Mapping the genetic landscape across 14 psychiatric disorders.
Grotzinger AD., Werme J., Peyrot WJ., Frei O., de Leeuw C., Bicks LK., Guo Q., Margolis MP., Coombes BJ., Batzler A., Pazdernik V., Biernacka JM., Andreassen OA., Anttila V., Børglum AD., Breen G., Cai N., Demontis D., Edenberg HJ., Faraone SV., Franke B., Gandal MJ., Gelernter J., Hatoum AS., Hettema JM., Johnson EC., Jonas KG., Knowles JA., Koenen KC., Maihofer AX., Mallard TT., Mattheisen M., Mitchell KS., Neale BM., Nievergelt CM., Nurnberger JI., O'Connell KS., Peterson RE., Robinson EB., Sanchez-Roige SS., Santangelo SL., Scharf JM., Stefansson H., Stefansson K., Stein MB., Strom NI., Thornton LM., Tucker-Drob EM., Verhulst B., Waldman ID., Walters GB., Wray NR., Yu D., Anxiety Disorders Working Group of the Psychiatric Genomics Consortium ., Attention-Deficit/Hyperactivity Disorder (ADHD) Working Group of the Psychiatric Genomics Consortium ., Autism Spectrum Disorders Working Group of the Psychiatric Genomics Consortium ., Bipolar Disorder Working Group of the Psychiatric Genomics Consortium ., Eating Disorders Working Group of the Psychiatric Genomics Consortium ., Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium ., Nicotine Dependence GenOmics (iNDiGO) Consortium ., Obsessive-Compulsive Disorder and Tourette Syndrome Working Group of the Psychiatric Genomics Consortium ., Post-Traumatic Stress Disorder Working Group of the Psychiatric Genomics Consortium ., Schizophrenia Working Group of the Psychiatric Genomics Consortium ., Substance Use Disorders Working Group of the Psychiatric Genomics Consortium ., Lee PH., Kendler KS., Smoller JW.
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.