Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

Accession codes

Accessions

NCBI Reference Sequence

References

  1. Purcell, S.M. et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752 (2009).

    CAS  PubMed  Google Scholar 

  2. Stefansson, H. et al. Common variants conferring risk of schizophrenia. Nature 460, 744–747 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Stefansson, H. et al. Large recurrent microdeletions associated with schizophrenia. Nature 455, 232–236 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. McCarthy, S.E. et al. Microduplications of 16p11.2 are associated with schizophrenia. Nat. Genet. 41, 1223–1227 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cardno, A.G. & Gottesman, I.I. Twin studies of schizophrenia: from bow-and-arrow concordances to star wars Mx and functional genomics. Am. J. Med. Genet. 97, 12–17 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).

  7. Roach, J.C. et al. Analysis of genetic inheritance in a family quartet by whole-genome sequencing. Science 328, 636–639 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Awadalla, P. et al. Direct measure of the de novo mutation rate in autism and schizophrenia cohorts. Am. J. Hum. Genet. 87, 316–324 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kryukov, G.V., Pennacchio, L.A. & Sunyaev, S.R. Most rare missense alleles are deleterious in humans: implications for complex disease and association studies. Am. J. Hum. Genet. 80, 727–739 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Allen, N.C. et al. Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nat. Genet. 40, 827–834 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Jones, J.M. & Simkus, C. The roles of the RAG1 and RAG2 “non-core” regions in V(D)J recombination and lymphocyte development. Arch. Immunol. Ther. Exp. (Warsz.) 57, 105–116 (2009).

    Article  CAS  Google Scholar 

  13. Willerford, D.M., Swat, W. & Alt, F.W. Developmental regulation of V(D)J recombination and lymphocyte differentiation. Curr. Opin. Genet. Dev. 6, 603–609 (1996).

    Article  CAS  PubMed  Google Scholar 

  14. Shi, J. et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 460, 753–757 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Liu, Q. et al. Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1. Neuron 56, 66–78 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hollenbach, E., Ackermann, S., Hyman, B.T. & Rebeck, G.W. Confirmation of an association between a polymorphism in exon 3 of the low-density lipoprotein receptor-related protein gene and Alzheimer's disease. Neurology 50, 1905–1907 (1998).

    Article  CAS  PubMed  Google Scholar 

  17. Hadano, S. et al. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat. Genet. 29, 166–173 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Ng, P.C. & Henikoff, S. Predicting deleterious amino acid substitutions. Genome Res. 11, 863–874 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Adzhubei, I.A. et al. A method and server for predicting damaging missense mutations. Nat. Methods 7, 248–249 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Pollard, K.S., Hubisz, M.J., Rosenbloom, K.R. & Siepel, A. Detection of nonneutral substitution rates on mammalian phylogenies. Genome Res. 20, 110–121 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Grantham, R. Amino acid difference formula to help explain protein evolution. Science 185, 862–864 (1974).

    Article  CAS  PubMed  Google Scholar 

  22. Li, W.H., Wu, C.I. & Luo, C.C. Nonrandomness of point mutation as reflected in nucleotide substitutions in pseudogenes and its evolutionary implications. J. Mol. Evol. 21, 58–71 (1984).

    Article  CAS  PubMed  Google Scholar 

  23. Lynch, M. Rate, molecular spectrum, and consequences of human mutation. Proc. Natl. Acad. Sci. USA 107, 961–968 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Vissers, L.E. et al. A de novo paradigm for mental retardation. Nat. Genet. 42, 1109–1112 (2010).

    Article  CAS  PubMed  Google Scholar 

  25. Hamdan, F.F. et al. De novo mutations in FOXP1 in cases with intellectual disability, autism, and language impairment. Am. J. Hum. Genet. 87, 671–678 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hamdan, F.F. et al. Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation. N. Engl. J. Med. 360, 599–605 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Koboldt, D.C. et al. VarScan: variant detection in massively parallel sequencing of individual and pooled samples. Bioinformatics 25, 2283–2285 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang, K., Li, M. & Hakonarson, H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 38, e164 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

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.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–4 and Supplementary Figure 1 (PDF 767 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.886

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing