{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T10:56:57Z","timestamp":1791197817187,"version":"4.1.0"},"posted":{"date-parts":[[2026,7,9]]},"group-title":"Genetic and Genomic Medicine","reference-count":83,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"National Institute of Mental Health of the National Institutes of Health"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Schizophrenia (SCZ) and bipolar disorder (BIP) share substantial genetic liability, yet exhibit heterogeneity in cognition, illness course and cardiometabolic health. Conventional disorder-level genome-wide association studies (GWASs) aggregate genetic liability obscuring this heterogeneity.<\/jats:p>\n                <jats:p>\n                  We applied zero-phase component analysis whitening and common factor GWAS to SCZ and BIP summary statistics, deriving a shared component (PSY\n                  <jats:sub>shared<\/jats:sub>\n                  ) and two mutually orthogonal, disorder-predominant components (SCZ\n                  <jats:sub>\u223cBIP<\/jats:sub>\n                  and BIP\n                  <jats:sub>\u223cSCZ<\/jats:sub>\n                  ). We then examined whether the three profiles differed in locus architecture, pathway enrichment, developmental expression and intermediate-phenotype associations.\n                <\/jats:p>\n                <jats:p>\n                  The decomposition identified 261 loci, of which 201 (77%) were component-specific and 16 loci were not reported in any previous larger SCZ and BIP GWASs or multivariate psychosis GWASs. PSY\n                  <jats:sub>shared<\/jats:sub>\n                  was enriched for synaptic architecture, nuclear organisation and protein trafficking, with developmental signals spanning early-and late-mid-prenatal stages, late infancy and young adulthood. SCZ\n                  <jats:sub>\u223cBIP<\/jats:sub>\n                  implicated cortical neuronal differentiation, DNA\/RNA regulation and protein turnover, with developmental associations in late infancy and young adulthood. BIP\n                  <jats:sub>\u223cSCZ<\/jats:sub>\n                  showed synaptic release and transport signals, alongside exploratory associations with gene\/protein regulation and mitochondrial translation (nominal P &lt; 0.001), with significant developmental enrichment in late infancy. Correlations of SCZ and BIP with intermediate traits were asymmetric, whereas SCZ\u223c\n                  <jats:sub>BIP<\/jats:sub>\n                  and BIP\u223c\n                  <jats:sub>SCZ<\/jats:sub>\n                  diverged in opposite directions across cognitive performance, educational attainment, metabolic syndrome, and systemic inflammatory markers. In contrast, both orthogonal components correlated positively with risk taking, with a larger estimate for BIP\n                  <jats:sub>\u223cSCZ<\/jats:sub>\n                  ; PSY\n                  <jats:sub>shared<\/jats:sub>\n                  showed the largest estimate among the derived components. Steiger tests showed that the components differed significantly across all six phenotypes. Component contrasts were 1.63-2.07-fold greater than corresponding SCZ-BIP contrasts with the increase reaching significance for cognitive performance and metabolic syndrome.\n                <\/jats:p>\n                <jats:p>These findings support a multidimensional representation of SCZ-BIP liability and provide a framework for testing whether relative component burdens account for variation in cognition, cardiometabolic and inflammatory burden, illness course, and treatment response beyond diagnosis.<\/jats:p>","DOI":"10.64898\/2026.07.07.26357436","type":"posted-content","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T17:20:56Z","timestamp":1783617656000},"source":"Crossref","is-referenced-by-count":0,"title":["Disorder-specific and shared genetic architecture underlying schizophrenia and bipolar disorder"],"prefix":"10.64898","author":[{"given":"Upasana","family":"Bhattacharyya","sequence":"first","affiliation":[{"name":"Northwell, New Hyde Park, NY, USA"},{"name":"Institute of Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jibin","family":"John","sequence":"additional","affiliation":[{"name":"Northwell, New Hyde Park, NY, USA"},{"name":"Institute of Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Preuss","sequence":"additional","affiliation":[{"name":"Northwell, New Hyde Park, NY, USA"},{"name":"Institute of Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max","family":"Lam","sequence":"additional","affiliation":[{"name":"Northwell, New Hyde Park, NY, USA"},{"name":"Institute of Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, NY, USA"},{"name":"Institute of Mental Health, Singapore"},{"name":"Lee Kong Chian School of