BD or schizoaffective disorder, bipolar type, were included. Data were collected from January 2000 to December 2013, and data were analyzed from June 2020 to February 2022.<\/jats:p><\/jats:sec><jats:sec id=\"ab-yoi220055-7\"><jats:title>Main Outcomes and Measures<\/jats:title><jats:p>PRS representing the components of liability were tested for association with mania and depression, psychosis, and mood incongruence of psychosis in participants with BD, measured using the Bipolar Affective Disorder Dimensional Scale.<\/jats:p><\/jats:sec><jats:sec id=\"ab-yoi220055-8\"><jats:title>Results<\/jats:title><jats:p>Of 4429 included participants, 3012 (68.0%) were female, and the mean (SD) age was 46.2 (12.3) years. Mania and psychosis were associated with the shared liability component (mania \u03b2\u2009=\u20090.29; 95% CI, 0.23-0.34; <jats:italic>P<\/jats:italic>\u2009=\u20093.04\u2009\u00d7\u200910<jats:sup>\u221225<\/jats:sup>; psychosis \u03b2\u2009=\u20090.05; 95% CI, 0.04-0.07; <jats:italic>P<\/jats:italic>\u2009=\u20092.33\u2009\u00d7\u200910<jats:sup>\u221213<\/jats:sup>) and the components that differentiate each of schizophrenia (mania \u03b2\u2009=\u20090.08; 95% CI, 0.03-0.14; <jats:italic>P<\/jats:italic>\u2009=\u2009.002; psychosis \u03b2\u2009=\u20090.03; 95% CI, 0.01-0.04; <jats:italic>P<\/jats:italic>\u2009=\u20091.0\u2009\u00d7\u200910<jats:sup>\u22124<\/jats:sup>) and BD (mania \u03b2\u2009=\u20090.14; 95% CI, 0.09-0.20; <jats:italic>P<\/jats:italic>\u2009=\u20091.99\u2009\u00d7\u200910<jats:sup>\u22127<\/jats:sup>; psychosis \u03b2\u2009=\u20090.02; 95% CI, 0.01-0.03; <jats:italic>P<\/jats:italic>\u2009=\u2009.006) from the other disorders. The BD differentiating component was associated with mania independently of effects on psychosis (\u03b2\u2009=\u20090.14; 95% CI, 0.08-0.20; <jats:italic>P<\/jats:italic>\u2009=\u20094.32\u2009\u00d7\u200910<jats:sup>\u22126<\/jats:sup>) but not with psychosis independently of mania. Conversely, the schizophrenia differentiating component was associated with psychosis independently of effects on mania (\u03b2\u2009=\u20090.01; 95% CI, 0.003-0.03; <jats:italic>P<\/jats:italic>\u2009=\u2009.02), but not with mania independently of psychosis. Mood incongruence of psychosis was associated only with the schizophrenia differentiating component (\u03b2\u2009=\u20090.03; 95% CI, 0.01-0.05; <jats:italic>P<\/jats:italic>\u2009=\u2009.005). Depression was associated with higher MDD differentiating component (\u03b2\u2009=\u20090.07; 95% CI, 0.01-0.12; <jats:italic>P<\/jats:italic>\u2009=\u2009.01) but lower BD differentiating component (\u03b2\u2009=\u2009\u22120.11; 95% CI, \u22120.17 to \u22120.06; <jats:italic>P<\/jats:italic>\u2009=\u20097.06\u2009\u00d7\u200910<jats:sup>\u22125<\/jats:sup>).<\/jats:p><\/jats:sec><jats:sec id=\"ab-yoi220055-9\"><jats:title>Conclusions and Relevance<\/jats:title><jats:p>In this study of BD, clinical heterogeneity reflected the burden of liability to BD and the contribution of alleles that have differentiating effects on risk for other disorders; mania, psychosis, and depression were associated with the components of genetic liability differentiating BD, MDD, and schizophrenia, respectively. Understanding the basis of this etiological heterogeneity will be critical for identifying the different pathophysiological processes underlying BD, stratifying patients, and developing precision therapeutics.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamapsychiatry.2022.2594","type":"journal-article","created":{"date-parts":[[2022,8,31]],"date-time":"2022-08-31T15:32:32Z","timestamp":1661959952000},"page":"1032","source":"Crossref","is-referenced-by-count":59,"title":["Genetic Liabilities Differentiating Bipolar Disorder, Schizophrenia, and Major Depressive Disorder, and Phenotypic Heterogeneity in Bipolar Disorder"],"prefix":"10.1001","volume":"79","author":[{"given":"Alexander L.","family":"Richards","sequence":"first","affiliation":[{"name":"MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alastair","family":"Cardno","sequence":"additional","affiliation":[{"name":"Leeds Institute of Health Sciences, Division of Psychological and Social Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gordon","family":"Harold","sequence":"additional","affiliation":[{"name":"MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom"},{"name":"Faculty of Education, University of Cambridge, Cambridge, United Kingdom"},{"name":"School of Medicine, Child and Adolescent Psychiatry Unit, University College Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J.","family":"Craddock","sequence":"additional","affiliation":[{"name":"MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arianna","family":"Di Florio","sequence":"additional","affiliation":[{"name":"MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Jones","sequence":"additional","affiliation":[{"name":"Psychological Medicine, University of Worcester, Worcester, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Gordon-Smith","sequence":"additional","affiliation":[{"name":"Psychological Medicine, University of Worcester, Worcester, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Jones","sequence":"additional","affiliation":[{"name":"MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Sellers","sequence":"additional","affiliation":[{"name":"MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom"},{"name":"Department of Primary Care & Public Health, Brighton & Sussex Medical School, University of Sussex, Brighton, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James T. 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