Multivariate GWAS of psychiatric disorders and their cardinal symptoms reveal two dimensions of cross-cutting genetic liabilities
Travis T. Mallard,
Richard Karlsson Linnér,
Andrew D. Grotzinger,
Sandra Sanchez-Roige,
Jakob Seidlitz,
Aysu Okbay,
Ronald de Vlaming,
S. Fleur W. Meddens,
Abraham A. Palmer,
Lea K. Davis,
Elliot M. Tucker-Drob,
Kenneth S. Kendler,
Matthew C. Keller,
Philipp D. Koellinger,
K. Paige Harden
Affiliations
Travis T. Mallard
Department of Psychology, University of Texas at Austin, Austin, TX, USA; Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Corresponding author
Richard Karlsson Linnér
Department of Economics, School of Business and Economics, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; Autism and Developmental Medicine Institute, Geisinger, Lewisburg, PA, USA
Andrew D. Grotzinger
Department of Psychology, University of Texas at Austin, Austin, TX, USA
Sandra Sanchez-Roige
Department of Psychiatry, University of California San Diego, La Jolla, CA, USA; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Jakob Seidlitz
Department of Child and Adolescent Psychiatry and Behavioral Science, Children’s Hospital of Philadelphia, Philadelphia, PA, USA; Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA
Aysu Okbay
Department of Economics, School of Business and Economics, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
Ronald de Vlaming
Department of Economics, School of Business and Economics, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
S. Fleur W. Meddens
Erasmus University Rotterdam Institute for Behavior and Biology, Erasmus School of Economics, Erasmus University Rotterdam, Rotterdam, the Netherlands
Abraham A. Palmer
Department of Psychiatry, University of California San Diego, La Jolla, CA, USA; Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA
Lea K. Davis
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA
Elliot M. Tucker-Drob
Department of Psychology, University of Texas at Austin, Austin, TX, USA; Population Research Center, University of Texas at Austin, Austin, TX, USA
Kenneth S. Kendler
Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA; Department of Psychiatry, Medical College of Virginia/Virginia Commonwealth University, Richmond, VA, USA
Matthew C. Keller
Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA; Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA
Philipp D. Koellinger
Department of Economics, School of Business and Economics, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
K. Paige Harden
Department of Psychology, University of Texas at Austin, Austin, TX, USA; Population Research Center, University of Texas at Austin, Austin, TX, USA; Corresponding author
Summary: Understanding which biological pathways are specific versus general across diagnostic categories and levels of symptom severity is critical to improving nosology and treatment of psychopathology. Here, we combine transdiagnostic and dimensional approaches to genetic discovery for the first time, conducting a novel multivariate genome-wide association study of eight psychiatric symptoms and disorders broadly related to mood disturbance and psychosis. We identify two transdiagnostic genetic liabilities that distinguish between common forms of psychopathology versus rarer forms of serious mental illness. Biological annotation revealed divergent genetic architectures that differentially implicated prenatal neurodevelopment and neuronal function and regulation. These findings inform psychiatric nosology and biological models of psychopathology, as they suggest that the severity of mood and psychotic symptoms present in serious mental illness may reflect a difference in kind rather than merely in degree.
