TY - JOUR
T1 - Mapping the genetic landscape across 14 psychiatric disorders
AU - Grotzinger, Andrew D.
AU - Werme, Josefin
AU - Peyrot, Wouter J.
AU - Frei, Oleksandr
AU - de Leeuw, Christiaan
AU - Bicks, Lucy K.
AU - Guo, Qiuyu
AU - Margolis, Michael P.
AU - Coombes, Brandon J.
AU - Batzler, Anthony
AU - Pazdernik, Vanessa
AU - Biernacka, Joanna M.
AU - Andreassen, Ole A.
AU - Anttila, Verneri
AU - Børglum, Anders D.
AU - Breen, Gerome
AU - Cai, Na
AU - Demontis, Ditte
AU - Edenberg, Howard J.
AU - Faraone, Stephen V.
AU - Franke, Barbara
AU - Gandal, Michael J.
AU - Gelernter, Joel
AU - Hatoum, Alexander S.
AU - Hettema, John M.
AU - Johnson, Emma C.
AU - Jonas, Katherine G.
AU - Knowles, James A.
AU - Koenen, Karestan C.
AU - Maihofer, Adam X.
AU - Mallard, Travis T.
AU - Mattheisen, Manuel
AU - Mitchell, Karen S.
AU - Neale, Benjamin M.
AU - Nievergelt, Caroline M.
AU - Nurnberger, John I.
AU - O'Connell, Kevin S.
AU - Peterson, Roseann E.
AU - Robinson, Elise B.
AU - Sanchez-Roige, Sandra S.
AU - Santangelo, Susan L.
AU - Scharf, Jeremiah M.
AU - Stefansson, Hreinn
AU - Stefansson, Kari
AU - Anxiety Disorders Working Group of the Psychiatric Genomics Consortium
AU - Stein, Murray B.
AU - Attention-Deficit/Hyperactivity Disorder (ADHD) Working Group of the Psychiatric Genomics Consortium
AU - Strom, Nora I.
AU - Autism Spectrum Disorders Working Group of the Psychiatric Genomics Consortium
AU - Thornton, Laura M.
AU - Bipolar Disorder Working Group of the Psychiatric Genomics Consortium
AU - Eating Disorders Working Group of the Psychiatric Genomics Consortium
AU - Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium
AU - Tucker-Drob, Elliot M.
AU - Verhulst, Brad
AU - Nicotine Dependence GenOmics (iNDiGO) Consortium
AU - Waldman, Irwin D.
AU - Walters, G. Bragi
AU - Obsessive Compulsive Disorder and Tourette Syndrome Working Group of the Psychiatric Genomics Consortium
AU - Post-Traumatic Stress Disorder Working Group of the Psychiatric Genomics Consortium
AU - Wray, Naomi R.
AU - Yu, Dongmei
AU - Lee, Phil H.
AU - Schizophrenia Working Group of the Psychiatric Genomics Consortium
AU - Substance Use Disorders Working Group of the Psychiatric Genomics Consortium
AU - Kendler, Kenneth S.
AU - Smoller, Jordan W.
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2026/1/8
Y1 - 2026/1/8
N2 - Psychiatric disorders display high levels of comorbidity and genetic overlap1,2, challenging current diagnostic boundaries. For disorders for which diagnostic separation has been most debated, such as schizophrenia and bipolar disorder3, genomic methods have revealed that the majority of genetic signal is shared4. While over a hundred pleiotropic loci have been identified by recent cross-disorder analyses5, 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 overlap6 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.
AB - Psychiatric disorders display high levels of comorbidity and genetic overlap1,2, challenging current diagnostic boundaries. For disorders for which diagnostic separation has been most debated, such as schizophrenia and bipolar disorder3, genomic methods have revealed that the majority of genetic signal is shared4. While over a hundred pleiotropic loci have been identified by recent cross-disorder analyses5, 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 overlap6 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.
UR - https://www.scopus.com/pages/publications/105027209630
U2 - 10.1038/s41586-025-09820-3
DO - 10.1038/s41586-025-09820-3
M3 - Article
C2 - 41372416
SN - 0028-0836
VL - 649
SP - 406
EP - 415
JO - Nature
JF - Nature
IS - 8096
ER -