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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Veröffentlicht in:	Molecular psychiatry Jg. 19; H. 6; S. 652 - 658
Hauptverfasser:	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
Sprache:	Englisch
Veröffentlicht:	London Nature Publishing Group UK 01.06.2014 Nature Publishing Group
Schlagworte:	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
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Zusammenfassung:	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.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1359-4184 1476-5578 1476-5578
DOI:	10.1038/mp.2014.29