The Landscape of Shared and Divergent Genetic Influences across 14 Psychiatric Disorders
Authors: Grotzinger Andrew D , Werme Josefin , Peyrot Wouter J , Frei Oleksandr , de Leeuw Christiaan , Bicks Lucy K , Guo Qiuyu , Margolis Michael P , Coombes Brandon J , Batzler Anthony , Pazdernik Vanessa , Biernacka Joanna M , Andreassen Ole A , Anttila Verneri , Børglum Anders D , Cai Na , Demontis Ditte , Edenberg Howard J , Faraone Stephen V , Franke Barbara , Gandal Michael J , Gelernter Joel , Hettema John M , Jonas Katherine G , Knowles James A , Koenen Karestan C , Maihofer Adam X , Mallard Travis T , Mattheisen Manuel , Mitchell Karen S , Neale Benjamin M , Nievergelt Caroline M , Nurnberger John I , O’Connell Kevin S , Robinson Elise B , Sanchez-Roige Sandra S , Santangelo Susan L , Stefansson Hreinn , Stefansson Kari , Stein Murray B , Strom Nora I , Thornton Laura M , Tucker-Drob Elliot M , Verhulst Brad , Waldman Irwin D , Walters G Bragi , Wray Naomi R ,   Anxiety Disorders Working Group,   Attention-Deficit/Hyperactivity Disorder (ADHD) Working Group,   Autism Spectrum Disorders Working Group,   Bipolar Disorder Working Group,   Eating Disorders Working Group,   Major Depressive Disorder Working Group,   Nicotine Dependence GenOmics (iNDiGO) Consortium,   Obsessive-Compulsive Disorder Working Group,   Post-Traumatic Stress Disorder Working Group,   Schizophrenia Working Group,   Substance Use Disorders Working Group,   Tourette Syndrome Working Group, Lee Phil H , Kendler Kenneth S , Smoller Jordan W 
Published: January 2025

AbstractPsychiatric disorders display high levels of comorbidity and genetic overlap1,2. Genomic methods have shown that even for schizophrenia and bipolar disorder, two disorders long-thought to be etiologically distinct3, the majority of genetic signal is shared4. Furthermore, recent cross-disorder analyses have uncovered over a hundred pleiotropic loci shared across eight disorders5. However, the full scope of shared and disorder-specific genetic basis of psychopathology remains largely uncharted. Here, we address this gap by triangulating across a suite of cutting-edge statistical genetic and functional genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders (1,056,201 cases). Our analyses identify and characterize five underlying genomic factors6that explain the majority of the genetic variance of the individual disorders (∼66% on average) and are associated with 268 pleiotropic loci. We observed particularly high levels of polygenic overlap7and local genetic correlation8and very few disorder-specific loci9for two factors defined by: (i) schizophrenia and bipolar disorder (“SB factor”), and by (ii) major depression, PTSD, and anxiety (“internalizing factor”). At the functional level, we applied multiple methods10–12which demonstrated that 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. By comparison, the genetic signal shared across all 14 disorders was enriched for broad biological processes (e.g., transcriptional regulation). These results indicate increasing differentiation of biological function at different levels of shared cross-disorder risk, from quite general vulnerability to more specific pathways associated with subsets of disorders. These observations may inform a more neurobiologically valid psychiatric nosology and implicate novel targets for therapeutic developments designed to treat commonly occurring comorbid presentations.