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Both common and rare genetic variants contribute to neural dysfunction, impacting cognition and behavior. This study investigates the molecular effects of genetic variants on human cortical single-cell types using a single-exon analysis approach. Integrating exon-level eQTLs (common variants influencing exon expression) and joint exon eQT-Scores (combining polygenic risk scores with exon-level gene expression) from a postmortem psychiatric cohort (BD\u2009=\u200915, MDD\u2009=\u200924, schizophrenia\u2009=\u200968, controls\u2009=\u200962) with schizophrenia-focused rare variant data from the SCHEMA consortium, we identified 110 core genes enriched in pathways including circadian entrainment (FDR\u2009=\u20090.02), cortisol synthesis and secretion (FDR\u2009=\u20090.026), and dopaminergic synapse (FDR\u2009=\u20090.038). Additional enriched pathways included hormone signaling (FDRs\u2009&lt;\u20090.0298, including insulin, GnRH, aldosterone, and growth hormone pathways) and, notably, adrenergic signaling in cardiomyocytes (FDR\u2009=\u20090.0028). These pathways highlight shared molecular mechanisms in the three disorders. Single-nuclei RNA sequencing data from three cortical regions revealed that these core set genes are predominantly expressed in excitatory neuron layers 2\u20136 of the dorsolateral prefrontal cortex, linking molecular changes to cell types involved in cognitive dysfunction. Our results demonstrate the power of integrating multimodal genetic and transcriptomic data at the exon level. This approach moves beyond symptom-based diagnoses toward molecular classifications, identifying potential therapeutic targets for psychiatric disorders.<\/jats:p>","DOI":"10.1038\/s41398-025-03366-8","type":"journal-article","created":{"date-parts":[[2025,4,19]],"date-time":"2025-04-19T05:39:22Z","timestamp":1745041162000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Exon-variant interplay and multi-modal evidence identify endocrine dysregulation in severe psychiatric disorders impacting excitatory neurons"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3190-3873","authenticated-orcid":false,"given":"Karolina","family":"Worf","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3208-1311","authenticated-orcid":false,"given":"Natalie","family":"Matosin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Gerstner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5911-924X","authenticated-orcid":false,"given":"Anna S.","family":"Fr\u00f6hlich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna C.","family":"Koller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franziska","family":"Degenhardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holger","family":"Thiele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5236-6149","authenticated-orcid":false,"given":"Marcella","family":"Rietschel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madhara","family":"Udawela","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Scarr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7773-4473","authenticated-orcid":false,"given":"Brian","family":"Dean","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian J.","family":"Theis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikola S.","family":"Mueller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3825-4279","authenticated-orcid":false,"given":"Janine","family":"Knauer-Arloth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,19]]},"reference":[{"key":"3366_CR1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2022.1046692","volume":"16","author":"Y Wang","year":"2022","unstructured":"Wang Y, Meng W, Liu Z, An Q, Hu X. 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The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All methods were performed in accordance with relevant guidelines and regulations. For Dataset 1, postmortem brains were collected with approval from the Ethics Committee of the Victorian Institute of Forensic Medicine, 1 and this study was further approved by the Human Ethics Committee of Melbourne Health []. For Dataset 2a, ethical approval was obtained from the Human Research Ethics Committees at the University of Wollongong (HE2018\/351) and the Ludwig-Maximilians-Universit\u00e4t Munich (17-085 and 18-393). Two publicly available datasets (Dataset 2b and 2c) were used, and ethical approval for these studies was obtained by the original data generators. For Dataset 1, written informed consent was obtained from the next of kin for all tissue donations. 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