Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Cross-Disorder Group of the Psychiatric Genomics Consortium, Phil H Lee, Verneri Anttila, Hyejung Won, Y. Feng, Jacob Rosenthal, Z. Zhu, Elliot M Tucker-Drob, Michel G. Nivard, Andrew D. Grotzinger, Danielle Posthuma, E.M. Derks, M.C.T. op Landt Slof, D.I. Boomsma, Eco J.C. de Geus, Jouke Jan Hottenga, Hamdi Mbarek, C.M. Middeldorp, Brenda W J H Penninx, Danielle C CathDamiaan Denys, Susan Santangelo, Jeremiah M Scharf, Murray B Stein, L.M. Thornton, James T R Walters, Naomi R Wray, Daniel H. Geschwind, Benjamin M Neale, Kenneth S Kendler, Jordan W Smoller

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.

Original languageEnglish
Pages (from-to)1469-1482.e11
Number of pages26
JournalCell
Volume179
Issue number7
DOIs
Publication statusPublished - 12 Dec 2019

Bibliographical note

Copyright © 2019 Elsevier Inc. All rights reserved.

Keywords

  • cross-disorder genetics
  • functional genomics
  • gene expression
  • genetic architecture
  • genetic correlation
  • GWAS
  • neurodevelopment
  • pleiotropy
  • psychiatric disorders
  • Psychiatric genetics

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    Cross-Disorder Group of the Psychiatric Genomics Consortium, Lee, P. H., Anttila, V., Won, H., Feng, Y., Rosenthal, J., ... Smoller, J. W. (2019). Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders. Cell, 179(7), 1469-1482.e11. https://doi.org/10.1016/j.cell.2019.11.020