{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:19:21Z","timestamp":1792790361603,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,27]]},"group-title":"Genetic and Genomic Medicine","reference-count":90,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:00:00Z","timestamp":1790467200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["R01MH113078"],"award-info":[{"award-number":["R01MH113078"]}],"id":[{"id":"https:\/\/ror.org\/04xeg9z08","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01MH123157"],"award-info":[{"award-number":["R01MH123157"]}],"id":[{"id":"https:\/\/ror.org\/04xeg9z08","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U01MH125042"],"award-info":[{"award-number":["U01MH125042"]}],"id":[{"id":"https:\/\/ror.org\/04xeg9z08","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U01MH125047"],"award-info":[{"award-number":["U01MH125047"]}],"id":[{"id":"https:\/\/ror.org\/04xeg9z08","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01MH101244"],"award-info":[{"award-number":["R01MH101244"]}],"id":[{"id":"https:\/\/ror.org\/04xeg9z08","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U24MH140953"],"award-info":[{"award-number":["U24MH140953"]}],"id":[{"id":"https:\/\/ror.org\/04xeg9z08","id-type":"ROR","asserted-by":"publisher"}]},{"name":"UCLA Clinical and Translational Science Institute","award":["UL1TR001881"],"award-info":[{"award-number":["UL1TR001881"]}],"id":[{"id":"https:\/\/ror.org\/04kpwcf85","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Breakthrough Discoveries for thriving with Bipolar Disorder","id":[{"id":"https:\/\/ror.org\/00z5dw933","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Stanley Center for Psychiatric Research at Broad Institute","id":[{"id":"https:\/\/ror.org\/05a0ya142","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Genetic studies of serious mental illness (SMI, including schizophrenia and bipolar disorder) have implicated two classes of risk variant: common variants\n                  <jats:sup>1\u20133<\/jats:sup>\n                  , each of small effect but collectively accounting for most population-level risk, and ultra-rare coding variants\n                  <jats:sup>4,5<\/jats:sup>\n                  which confer large risk in a small number of individuals. Most such studies cannot directly assess the impact of specific variants on SMI, transdiagnostically, as the phenotypic information that they collect is focused on a single diagnosis. Here we report results of association analysis of predicted deleterious variants from exome sequencing of 21,958 cases (SMI and severe major depressive disorder) and 19,826 controls from the Mision Origen biobank in the Paisa genetic isolate of Colombia. We identified transdiagnostic associations to seven genes, three at an exome-wide and four at a false discovery rate significance threshold. Five of these genes have not previously been implicated in SMI (\n                  <jats:italic>ADAP1<\/jats:italic>\n                  ,\n                  <jats:italic>WIPI1<\/jats:italic>\n                  ,\n                  <jats:italic>NFE2L1<\/jats:italic>\n                  ,\n                  <jats:italic>FBXO10<\/jats:italic>\n                  , and\n                  <jats:italic>HLA-DPB1<\/jats:italic>\n                  ); for the first four of these the association is driven by variants enriched in the Paisa due to a founder effect, filling the gap between ultra-rare and common variants. The strongest association that we observe is to a frameshift variant (7:904169:T:TC) in\n                  <jats:italic>ADAP1<\/jats:italic>\n                  that is genome-wide significant for SMI, schizophrenia, and bipolar disorder and increases risk for both diagnoses by more than threefold; it truncates ADAP1, a brain-enriched Arf6 GTPase-activating\/scaffolding protein that has been mechanistically linked to post-mitotic neuronal morphogenesis and regulation of dendritic differentiation\n                  <jats:sup>6<\/jats:sup>\n                  . Variant carriers differ significantly from other SMI cases in Mision Origen for psychotic, manic, and cognitive item-level phenotypes assessed through analyses of electronic health records\n                  <jats:sup>7\u20139<\/jats:sup>\n                  and displayed impaired executive function on neurocognitive testing. Variant carriers differ significantly from other SMI cases in Mision Origen for multiple item-level phenotypes (psychotic, manic, and cognitive) assigned through natural language processing of longitudinal electronic health records. Although the 7:904169:T:TC variant is not significantly associated with major depressive disorder, carriers compared to others with this diagnosis display a significant increase in symptoms typical of bipolar disorder. The variant\u2019s high allele frequency in Mision Origen (\u223c0.4%) will enable population-level studies to stratify SMI based on causation and identify additional factors influencing risk and resilience.