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Genetic architecture of 11 major psychiatric disorders at biobehavioral, functional genomic and molecular genetic levels of analysis

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  • Andrew D. Grotzinger, University of Colorado Boulder
  • ,
  • Travis T. Mallard, University of Texas at Austin
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  • Wonuola A. Akingbuwa, Vrije Universiteit Amsterdam, University of Amsterdam
  • ,
  • Hill F. Ip, Vrije Universiteit Amsterdam
  • ,
  • Mark J. Adams, University of Edinburgh
  • ,
  • Cathryn M. Lewis, King's College London
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  • Andrew M. McIntosh, University of Edinburgh
  • ,
  • Jakob Grove
  • Søren Dalsgaard
  • Klaus Peter Lesch, University of Würzburg, Sechenov First Moscow State Medical University, Maastricht University
  • ,
  • Nora Strom, Humboldt University of Berlin, Karolinska Institutet, LMU Munich
  • ,
  • Sandra M. Meier
  • Manuel Mattheisen, Karolinska Institutet, Dalhousie University, Faculty of Medicine, LMU Munchen, iSEQ - Centre for Integrative Sequencing
  • ,
  • Anders D. Børglum
  • Ole Mors
  • Gerome Breen, King's College London
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  • iPSYCH
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  • Tourette Syndrome and Obsessive Compulsive Disorder Working Group of the Psychiatric Genetics Consortium
  • ,
  • Bipolar Disorder Working Group of the Psychiatric Genetics Consortium
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  • Major Depressive Disorder Working Group of the Psychiatric Genetics Consortium
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  • Schizophrenia Working Group of the Psychiatric Genetics Consortium
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  • Phil H. Lee, Harvard University
  • ,
  • Kenneth S. Kendler, Virginia Commonwealth University
  • ,
  • Jordan W. Smoller, Harvard University
  • ,
  • Elliot M. Tucker-Drob, University of Texas at Austin
  • ,
  • Michel G. Nivard, Vrije Universiteit Amsterdam

We interrogate the joint genetic architecture of 11 major psychiatric disorders at biobehavioral, functional genomic and molecular genetic levels of analysis. We identify four broad factors (neurodevelopmental, compulsive, psychotic and internalizing) that underlie genetic correlations among the disorders and test whether these factors adequately explain their genetic correlations with biobehavioral traits. We introduce stratified genomic structural equation modeling, which we use to identify gene sets that disproportionately contribute to genetic risk sharing. This includes protein-truncating variant-intolerant genes expressed in excitatory and GABAergic brain cells that are enriched for genetic overlap across disorders with psychotic features. Multivariate association analyses detect 152 (20 new) independent loci that act on the individual factors and identify nine loci that act heterogeneously across disorders within a factor. Despite moderate-to-high genetic correlations across all 11 disorders, we find little utility of a single dimension of genetic risk across psychiatric disorders either at the level of biobehavioral correlates or at the level of individual variants.

Original languageEnglish
JournalNature Genetics
Volume54
Issue5
Pages (from-to)548-559
Number of pages12
ISSN1061-4036
DOIs
Publication statusPublished - May 2022

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© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

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