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Nature. 2014 Feb 13;506(7487):185-90. doi: 10.1038/nature12975. Epub 2014 Jan 22.

A polygenic burden of rare disruptive mutations in schizophrenia.

Author information

1
1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [3] Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [4] Analytic and Translational Genetics Unit, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA [5] Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
2
1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2].
3
1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [3] Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [4] Analytic and Translational Genetics Unit, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA [5].
4
1] Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2] Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [3].
5
Analytic and Translational Genetics Unit, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
6
1] Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2] Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
7
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
8
1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-171 77, Sweden.
9
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-171 77, Sweden.
10
1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Analytic and Translational Genetics Unit, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA [3] Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
11
1] Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium [2] VIB Center for Biology of Disease, 3000 Leuven, Belgium.
12
Proteomic Mass Spectrometry, The Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
13
Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
14
Genes to Cognition Programme, Centre for Clinical Brain Sciences and Centre for Neuroregeneration, The University of Edinburgh, Edinburgh EH16 4SB, UK.
15
1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Analytic and Translational Genetics Unit, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA [3] Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
16
Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, North Carolina 27599-7264, USA.
17
1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [3] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
18
1] Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2] Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [3] Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.

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.

Comment in

PMID:
24463508
PMCID:
PMC4136494
DOI:
10.1038/nature12975
[Indexed for MEDLINE]
Free PMC Article

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