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Nat Genet. 2017 Aug;49(8):1167-1173. doi: 10.1038/ng.3903. Epub 2017 Jun 26.

The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability.

Author information

1
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
2
MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
3
Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK.
4
University College London Genetics Institute, University College London, London, UK.
5
Centre for Psychiatry, Barts and the London School of Medicine and Dentistry, London, UK.
6
National Institute for Health and Welfare, Helsinki, Finland.
7
Institute of Psychiatry, King's College London, London, UK.
8
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
9
Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
10
Division of Psychiatry, University College London, London, UK.
11
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
12
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
13
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
14
Program in Medical and Population Genetics and Genetic Analysis Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
15
Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, North Carolina, USA.

Abstract

By performing a meta-analysis of rare coding variants in whole-exome sequences from 4,133 schizophrenia cases and 9,274 controls, de novo mutations in 1,077 family trios, and copy number variants from 6,882 cases and 11,255 controls, we show that individuals with schizophrenia carry a significant burden of rare, damaging variants in 3,488 genes previously identified as having a near-complete depletion of loss-of-function variants. In patients with schizophrenia who also have intellectual disability, this burden is concentrated in risk genes associated with neurodevelopmental disorders. After excluding known risk genes for neurodevelopmental disorders, a significant rare variant burden persists in other genes intolerant of loss-of-function variants; although this effect is notably stronger in patients with both schizophrenia and intellectual disability, it is also seen in patients with schizophrenia who do not have intellectual disability. Together, our results show that rare, damaging variants contribute to the risk of schizophrenia both with and without intellectual disability and support an overlap of genetic risk between schizophrenia and other neurodevelopmental disorders.

PMID:
28650482
PMCID:
PMC5533219
DOI:
10.1038/ng.3903
[Indexed for MEDLINE]
Free PMC Article

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