Genetic Associations and Epidemiology
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Five underlying genomic factors are identified and characterized that explained the majority of the genetic variance of the individual disorders and were associated with 238 pleiotropic loci, which may inform a more neurobiologically valid psychiatric nosology and implicate targets for therapeutic development designed to treat commonly occurring comorbid presentations.
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Psychiatric disorders display high levels of comorbidity and genetic overlap 1,2 , challenging current diagnostic boundaries. For disorders for which diagnostic separation has been most debated, such as schizophrenia and bipolar disorder 3 , genomic methods have revealed that the majority of genetic signal is shared 4 . While over a hundred pleiotropic loci have been identified by recent cross-disorder analyses 5 , the full scope of shared and disorder-specific genetic influences remains poorly defined. Here we addressed this gap by triangulating across a suite of cutting-edge statistical and functional genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders (1,056,201 cases). Using genetic association data from common variants, we identified and characterized five underlying genomic factors that explained the majority of the genetic variance of the individual disorders (around 66% on average) and were associated with 238 pleiotropic loci. The two factors defined by (1) Schizophrenia and bipolar disorders (SB factor); and (2) major depression, PTSD and anxiety (Internalizing factor) showed high levels of polygenic overlap 6 and local genetic correlation and very few disorder-specific loci. The genetic signal shared across all 14 disorders was enriched for broad biological processes (for example, transcriptional regulation), while more specific pathways were shared at the level of the individual factors. The shared genetic signal across the SB factor was substantially enriched in genes expressed in excitatory neurons, whereas the Internalizing factor was associated with oligodendrocyte biology. These observations may inform a more neurobiologically valid psychiatric nosology and implicate targets for therapeutic development designed to treat commonly occurring comorbid presentations.
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@article{Grotzinger2025Mapping,
title = {Mapping the genetic landscape across 14 psychiatric disorders},
author = {Andrew D. Grotzinger and Josefin Werme and Wouter J. Peyrot and Oleksandr Frei and Christiaan de Leeuw and Lucy Bicks and Qiuyu Guo and Michael Margolis and Brandon J. Coombes and Anthony Batzler and Vanessa Pazdernik and Joanna M. Biernacka and Ole A. Andreassen and Verneri Anttila and Anders D. Børglum and Gerome Breen and Na Cai and Ditte Demontis and Howard J. Edenberg and Stephen V. Faraone and Barbara Franke and Michael J. Gandal and Joel Gelernter and Alexander S. Hatoum and John M. Hettema and Emma C. Johnson and Katherine Jonas and James A. Knowles and Karestan C. Koenen and Adam X. Maihofer and Travis T. Mallard and Manuel Mattheisen and Karen S. Mitchell and Benjamin M. Neale and Caroline M. Nievergelt and John I. Nürnberger and Kevin S. O’Connell and Roseann E. Peterson and Elise Robinson and Sandra Sanchez‐Roige and Susan L. Santangelo and Jeremiah M. Scharf and Murray B. Stein and Nora I. Strom and Laura M. Thornton and Elliot M Tucker-Drob and Brad Verhulst and Irwin D. Waldman and G. Bragi Walters and Naomi R. Wray and Dongmei Yu and Daniel E. Adkins and Georg W. Alpers and Síntia Belangero and Ottar Bjerkeset and Sigrid Børte and Sandra A. Brown and Enrique Castelao and Hilary Coon and Elizabeth C. Corfield and Darina Czamara and Jürgen Deckert and Anna R. Docherty and Katharina Domschke and Ole Kristian Drange and Thalia C. Eley and Angelika Erhardt and Andreas J. Forstner and Miguel Garcia‐Argibay and Scott D. Gordon and Ian B. Hickie and Iiris Hovatta and Matthew H. Iveson and James L. Kennedy and Henrik Larsson and Daniel Levey and Christine Löchner and Michelle K. Lupton and Hermine HM Maes and Eduard Maron and Nicholas G. Martin and Sandra Meier and Christiane A. Melzig and Brittany L. Mitchell and Teemu Palviainen and Giorgio Pistis and Martin Preisig and Börge Schmidt and Johannes Schumacher and Andrey A. Shabalin and Anne Heidi Skogholt and Dan J. Stein and Eystein Stordal and Andreas Ströhle and Elisa Tasanko and Laurent F. Thomas},
journal = {Nature},
year = {2025},
doi = {10.1038/s41586-025-09820-3},
url = {https://doi.org/10.1038/s41586-025-09820-3}
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