Medicine, Population and Global Health, Nanyang Technological University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8586-338X","authenticated-orcid":false,"given":"Todd","family":"Lencz","sequence":"additional","affiliation":[{"name":"Northwell, New Hyde Park, NY, USA"},{"name":"Institute of Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, NY, USA"},{"name":"Departments of Psychiatry and Molecular Medicine, Zucker School of Medicine at Hofstra\/Northwell, Hempstead, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026100502550791000_2026.07.07.26357436v3.1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)61611-6"},{"key":"2026100502550791000_2026.07.07.26357436v3.2","first-page":"137","article-title":"Mental Disorders Collaborators. Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019","volume":"9","year":"2019","journal-title":"Lancet Psychiatry"},{"key":"2026100502550791000_2026.07.07.26357436v3.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-021-01161-7"},{"key":"2026100502550791000_2026.07.07.26357436v3.4","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1176\/appi.ajp.20260051","article-title":"Bipolar disorder: an update on neurobiology and treatment","volume":"183","year":"2026","journal-title":"Am. J. Psychiatry"},{"key":"2026100502550791000_2026.07.07.26357436v3.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2017.08.017"},{"key":"2026100502550791000_2026.07.07.26357436v3.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.psychres.2019.06.010"},{"key":"2026100502550791000_2026.07.07.26357436v3.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.11.020"},{"key":"2026100502550791000_2026.07.07.26357436v3.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01057-4"},{"key":"2026100502550791000_2026.07.07.26357436v3.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-09214-w"},{"key":"2026100502550791000_2026.07.07.26357436v3.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.jad.2021.04.064"},{"key":"2026100502550791000_2026.07.07.26357436v3.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-024-02866-3"},{"key":"2026100502550791000_2026.07.07.26357436v3.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.euroneuro.2022.12.005"},{"key":"2026100502550791000_2026.07.07.26357436v3.13","doi-asserted-by":"crossref","unstructured":"Griffiths, S. L. , Lalousis, P. A. , Wood, S. J. & Upthegrove, R . Heterogeneity in treatment outcomes and incomplete recovery in first episode psychosis: does one size fit all? Transl. Psychiatry 12, 485 (2022).","DOI":"10.1038\/s41398-022-02256-7"},{"key":"2026100502550791000_2026.07.07.26357436v3.14","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1038\/s41586-024-08468-9","article-title":"Genomics yields biological and phenotypic insights into bipolar disorder","volume":"639","year":"2025","journal-title":"Nature"},{"key":"2026100502550791000_2026.07.07.26357436v3.15","doi-asserted-by":"publisher","DOI":"10.1038\/S41586-022-04434-5"},{"key":"2026100502550791000_2026.07.07.26357436v3.16","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1038\/s41586-025-10000-6","article-title":"Biological insights into schizophrenia from ancestrally diverse populations","volume":"651","year":"2026","journal-title":"Nature"},{"key":"2026100502550791000_2026.07.07.26357436v3.17","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-025-02467-w"},{"key":"2026100502550791000_2026.07.07.26357436v3.18","doi-asserted-by":"crossref","first-page":"e1002654","DOI":"10.1371\/journal.pmed.1002654","article-title":"Type 2 diabetes genetic loci informed by multi-trait associations point to disease mechanisms and subtypes: a soft clustering analysis","volume":"15","year":"2018","journal-title":"PLoS Med"},{"key":"2026100502550791000_2026.07.07.26357436v3.19","doi-asserted-by":"crossref","unstructured":"Udler, M. S . Type 2 diabetes: multiple genes, multiple diseases. Curr. Diab. Rep. 19, 55 (2019).","DOI":"10.1007\/s11892-019-1169-7"},{"key":"2026100502550791000_2026.07.07.26357436v3.20","doi-asserted-by":"publisher","DOI":"10.1038\/s41562-019-0566-x"},{"key":"2026100502550791000_2026.07.07.26357436v3.21","doi-asserted-by":"crossref","first-page":"2070","DOI":"10.1038\/s41380-020-0705-9","article-title":"Conditional GWAS analysis to identify disorder-specific SNPs for psychiatric disorders","volume":"26","year":"2021","journal-title":"Mol. Psychiatry"},{"key":"2026100502550791000_2026.07.07.26357436v3.22","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00787-1"},{"key":"2026100502550791000_2026.07.07.26357436v3.23","doi-asserted-by":"publisher","DOI":"10.1093\/schbul\/sbt179"},{"key":"2026100502550791000_2026.07.07.26357436v3.24","doi-asserted-by":"publisher","DOI":"10.1016\/J.AJHG.2019.06.012"},{"key":"2026100502550791000_2026.07.07.26357436v3.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2025.02.890"},{"key":"2026100502550791000_2026.07.07.26357436v3.26","doi-asserted-by":"crossref","first-page":"2955","DOI":"10.1038\/s41380-025-02900-w","article-title":"Neural signatures of risk-taking adaptions across health, bipolar disorder, and lithium treatment","volume":"30","year":"2025","journal-title":"Mol. Psychiatry"},{"key":"2026100502550791000_2026.07.07.26357436v3.27","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-021-00908-3"},{"key":"2026100502550791000_2026.07.07.26357436v3.28","doi-asserted-by":"crossref","unstructured":"Polcwiartek, C. , Jensen, S. E. , Frokjaer, J. B. & Nielsen, R. E . Prevalence of cardiovascular risk factors and disease in patients with schizophrenia: baseline results from a prospective cohort study with long-term clinical follow-up. Schizophrenia (Heidelb .) 11, 95 (2025).","DOI":"10.1038\/s41537-025-00642-w"},{"key":"2026100502550791000_2026.07.07.26357436v3.29","doi-asserted-by":"crossref","unstructured":"Strawbridge, R. J. et al. The overlap of genetic susceptibility to schizophrenia and cardiometabolic disease can be used to identify metabolically different groups of individuals. Sci. Rep. 11, 632 (2021).","DOI":"10.1038\/s41598-020-79964-x"},{"key":"2026100502550791000_2026.07.07.26357436v3.30","doi-asserted-by":"publisher","DOI":"10.1016\/S2215-0366(15)00115-7"},{"key":"2026100502550791000_2026.07.07.26357436v3.31","doi-asserted-by":"publisher","DOI":"10.1016\/S2215-0366(14)00122-9"},{"key":"2026100502550791000_2026.07.07.26357436v3.32","doi-asserted-by":"publisher","DOI":"10.2139\/ssrn.6385063"},{"key":"2026100502550791000_2026.07.07.26357436v3.33","doi-asserted-by":"crossref","unstructured":"Koskeridis, F. et al. Pleiotropic genetic architecture and novel loci for C-reactive protein levels. Nat. Commun. 13, 6939 (2022).","DOI":"10.1038\/s41467-022-34688-6"},{"key":"2026100502550791000_2026.07.07.26357436v3.34","doi-asserted-by":"publisher","DOI":"10.1038\/s41537-021-00161-4"},{"key":"2026100502550791000_2026.07.07.26357436v3.35","doi-asserted-by":"publisher","DOI":"10.1016\/S2215-0366(16)30370-4"},{"key":"2026100502550791000_2026.07.07.26357436v3.36","doi-asserted-by":"publisher","DOI":"10.1093\/schbul\/sbad082"},{"key":"2026100502550791000_2026.07.07.26357436v3.37","doi-asserted-by":"publisher","DOI":"10.21203\/rs.3.rs-8502917\/v1"},{"key":"2026100502550791000_2026.07.07.26357436v3.38","doi-asserted-by":"publisher","DOI":"10.1080\/00031305.2016.1277159"},{"key":"2026100502550791000_2026.07.07.26357436v3.39","doi-asserted-by":"crossref","first-page":"i212","DOI":"10.1093\/bioinformatics\/btac228","article-title":"PolarMorphism enables discovery of shared genetic variants across multiple traits from GWAS summary statistics","volume":"38","year":"2022","journal-title":"Bioinformatics"},{"key":"2026100502550791000_2026.07.07.26357436v3.40","doi-asserted-by":"crossref","unstructured":"Cao, R. et al. Subset scanning for multi-trait analysis using GWAS summary statistics. Bioinformatics 40, btad777 (2024).","DOI":"10.1093\/bioinformatics\/btad777"},{"key":"2026100502550791000_2026.07.07.26357436v3.41","doi-asserted-by":"crossref","unstructured":"Watanabe, K. , Taskesen, E. , van Bochoven, A. & Posthuma, D . Functional mapping and annotation of genetic associations with FUMA. Nat. Commun. 8, 1826 (2017).","DOI":"10.1038\/s41467-017-01261-5"},{"key":"2026100502550791000_2026.07.07.26357436v3.42","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq033"},{"key":"2026100502550791000_2026.07.07.26357436v3.43","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1004219"},{"key":"2026100502550791000_2026.07.07.26357436v3.44","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.05.002"},{"key":"2026100502550791000_2026.07.07.26357436v3.45","doi-asserted-by":"publisher","DOI":"10.1038\/nature13595"},{"key":"2026100502550791000_2026.07.07.26357436v3.46","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0059-2"},{"key":"2026100502550791000_2026.07.07.26357436v3.47","doi-asserted-by":"publisher","DOI":"10.1038\/S41588-019-0512-X"},{"key":"2026100502550791000_2026.07.07.26357436v3.48","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00857-4"},{"key":"2026100502550791000_2026.07.07.26357436v3.49","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0397-8"},{"key":"2026100502550791000_2026.07.07.26357436v3.50","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-02205473-8"},{"key":"2026100502550791000_2026.07.07.26357436v3.51","doi-asserted-by":"publisher","DOI":"10.1038\/s41386-021-01023-4"},{"key":"2026100502550791000_2026.07.07.26357436v3.52","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0147-3"},{"key":"2026100502550791000_2026.07.07.26357436v3.53","doi-asserted-by":"crossref","first-page":"2408","DOI":"10.1038\/s41588-025-02335-7","article-title":"Pan-UK Biobank genome-wide association