Skip to main content

Correcting for Sample Heterogeneity in Methylome-Wide Association Studies

  • Protocol
  • First Online:

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1589))

Abstract

Epigenome-wide association studies (EWAS) face many of the same challenges as genome-wide association studies (GWAS), but have an added challenge in that the epigenome can vary dramatically across cell types. When cell-type composition differs between cases and controls, this leads to spurious associations that may obscure true associations. We have developed a computational method, FaST-LMM-EWASher, which automatically corrects for cell-type composition without needing explicit knowledge of it. In this chapter, we provide a tutorial on using FaST-LMM-EWASher for DNA methylation data and discuss data analysis strategies.

This is a preview of subscription content, log in via an institution.

Buying options

Protocol
USD   49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   159.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Springer Nature is developing a new tool to find and evaluate Protocols. Learn more

References

  1. Jones P (2012) Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet 13:484–492

    Article  CAS  PubMed  Google Scholar 

  2. Portela A, Esteller M (2010) Epigenetic modifications and human disease. Nat Biotechnol 28:1057–1068

    Article  CAS  PubMed  Google Scholar 

  3. Kulis M, Esteller M (2010) DNA methylation and cancer. Adv Genet 70:27–56

    PubMed  Google Scholar 

  4. Lechner M, Boshoff C, Beck S (2010) Cancer epigenome. Adv Genet 70:247–276

    CAS  PubMed  Google Scholar 

  5. Rakyan VK, Down TA, Balding DJ, Beck S (2011) Epigenome-wide association studies for common human diseases. Nat Rev Genet 12:529–541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Balding DJ (2006) A tutorial on statistical methods for population association studies. Nat Rev Genet 7:781–791

    Article  CAS  PubMed  Google Scholar 

  7. Listgarten J et al (2013) A powerful and efficient set test for genetic markers that handles confounders. Bioinformatics 29:1526–1533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhu J et al (2013) Genome-wide chromatin state transitions elicited by developmental and environmental cues. Cell 152:642–654

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Liu Y et al (2013) Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nat Biotechnol 31:142–147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Houseman EA et al (2012) Open Access DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinformatics 13

    Google Scholar 

  11. Zou J et al (2014) Epigenome-wide association studies without the need for cell-type composition. Nat Methods 11:309–311

    Article  CAS  PubMed  Google Scholar 

  12. Lippert C et al (2011) FaST linear mixed models for genome-wide association studies. Nat Methods 8:833–835

    Article  CAS  PubMed  Google Scholar 

  13. Listgarten J et al (2012) Improved linear mixed models for genome-wide association studies. Nat Methods 9:525–526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lippert C, Quon G, Listgarten J, Heckerman D (2013) The benefits of selecting phenotype-specific variants for applications of mixed models in genomics. Sci Rep 3:1815

    PubMed  PubMed Central  Google Scholar 

  15. Listgarten J, Lippert C, Heckerman D (2013) Fast-LMM-Select tackles confounding from spatial structure and rare variants. Nat Genet 45:470–471

    Article  CAS  PubMed  Google Scholar 

  16. Price AL et al (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38:904–909

    Article  CAS  PubMed  Google Scholar 

  17. Leek JT, Storey JD (2007) Capturing heterogeneity in gene expression studies by surrogate variable analysis. PLoS Genet 3:1724–1735

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

FaST-LMM-EWASher was developed in collaboration with Jennifer Listgarten, Martin Aryee, and the Microsoft Research Los Angeles group. We would also like to thank Yvonne Yamanaka for helpful feedback.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to James Y. Zou .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer Science+Business Media New York

About this protocol

Cite this protocol

Zou, J.Y. (2015). Correcting for Sample Heterogeneity in Methylome-Wide Association Studies. In: Haggarty, P., Harrison, K. (eds) Population Epigenetics. Methods in Molecular Biology, vol 1589. Humana Press, New York, NY. https://doi.org/10.1007/7651_2015_266

Download citation

  • DOI: https://doi.org/10.1007/7651_2015_266

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-6901-2

  • Online ISBN: 978-1-4939-6903-6

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics