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De novo mutations in schizophrenia implicate chromatin remodeling and support a genetic overlap with autism and intellectual disability

Abstract

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 × 105, corrected P=2.1 × 103). 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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Acknowledgements

We would like to thank Stephanie Muller, Gloria Cheang, Senem Mavruk, Manasa Kolli, Nabil Azamy, Anthony DeSantis and Patricia Mocombe for contributing their expertise and help to perform exome capture, sequencing, validations and genotyping. We are grateful to Elodie Portales-Casamar for assistance with Neurocarta. We thank Jianchao Yao for helpful discussion and feedback. Funding for this study was provided by grants from T and V Stanley to SEM, JG, MK, JL, SY, YB, RS, EG, EA and WRM and from Science Foundation Ireland (08/IN.1/B1916) to AC, MG and DWM. PP was supported by NIH Grant GM076990 and salary awards from the Michael Smith Foundation for Health Research and the Canadian Institutes for Health Research. We thank James Watson for his constant support and encouragement.

Author Contributions

SEM, WRM and AC designed the study. DWM, EK, CO'B, GD, MG and AC collected all genomic DNA samples for the study. AC made the final diagnoses. MK, RS, EG and EA organized and performed exome capture, sequencing, data handling and validation genotyping. MM and PP provided data from Neurocarta and co-expression meta-analysis data. SEM, JG, JL and SY performed the analysis. SEM, JG, SY, RS, WRM and AC wrote the paper with comments and critique from all co-authors.

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Correspondence to S E McCarthy, W R McCombie or A Corvin.

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WRM has participated in Illumina sponsored meetings over the past 4 years and received travel reimbursement and an honorarium for presenting at these events. Illumina had no role in decisions relating to the study/work to be published, data collection and analysis of data and the decision to publish. WRM has participated in Pacific Biosciences sponsored meetings over the past 3 years and received travel reimbursement for presenting at these events. WRM is a founder and share holder of Orion Genomics, which focuses on plant genomics and cancer genetics.

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McCarthy, S., Gillis, J., Kramer, M. et al. De novo mutations in schizophrenia implicate chromatin remodeling and support a genetic overlap with autism and intellectual disability. Mol Psychiatry 19, 652–658 (2014). https://doi.org/10.1038/mp.2014.29

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