analyses enhance discovery and resolution of ancestry-enriched effects","volume":"57","year":"2025","journal-title":"Nat. Genet"},{"key":"2026100502550791000_2026.07.07.26357436v3.54","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-024-01933-1"},{"key":"2026100502550791000_2026.07.07.26357436v3.55","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-024-02044-7"},{"key":"2026100502550791000_2026.07.07.26357436v3.56","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3406"},{"key":"2026100502550791000_2026.07.07.26357436v3.57","doi-asserted-by":"publisher","DOI":"10.1037\/\/0033-2909.87.2.245"},{"key":"2026100502550791000_2026.07.07.26357436v3.58","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07429-6"},{"key":"2026100502550791000_2026.07.07.26357436v3.59","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-026-10832-w"},{"key":"2026100502550791000_2026.07.07.26357436v3.60","doi-asserted-by":"publisher","DOI":"10.1126\/science.aat8127"},{"key":"2026100502550791000_2026.07.07.26357436v3.61","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnpbp.2008.04.017"},{"key":"2026100502550791000_2026.07.07.26357436v3.62","doi-asserted-by":"publisher","DOI":"10.1016\/j.schres.2004.03.002"},{"key":"2026100502550791000_2026.07.07.26357436v3.63","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2020.02.005"},{"key":"2026100502550791000_2026.07.07.26357436v3.64","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2010.01.020"},{"key":"2026100502550791000_2026.07.07.26357436v3.65","doi-asserted-by":"publisher","DOI":"10.1038\/nature10523"},{"key":"2026100502550791000_2026.07.07.26357436v3.66","unstructured":"Li, M. et al. Integrative functional genomic analysis of human brain development and neuropsychiatric risks. Science 362, eaat7615 (2018)."},{"key":"2026100502550791000_2026.07.07.26357436v3.67","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1648"},{"key":"2026100502550791000_2026.07.07.26357436v3.68","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2015.03.010"},{"key":"2026100502550791000_2026.07.07.26357436v3.69","doi-asserted-by":"publisher","DOI":"10.1038\/nature19847"},{"key":"2026100502550791000_2026.07.07.26357436v3.70","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-026-71281-7"},{"key":"2026100502550791000_2026.07.07.26357436v3.71","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2023.102801"},{"key":"2026100502550791000_2026.07.07.26357436v3.72","doi-asserted-by":"publisher","DOI":"10.3390\/genes11101185"},{"key":"2026100502550791000_2026.07.07.26357436v3.73","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-023-02096-x"},{"key":"2026100502550791000_2026.07.07.26357436v3.74","doi-asserted-by":"publisher","DOI":"10.1159\/000549993"},{"key":"2026100502550791000_2026.07.07.26357436v3.75","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpsc.2024.07.011"},{"key":"2026100502550791000_2026.07.07.26357436v3.76","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.2013.12101298"},{"key":"2026100502550791000_2026.07.07.26357436v3.77","doi-asserted-by":"publisher","DOI":"10.1016\/S2215-0366(26)00196-3"},{"key":"2026100502550791000_2026.07.07.26357436v3.78","doi-asserted-by":"publisher","DOI":"10.1016\/S2215-0366(23)00025-1"},{"key":"2026100502550791000_2026.07.07.26357436v3.79","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.euroneuro.2024.10.008","article-title":"A meta-analysis of data-driven cognitive subgroups in bipolar disorder","volume":"90","year":"2025","journal-title":"Eur. Neuropsychopharmacol"},{"key":"2026100502550791000_2026.07.07.26357436v3.80","doi-asserted-by":"publisher","DOI":"10.1017\/S0033291717000307"},{"key":"2026100502550791000_2026.07.07.26357436v3.81","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-020-00754-2"},{"key":"2026100502550791000_2026.07.07.26357436v3.82","doi-asserted-by":"crossref","first-page":"3098","DOI":"10.1038\/s41380-026-03444-3","article-title":"Splitting schizophrenia: divergent cognitive and educational outcomes revealed by genomic structural equation modelling","volume":"31","year":"2026","journal-title":"Mol. Psychiatry"},{"key":"2026100502550791000_2026.07.07.26357436v3.83","doi-asserted-by":"crossref","unstructured":"Zhu, Z. et al. Causal associations between risk factors and common diseases inferred from GWAS summary data. Nat. Commun. 9, 224 (2018).","DOI":"10.1038\/s41467-017-02317-2"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.07.07.26357436","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T09:55:18Z","timestamp":1791194118000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.07.07.26357436"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,9]]},"references-count":83,"URL":"https:\/\/doi.org\/10.64898\/2026.07.07.26357436","relation":{},"subject":[],"published":{"date-parts":[[2026,7,9]]},"subtype":"preprint"}}