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Interpreting the role of de novo protein-coding mutations in neuropsychiatric disease

Nature Genetics volume 45, pages 234238 (2013) | Download Citation

Abstract

Pedigree, linkage and association studies are consistent with heritable variation for complex disease due to the segregation of genetic factors in families and in the population. In contrast, de novo mutations make only minor contributions to heritability estimates for complex traits. Nonetheless, some de novo variants are known to be important in disease etiology. The identification of risk-conferring de novo variants will contribute to the discovery of etiologically relevant genes and pathways and may help in genetic counseling. There is considerable interest in the role of such mutations in complex neuropsychiatric disease, largely driven by new genotyping and sequencing technologies. An important role for large de novo copy number variations has been established. Recently, whole-exome sequencing has been used to extend the investigation of de novo variation to point mutations in protein-coding regions. Here, we consider several challenges for the interpretation of such mutations in the context of their role in neuropsychiatric disease.

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Acknowledgements

We acknowledge funding from the Australian Research Council to N.R.W. (FT0991360), the Australian National Health and Medical Research Council to P.M.V. (grants 613672, 613601 and 1011506), B.J.M. (grants 631406 and 631671) and N.R.W. (grant 613602, 613608) and Queensland Health to B.J.M.

Author information

Affiliations

  1. The University of Queensland, Queensland Brain Institute, Brisbane, Queensland, Australia.

    • Jacob Gratten
    • , Peter M Visscher
    • , Bryan J Mowry
    •  & Naomi R Wray
  2. The University of Queensland Diamantina Institute, Brisbane, Queensland, Australia.

    • Peter M Visscher
  3. Queensland Centre for Mental Health Research, Wacol, Queensland, Australia.

    • Bryan J Mowry

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Contributions

All authors conceived and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jacob Gratten.

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DOI

https://doi.org/10.1038/ng.2555

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