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 sporad...

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Bibliographic Details
Published in:Molecular psychiatry Vol. 19; no. 6; pp. 652 - 658
Main Authors: McCarthy, S E, Gillis, J, Kramer, M, Lihm, J, Yoon, S, Berstein, Y, Mistry, M, Pavlidis, P, Solomon, R, Ghiban, E, Antoniou, E, Kelleher, E, O'Brien, C, Donohoe, G, Gill, M, Morris, D W, McCombie, W R, Corvin, A
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 01.06.2014
Nature Publishing Group
Subjects:
692/420/2489/144
692/699/476/1373
692/699/476/1799
Adolescent
Adult
Adult and adolescent clinical studies
Autism
Autistic Disorder - genetics
Behavioral Sciences
Biological and medical sciences
Biological Psychology
Child clinical studies
Chromatin Assembly and Disassembly - genetics
Chromatin remodeling
Codon, Nonsense
Cognition
Developmental disorders
DNA Mutational Analysis
Epigenetics
Etiology
Exome
Family
Female
Gene mutations
Gene regulation
Genetic aspects
Genetic diversity
Genetic Predisposition to Disease
Genetic research
Genetic susceptibility
Haploinsufficiency
Humans
Huwe1 protein
Identification and classification
immediate-communication
Infantile autism
Intellectual deficiency
Intellectual disabilities
Intellectual Disability - genetics
Male
MeCP2 protein
Medical sciences
Medicine
Medicine & Public Health
Mental disorders
Methyl-CpG binding protein
Middle Aged
Mutation
Neurodevelopmental disorders
Neurosciences
Pharmacotherapy
Psychiatry
Psychology. Psychoanalysis. Psychiatry
Psychopathology. Psychiatry
Psychoses
Schizophrenia
Schizophrenia - genetics
Transcription
Young Adult
Psychosis
Handicap
Autism
Chromatin
Intellectual deficiency
Schizophrenia
Genetics
Developmental disorder
Mutation
Mental retardation
ISSN:1359-4184, 1476-5578, 1476-5578
Online Access:Get full text
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Summary: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.
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ISSN:1359-4184
1476-5578
1476-5578
DOI:10.1038/mp.2014.29