{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T19:30:12Z","timestamp":1786995012295,"version":"build-2736575974"},"posted":{"date-parts":[[2025,6,25]]},"group-title":"Genetic and Genomic Medicine","reference-count":128,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T00:00:00Z","timestamp":1750809600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"funder":[{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"crossref","award":["R01 MH124839"],"award-info":[{"award-number":["R01 MH124839"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"crossref","award":["U01 MH109528"],"award-info":[{"award-number":["U01 MH109528"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"crossref","award":["U01 MH094421"],"award-info":[{"award-number":["U01 MH094421"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"crossref","award":["U01 MH085520"],"award-info":[{"award-number":["U01 MH085520"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["Graduate Partnership Program (GPP)"],"award-info":[{"award-number":["Graduate Partnership Program (GPP)"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,13]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Bipolar disorder\u2019s (BD) clinical heterogeneity has an unresolved genetic basis. We meta-analyzed genome-wide association studies (GWAS) of 16 BD subphenotypes in 226,032 individuals from 57 cohorts (38,022 cases); 10 advanced to multivariate and multi-trait analyses. Four factors (compulsive, psychotic, dysregulated, internalizing) explained 82.8% of shared genetic variance. BD1 and BD2 loaded on distinct factors despite a high genetic correlation; 87.0% of common-factor loci were significant in neither subtype. Unipolar mania aligned with psychosis over internalizing, and was distinguishable from BD1, and rapid cycling showed heritable cross-domain liability. We identified 356 risk loci, 158 novel, including the first univariate-GWAS associations for psychosis, unipolar mania, rapid cycling and schizoaffective disorder\u2014and 249 credible genes (89 high-confidence), 12 with approved-drug or clinical-phase annotations. Cell-type association showed a midbrain dopaminergic\u2013GABAergic gradient along the psychotic factor.\n                  <jats:bold>BD\u2019s genetic architecture appears hierarchical\u2014a general liability resolving into dimensions of course and comorbidity beyond diagnostic subtypes.<\/jats:bold>\n                <\/jats:p>","DOI":"10.1101\/2025.06.23.25330155","type":"posted-content","created":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T10:40:10Z","timestamp":1750848010000},"source":"Crossref","is-referenced-by-count":2,"title":["Genomic dimensions deconstruct the clinical heterogeneity of bipolar disorder"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-5159-1387","authenticated-orcid":false,"given":"Tracey","family":"van der Veen","sequence":"first","affiliation":[{"name":"Division of Psychiatry, University College London, London, UK"},{"name":"Human Genetics Branch, Intramural Research Program, National Institute of Mental Health, NIH, US Dept of HHS, Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3351-701X","authenticated-orcid":false,"given":"Markos","family":"Tesfaye","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY, USA"},{"name":"Institute for Genomics in Health, SUNY Downstate Health Sciences University, Brooklyn, NY, USA"},{"name":"NORMENT Centre, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway"},{"name":"Center for Precision Psychiatry, University of Oslo, Oslo, Norway"},{"name":"Department of Clinical Science, University of Bergen, Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3685-4126","authenticated-orcid":false,"given":"Jessica Mei Kay","family":"Yang","sequence":"additional","affiliation":[{"name":"Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0226-7924","authenticated-orcid":false,"given":"Toni","family":"Boltz","sequence":"additional","affiliation":[{"name":"Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"name":"Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA"},{"name":"Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9521-5669","authenticated-orcid":false,"given":"Friederike S.","family":"David","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany"},{"name":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0041-6669","authenticated-orcid":false,"given":"Shane","family":"Crinion","sequence":"additional","affiliation":[{"name":"Centre for Neuroimaging, Cognition and Genomics, School of Biological and Chemical Sciences and School of Psychology, University of Galway, Galway, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8843-082X","authenticated-orcid":false,"given":"Maria","family":"Koromina","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"name":"Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Till F. 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