A polygenic burden of rare disruptive mutations in schizophrenia

Shaun M. Purcell (), Jennifer L. Moran, Menachem Fromer, Douglas Ruderfer, Nadia Solovieff, Panos Roussos, Colm O’Dushlaine, Kimberly Chambert, Sarah E. Bergen, Anna Kähler, Laramie Duncan, Eli Stahl, Giulio Genovese, Esperanza Fernández, Mark O. Collins, Noboru H. Komiyama, Jyoti S. Choudhary, Patrik K. E. Magnusson, Eric Banks, Khalid Shakir, Kiran Garimella, Tim Fennell, Mark DePristo, Seth G. N. Grant, Stephen J. Haggarty, Stacey Gabriel, Edward M. Scolnick, Eric S. Lander, Christina M. Hultman, Patrick F. Sullivan, Steven A. McCarroll and Pamela Sklar
Additional contact information
Shaun M. Purcell: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
Jennifer L. Moran: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
Menachem Fromer: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
Douglas Ruderfer: Icahn School of Medicine at Mount Sinai
Nadia Solovieff: Analytic and Translational Genetics Unit, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital
Panos Roussos: Icahn School of Medicine at Mount Sinai
Colm O’Dushlaine: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
Kimberly Chambert: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
Sarah E. Bergen: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
Anna Kähler: Karolinska Institutet, Stockholm SE-171 77, Sweden
Laramie Duncan: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
Eli Stahl: Icahn School of Medicine at Mount Sinai
Giulio Genovese: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
Esperanza Fernández: Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium
Mark O. Collins: Proteomic Mass Spectrometry, The Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK
Noboru H. Komiyama: Proteomic Mass Spectrometry, The Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK
Jyoti S. Choudhary: Proteomic Mass Spectrometry, The Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK
Patrik K. E. Magnusson: Karolinska Institutet, Stockholm SE-171 77, Sweden
Eric Banks: Medical and Population Genetics Program, Broad Institute of MIT and Harvard
Khalid Shakir: Medical and Population Genetics Program, Broad Institute of MIT and Harvard
Kiran Garimella: Medical and Population Genetics Program, Broad Institute of MIT and Harvard
Tim Fennell: Medical and Population Genetics Program, Broad Institute of MIT and Harvard
Mark DePristo: Medical and Population Genetics Program, Broad Institute of MIT and Harvard
Seth G. N. Grant: Genes to Cognition Programme, Centre for Clinical Brain Sciences and Centre for Neuroregeneration, The University of Edinburgh, Edinburgh EH16 4SB, UK
Stephen J. Haggarty: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
Stacey Gabriel: Medical and Population Genetics Program, Broad Institute of MIT and Harvard
Edward M. Scolnick: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
Eric S. Lander: Medical and Population Genetics Program, Broad Institute of MIT and Harvard
Christina M. Hultman: Karolinska Institutet, Stockholm SE-171 77, Sweden
Patrick F. Sullivan: University of North Carolina, Chapel Hill, North Carolina 27599-7264, USA
Steven A. McCarroll: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
Pamela Sklar: Icahn School of Medicine at Mount Sinai

Nature, 2014, vol. 506, issue 7487, 185-190

Abstract: Abstract Schizophrenia is a common disease with a complex aetiology, probably involving multiple and heterogeneous genetic factors. Here, by analysing the exome sequences of 2,536 schizophrenia cases and 2,543 controls, we demonstrate a polygenic burden primarily arising from rare (less than 1 in 10,000), disruptive mutations distributed across many genes. Particularly enriched gene sets include the voltage-gated calcium ion channel and the signalling complex formed by the activity-regulated cytoskeleton-associated scaffold protein (ARC) of the postsynaptic density, sets previously implicated by genome-wide association and copy-number variation studies. Similar to reports in autism, targets of the fragile X mental retardation protein (FMRP, product of FMR1) are enriched for case mutations. No individual gene-based test achieves significance after correction for multiple testing and we do not detect any alleles of moderately low frequency (approximately 0.5 to 1 per cent) and moderately large effect. Taken together, these data suggest that population-based exome sequencing can discover risk alleles and complements established gene-mapping paradigms in neuropsychiatric disease.

Date: 2014
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DOI: 10.1038/nature12975

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