De novo mutations in schizophrenia implicate chromatin remodeling and support a genetic overlap with autism and intellectual disability.
Schizophrenia is a serious psychiatric disorder with a broadly undiscovered genetic etiology. Recent studies of de novo mutations (DNMs) in schizophrenia and autism have reinforced the hypothesis that rare genetic variation contributes to risk. We carried out exome sequencing on 57 trios with sporadic or familial schizophrenia. In sporadic trios, we observed a ~3.5-fold increase in the proportion of nonsense DNMs (0.101 vs 0.031, empirical P=0.01, Benjamini-Hochberg-corrected P=0.044). These mutations were significantly more likely to occur in genes with highly ranked probabilities of haploinsufficiency (P=0.0029, corrected P=0.006). DNMs of potential functional consequence were also found to occur in genes predicted to be less tolerant to rare variation (P=2.01 × 10(-)(5), corrected P=2.1 × 10(-)(3)). Genes with DNMs overlapped with genes implicated in autism (for example, AUTS2, CHD8 and MECP2) and intellectual disability (for example, HUWE1 and TRAPPC9), supporting a shared genetic etiology between these disorders. Functionally CHD8, MECP2 and HUWE1 converge on epigenetic regulation of transcription suggesting that this may be an important risk mechanism. Our results were consistent in an analysis of additional exome-based sequencing studies of other neurodevelopmental disorders. These findings suggest that perturbations in genes, which function in the epigenetic regulation of brain development and cognition, could have a central role in the susceptibility to, pathogenesis and treatment of mental disorders.
The Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
S E
SE
McCarthy
The Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
J
J
Gillis
The Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
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M
Kramer
The Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
J
J
Lihm
The Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
S
S
Yoon
The Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
Y
Y
Berstein
Department of Psychiatry and Centre for High-throughput Biology, The University of British Columbia, Vancouver, BC, Canada.
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M
Mistry
Department of Psychiatry and Centre for High-throughput Biology, The University of British Columbia, Vancouver, BC, Canada.
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P
Pavlidis
The Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
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R
Solomon
The Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
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E
Ghiban
The Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
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E
Antoniou
Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland.
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E
Kelleher
Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland.
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C
O'Brien
Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland.
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G
Donohoe
Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland.
M
M
Gill
Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland.
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DW
Morris
1] The Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA [2] The Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
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WR
McCombie
Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland.
A
A
Corvin
D000293:Adolescent; D000328:Adult; D001321:Autistic Disorder / Q000235:genetics; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D059472:Exome; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D057895:Haploinsufficiency; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012559:Schizophrenia / Q000235:genetics*; D055815:Young Adult
D018389:Codon, Nonsense