Mapping the genetic landscape across 14 psychiatric disorders

Abstract

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 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.

Affiliated Institutions

• VA San Diego Healthcare System US
• Harvard University US
• University of Utah US
• Helsinki University Hospital FI
• University of California, Los Angeles US
• Huntsman Cancer Institute US
• King's College London GB
• Yale University US
• Helmholtz Zentrum München DE
• Indiana University – Purdue University Indianapolis US
• Virginia Commonwealth University US
• University of Toronto CA
• Charité - Universitätsmedizin Berlin DE
• University of Pennsylvania US
• Norwegian University of Science and Technology
• University of Oslo
• Broad Institute US
• University of North Carolina at Chapel Hill US
• Technical University of Munich DE
• Ludwig-Maximilians-Universität München DE
• Karolinska Institutet SE
• University of Edinburgh GB
• The University of Texas at Austin US
• Stellenbosch University ZA
• Massachusetts General Hospital US
• deCODE Genetics (Iceland) IS
• The University of Queensland AU
• University of Duisburg-Essen DE
• Institute for Molecular Medicine Finland FI
• Lundbeck Foundation DK
• Queensland University of Technology AU
• University of Cape Town ZA
• QIMR Berghofer Medical Research Institute AU
• University of Freiburg DE
• Imperial College London GB
• Amsterdam Neuroscience NL
• University of Helsinki FI
• Dalhousie University CA
• Huntsman (United States) US
• Vrije Universiteit Amsterdam NL
• Norwegian Institute of Public Health
• The University of Sydney AU
• Philipps University of Marburg DE
• Lifespan US
• Texas A&M University US
• University of Würzburg DE
• Aarhus University DK
• Mayo Clinic in Florida US
• University Medical Center Freiburg DE
• Örebro University SE
• Emory University US
• Sørlandet Sykehus
• Max Planck Institute of Psychiatry DE
• Boston University US
• University of Oxford GB
• University of Colorado Boulder US
• Erasmus MC NL
• Stockholm Health Care Services SE
• University of Iceland IS
• Children's Hospital of Philadelphia US
• Tufts University US
• Oslo University Hospital
• SUNY Downstate Health Sciences University US
• South African Medical Research Council ZA
• Indiana University School of Medicine
• University of Mannheim DE
• ETH Zurich CH
• Universidade Federal de São Paulo BR
• University of California, San Diego US
• VA Connecticut Healthcare System US
• Forschungszentrum Jülich DE
• University of Tartu EE
• Radboud University Medical Center NL
• Rutgers, The State University of New Jersey US
• Washington University in St. Louis US
• Stony Brook University US
• Radboud University Nijmegen NL
• University of Lausanne CH
• University of Vermont US
• SUNY Upstate Medical University US

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