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Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders
Journal article   Open access   Peer reviewed

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

Phil H. Lee, Verneri Anttila, Hyejung Won, Yen-Chen A. Feng, Jacob Rosenthal, Zhaozhong Zhu, Elliot M. Tucker-Drob, Michel G. Nivard, Andrew D. Grotzinger, Danielle Posthuma, …
Cell, Vol.179(7), pp.1469-1482.e11
12/12/2019
DOI: 10.1016/j.cell.2019.11.020
PMCID: PMC7077032
PMID: 31835028
url
https://doi.org/10.1016/j.cell.2019.11.020View
Published (Version of record) Open Access

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. [Display omitted] •Three groups of highly genetically-related disorders among 8 psychiatric disorders•Identified 109 pleiotropic loci affecting more than one disorder•Pleiotropic genes show heightened expression beginning in 2nd prenatal trimester•Pleiotropic genes play prominent roles in neurodevelopmental processes Genome-wide analyses of eight different psychiatric disorders reveals common loci and shared genetic structures underlying many of them.
 cross-disorder genetics functional genomics gene expression genetic architecture genetic correlation GWAS neurodevelopment pleiotropy psychiatric disorders Psychiatric genetics

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