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Increased exonic de novo mutation rate in individuals with schizophrenia

Abstract

Schizophrenia is a severe psychiatric disorder that profoundly affects cognitive, behavioral and emotional processes. The wide spectrum of symptoms and clinical variability in schizophrenia suggest a complex genetic etiology, which is consistent with the numerous loci thus far identified by linkage, copy number variation and association studies1,2,3,4. Although schizophrenia heritability may be as high as 80%, the genes responsible for much of this heritability remain to be identified5. Here we sequenced the exomes of 14 schizophrenia probands and their parents. We identified 15 de novo mutations (DNMs) in eight probands, which is significantly more than expected considering the previously reported DNM rate6,7,8. In addition, 4 of the 15 identified DNMs are nonsense mutations, which is more than what is expected by chance9. Our study supports the notion that DNMs may account for some of the heritability reported for schizophrenia while providing a list of genes possibly involved in disease pathogenesis.

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Acknowledgements

Subjects were selected from the Psydev study, promoted by INSERM, through the Collaborative Network for Family Study in Psychiatry ('Réseau d'étude familiale en Psychiatry', REFAPSY), supported by the Fondation Pierre Deniker. We wish to thank S. Bannour, M.-J. Dos Santos, M.A. Gorsane, N. Benjemaa, M. Chayet, S. Leroy, F. Mouaffak, K. Ossian and F. Polides for participating in recruitment of subjects and for their technical help. This work was supported by Genome Canada and Génome Québec and received co-funding from Université de Montréal for the Synapse to Disease (S2D) project as well as funding from the Canadian Foundation for Innovation, Brain & Behavior Research Foundation. Bioinformatic analysis was supported by a Canadian Institutes of Health Research (CIHR) Team grant (RMF92086). G.A.R. is grateful for the support received through his positions as Canada Research Chair in Genetics of the Nervous System and Jeanne-et-J.-Louis-Levesque Chair for the Genetics of Brain Diseases. N. Jaafari was supported by an award, bourse chercheur invité, of the Région Poitou-Charente.

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Contributions

J.G., L.X., S.L.G. and G.A.R. designed the study. M.-O.K., L.X., B.M., R.J. and N.J. recruited cases and collected clinical information. I.B. and A.H.Y.T. performed exome capture and sequencing. S.L.G., D.S., J.Y.J.B. and C.-H.L. performed alignments and variant detection. A.N., S.Z., L.J., S.L.G. and P.T. performed variant validation. S.L.G., A.D.-L., D.S., E.H., O.D., A.H.Y.T., J.Y.J.B., C.-H.L. and S.L. performed bioinformatic analyses. S.L.G., P.A.D., M.-O.K., S.L. and G.A.R. wrote the paper.

Corresponding author

Correspondence to Guy A Rouleau.

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The authors declare no competing financial interests.

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Girard, S., Gauthier, J., Noreau, A. et al. Increased exonic de novo mutation rate in individuals with schizophrenia. Nat Genet 43, 860–863 (2011). https://doi.org/10.1038/ng.886

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