Letter | Published:

Brain-expressed exons under purifying selection are enriched for de novo mutations in autism spectrum disorder

Nature Genetics volume 46, pages 742747 (2014) | Download Citation

Abstract

A universal challenge in genetic studies of autism spectrum disorders (ASDs) is determining whether a given DNA sequence alteration will manifest as disease. Among different population controls, we observed, for specific exons, an inverse correlation between exon expression level in brain and burden of rare missense mutations. For genes that harbor de novo mutations predicted to be deleterious, we found that specific critical exons were significantly enriched in individuals with ASD relative to their siblings without ASD (P < 1.13 × 10−38; odds ratio (OR) = 2.40). Furthermore, our analysis of genes with high exonic expression in brain and low burden of rare mutations demonstrated enrichment for known ASD-associated genes (P < 3.40 × 10−11; OR = 6.08) and ASD-relevant fragile-X protein targets (P < 2.91 × 10−157; OR = 9.52). Our results suggest that brain-expressed exons under purifying selection should be prioritized in genotype-phenotype studies for ASD and related neurodevelopmental conditions.

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Acknowledgements

We thank the Centre for Applied Genomics for informatics support, the Allen Institute of Brain Science, the National Heart, Lung, and Blood Institute (NHLBI) and the Autism Genome Project for sharing data. We thank J. Buchanan for critical review and editing of the manuscript. This work was supported by grants from the University of Toronto McLaughlin Centre, NeuroDevNet, Genome Canada and the Ontario Genomics Institute (project 4445), the Canadian Institutes for Health Research (CIHR) (FRN 74527 and FRNXGG818), the Canadian Institute for Advanced Research, the Canada Foundation for Innovation, the government of Ontario (GL2-01-013), the Ontario Brain Institute and Autism Speaks. R.K.C.Y. holds an Autism Speaks Meixner Fellowship in Translational Research. K.T. holds a fellowship from the Swedish Research Council. S.W.S. holds the GlaxoSmithKline-CIHR Chair in Genome Sciences at the University of Toronto and the Hospital for Sick Children.

Author information

Affiliations

  1. The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.

    • Mohammed Uddin
    • , Kristiina Tammimies
    • , Giovanna Pellecchia
    • , Pingzhao Hu
    • , Zhuozhi Wang
    • , Lynette Lau
    • , Thomas Nalpathamkalam
    • , Christian R Marshall
    • , Daniele Merico
    • , Ryan K C Yuen
    •  & Stephen W Scherer
  2. Center of Neurodevelopmental Disorders (KIND), Neuropsychiatric Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.

    • Kristiina Tammimies
  3. Department of Electrical and Computer Engineering, University of Toronto, Toronto, Ontario, Canada.

    • Babak Alipanahi
    •  & Brendan J Frey
  4. Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Dalila Pinto
  5. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Dalila Pinto
  6. Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Dalila Pinto
  7. McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada.

    • Christian R Marshall
    •  & Stephen W Scherer
  8. Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.

    • Benjamin J Blencowe
    •  & Brendan J Frey
  9. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.

    • Benjamin J Blencowe
    •  & Stephen W Scherer

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Contributions

M.U. and S.W.S. conceived the project, designed its components and contributed to the original concept of the project. K.T. performed quantitative PCR and RT-PCR analysis on brain tissues. M.U., G.P., D.M., P.H., R.K.C.Y., Z.W., D.P., L.L., T.N. and C.R.M. helped perform different components of the transcriptome and exome mutation analyses. M.U., G.P. and D.M. designed and performed the pathway analysis. B.A., B.J.F. and B.J.B. conducted the splicing code analysis. M.U., K.T. and S.W.S. coordinated the entire study and wrote the manuscript.

Competing interests

The concept of an exon transcriptome-mutation contingency index for autism diagnosis has been filed under reference H8312944USP (US provisional application number 61/892920) with the US Patent and Trademark Office.

Corresponding author

Correspondence to Stephen W Scherer.

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    Supplementary Note, Supplementary Figures 1–21 and Supplementary Tables 1–3, 5, 6 and 10

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About this article

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DOI

https://doi.org/10.1038/ng.2980

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