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Allele-specific expression reveals interactions between genetic variation and environment

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Abstract

Identifying interactions between genetics and the environment (GxE) remains challenging. We have developed EAGLE, a hierarchical Bayesian model for identifying GxE interactions based on associations between environmental variables and allele-specific expression. Combining whole-blood RNA-seq with extensive environmental annotations collected from 922 human individuals, we identified 35 GxE interactions, compared with only four using standard GxE interaction testing. EAGLE provides new opportunities for researchers to identify GxE interactions using functional genomic data.

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Figure 1: EAGLE associates allele-specific expression (ASE) with environmental covariates to detect GxE interactions.
Figure 2: EAGLE detects GxE interactions missed by standard interaction QTL testing.
Figure 3: EAGLE detects allele-specific effects of direct perturbations and environments measured by 'proxy' genes.

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Gene Expression Omnibus

Sequence Read Archive

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Acknowledgements

We would like to thank J. Leek for helpful comments and S. Kersten for providing the graphic from which the PPARα network figure was adapted. D.A.K. is supported by NIH U54CA149145. M.-J.F. is supported by a CIHR Neuroinflammation fellowship. P.A. is supported by the Ontario Ministry of Research and Innovation. A.B. and S.B.M. are supported by NIH R01MH101814 and NIH R01HG008150. A.B. is supported by the Searle Scholars Program, NIH R01MH101820, NIH 1R01MH109905-01, and NIH 1R01GM120167-010. S.B.M. is supported by the Edward Mallinckrodt Jr. Foundation.

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Authors and Affiliations

  1. Department of Genetics, Stanford University School of Medicine, Stanford, California, USA

    David A Knowles, Joe R Davis, Anil Raj & Stephen B Montgomery

  2. Department of Radiology, Stanford University School of Medicine, Stanford, California, USA

    David A Knowles

  3. Ontario Institute for Cancer Research, Toronto, Ontario, Canada

    Hilary Edgington, Marie-Julie Favé & Philip Awadalla

  4. University of Toronto, Toronto, Ontario, Canada

    Hilary Edgington & Philip Awadalla

  5. CHU Sainte Justine, Montréal, Quebec, Canada

    Marie-Julie Favé & Philip Awadalla

  6. Department of Psychiatry, Stanford University School of Medicine, Stanford, California, USA

    Xiaowei Zhu & Douglas F Levinson

  7. Department of Psychiatry, University of Iowa Hospitals & Clinics, Iowa City, Iowa, USA

    James B Potash

  8. Department of Psychiatry, Columbia University and New York State Psychiatric Institute, New York, New York, USA

    Myrna M Weissman

  9. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA

    Jianxin Shi

  10. Department of Statistics, University of British Columbia, Vancouver, British Columbia, Canada

    Sara Mostafavi

  11. Department of Pathology, Stanford University School of Medicine, Stanford, California, USA

    Stephen B Montgomery

  12. Department of Computer Science, Johns Hopkins University, Baltimore, Maryland, USA

    Alexis Battle

Authors
  1. David A Knowles
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  2. Joe R Davis
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  3. Hilary Edgington
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  4. Anil Raj
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  5. Marie-Julie Favé
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  6. Xiaowei Zhu
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  7. James B Potash
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  8. Myrna M Weissman
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  9. Jianxin Shi
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  10. Douglas F Levinson
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  11. Philip Awadalla
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  12. Sara Mostafavi
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  13. Stephen B Montgomery
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  14. Alexis Battle
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Contributions

D.A.K., S.B.M. and A.B. conceived the project and wrote the manuscript. D.A.K. and A.B. developed the method. D.A.K. implemented the software and performed the main analyses. J.R.D. and A.R. performed additional statistical analyses. X.Z., J.B.P., M.M.W., J.S., S.M. and D.F.L. gave input regarding the DGN cohort. Supervised by P.A. and M.-J.F., H.E. ran EAGLE on the CARTaGENE replication cohort. S.B.M. and A.B. supervised the project.

Corresponding authors

Correspondence to Stephen B Montgomery or Alexis Battle.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–14, Supplementary Tables 1–4 and Supplementary Notes 1–11. (PDF 3649 kb)

Supplementary Software

Source code for EAGLE software. (ZIP 36 kb)

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Knowles, D., Davis, J., Edgington, H. et al. Allele-specific expression reveals interactions between genetic variation and environment. Nat Methods 14, 699–702 (2017). https://doi.org/10.1038/nmeth.4298

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  • DOI: https://doi.org/10.1038/nmeth.4298

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