Genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders

Lee, Phil H., Anttila, Verneri, Won, Hyejung, Feng, Yen-Chen A., Rosenthal, Jacob, Zhu, Zhaozhong, Tucker-Drob, Elliot M., Nivard, Michel G., Grotzinger, Andrew D., Posthuma, Danielle, Wang, Meg M.-J., Yu, Dongmei, Stahl, Eli A., Walters, Raymond K. ORCID: https://orcid.org/0000-0002-6980-4053, Anney, Richard J. L. 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ORCID: https://orcid.org/0000-0001-7073-2379, Zheutlin, Amanda, Andreassen, Ole A., Børglum, Anders D., Breen, Gerome, Edenberg, Howard J., Fanous, Ayman H., Faraone, Stephen V., Gelernter, Joel, Mathews, Carol A., Mattheisen, Manuel, Mitchell, Karen S., Neale, Michael C., Nurnberger, John I., Ripke, Stephan, Santangelo, Susan L., Scharf, Jeremiah M., Stein, Murray B., Thornton, Laura M., Walters, James T. R. ORCID: https://orcid.org/0000-0002-6980-4053, Wray, Naomi R., Geschwind, Daniel H., Neale, Benjamin M., Kendler, Kenneth S. and Smoller, Jordan W. 2019. Genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders. Cell 179 (7) , 1469-1482.e11. 10.1016/j.cell.2019.11.020

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information:	Cross-Disorder Group of the Psychiatric Genomics Consortium
Publisher:	Elsevier
ISSN:	0092-8674
Date of First Compliant Deposit:	4 February 2020
Date of Acceptance:	14 November 2019
Last Modified:	07 Nov 2024 00:00
URI:	https://orca.cardiff.ac.uk/id/eprint/129324

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