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Genome wide meta-analysis identifies genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders

bioRxiv (Cold Spring Harbor Laboratory)2019

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Phil H. Lee, Verneri Anttila, Hyejung Won, Yen‐Chen Anne Feng, Jacob Rosenthal, Zhaozhong Zhu, Elliot M. Tucker–Drob, Michel G. Nivard, Andrew D. Grotzinger, Daniëlle Posthuma, Meg M.-J. Wang, Dongmei Yu, Eli Stahl, Raymond K. Walters, Richard Anney, Laramie E. Duncan, Síntia Belangero, Jurjen J. Luykx, Henry R. Kranzler, Anna Keski‐Rahkonen, Edwin H. Cook, George Kirov, Giovanni Coppola, Jaakko Kaprio, Clement C. Zai, Pieter J. Hoekstra, Tobias Banaschewski, Luís Augusto Rohde, PGC Attention Deficit Hyperactivity Disorder Group, PGC Autism Spectrum Disorder Group, PGC Bipolar Disorder Group, PGC Eating Disorders Group, PGC Major Depressive Disorder Group, PGC Obsessive Compulsive Disorder and Tourette Syndrome Group, PGC Schizophrenia Group, Patrick F. Sullivan, Barbara Franke, Mark J. Daly, Cynthia M. Bulik, Cathryn M. Lewis, Andrew M. McIntosh, Michael O’Donovan, Amanda B. Zheutlin, Ole A. Andreassen, Anders D. Børglum, Gerome Breen, Howard J. Edenberg, Ayman H. Fanous, Stephen V. Faraone, Joel Gelernter, Carol A. Mathews, Manuel Mattheisen, Karen S. Mitchell, Michael C. Neale, John I. Nürnberger, Stephan Ripke, Susan L. Santangelo, Jeremiah M. Scharf, Murray B. Stein, Laura M. Thornton, James Walters, Naomi R. Wray, Daniel H. Geschwind, Benjamin M. Neale, Kenneth S. Kendler, Jordan W. Smoller

Abstract

Summary 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 a meta-analysis 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. We 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 in the second trimester prenatally, and play prominent roles in a suite of neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.

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Abstract

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