\n                <\/jats:p>","DOI":"10.64898\/2026.09.25.26363706","type":"posted-content","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T21:45:10Z","timestamp":1790545510000},"source":"Crossref","is-referenced-by-count":0,"title":["A founder population reveals genetic variation with major effect on serious mental illness"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-8348-8550","authenticated-orcid":false,"given":"Greta","family":"Gerdes","sequence":"first","affiliation":[{"name":"Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8538-9198","authenticated-orcid":false,"given":"Veronica","family":"Tozzo","sequence":"additional","affiliation":[{"name":"Department of Computational Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4686-2466","authenticated-orcid":false,"given":"Susan K.","family":"Service","sequence":"additional","affiliation":[{"name":"Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9025-3690","authenticated-orcid":false,"given":"Clara","family":"Frydman-Gani","sequence":"additional","affiliation":[{"name":"Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana M.","family":"Diaz-Zuluaga","sequence":"additional","affiliation":[{"name":"Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California, USA"},{"name":"BD2: Breakthrough Discoveries for Thriving with Bipolar Disorder, Santa Monica, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Valencia-Echeverry","sequence":"additional","affiliation":[{"name":"Research Group in Psychiatry, Department of Psychiatry, School of Medicine, Universidad de Antioquia, Medell\u00edn, Antioquia, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Arias","sequence":"additional","affiliation":[{"name":"Research Group in Psychiatry, Department of Psychiatry, School of Medicine, Universidad de Antioquia, Medell\u00edn, Antioquia, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9884-0133","authenticated-orcid":false,"given":"Lucy K.","family":"Bicks","sequence":"additional","affiliation":[{"name":"Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana M.","family":"Ramirez-Diaz","sequence":"additional","affiliation":[{"name":"Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9346-3498","authenticated-orcid":false,"given":"Julia M.","family":"Sealock","sequence":"additional","affiliation":[{"name":"Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA"},{"name":"Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6169-7137","authenticated-orcid":false,"given":"Calwing","family":"Liao","sequence":"additional","affiliation":[{"name":"Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA"},{"name":"Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA"},{"name":"Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7721-4838","authenticated-orcid":false,"given":"Daniel P.","family":"Howrigan","sequence":"additional","affiliation":[{"name":"Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA"},{"name":"Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2078-651X","authenticated-orcid":false,"given":"Christiana","family":"Liu","sequence":"additional","affiliation":[{"name":"Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5862-3938","authenticated-orcid":false,"given":"Esteban A.","family":"Lopera-Maya","sequence":"additional","affiliation":[{"name":"Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5660-7210","authenticated-orcid":false,"given":"Aditya","family":"Pimplaskar","sequence":"additional","affiliation":[{"name":"Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5584-7511","authenticated-orcid":false,"given":"Juan F.","family":"De la Hoz","sequence":"additional","affiliation":[{"name":"Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California, USA"},{"name":"Center for Precision Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA"},{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario A.","family":"Arango-G\u00f3mez","sequence":"additional","affiliation":[{"name":"Research Group in Psychiatry, Department of Psychiatry, School of Medicine, Universidad de Antioquia, Medell\u00edn, Antioquia, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camila","family":"Arango-Restrepo","sequence":"additional","affiliation":[{"name":"Research Group in Psychiatry, Department of Psychiatry, School of Medicine, Universidad de Antioquia, Medell\u00edn, Antioquia, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria C.","family":"Arbelaez-Herrera","sequence":"additional","affiliation":[{"name":"Research Group in Psychiatry, Department of Psychiatry, School of Medicine, Universidad de Antioquia, Medell\u00edn, Antioquia, 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Discoveries for Thriving with Bipolar Disorder, Santa Monica, California, USA"},{"name":"Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA"},{"name":"Institute for Precision Health, University of California Los Angeles, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3327-7837","authenticated-orcid":false,"given":"Loes M.","family":"Olde Loohuis","sequence":"additional","affiliation":[{"name":"Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California, USA"},{"name":"Department of Computational Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA"},{"name":"BD2: Breakthrough Discoveries for Thriving with Bipolar Disorder, Santa Monica, California, USA"},{"name":"Department of Human Genetics, David Geffen School of Medicine, 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