Accounting for population stratification in DNA methylation studies.

Genet Epidemiol 2014 Apr 29;38(3):231-41. Epub 2014 Jan 29.

Department of Biostatistics, Harvard University, Boston, Massachusetts, United States of America.

DNA methylation is an important epigenetic mechanism that has been linked to complex diseases and is of great interest to researchers as a potential link between genome, environment, and disease. As the scale of DNA methylation association studies approaches that of genome-wide association studies, issues such as population stratification will need to be addressed. It is well-documented that failure to adjust for population stratification can lead to false positives in genetic association studies, but population stratification is often unaccounted for in DNA methylation studies. Here, we propose several approaches to correct for population stratification using principal components (PCs) from different subsets of genome-wide methylation data. We first illustrate the potential for confounding due to population stratification by demonstrating widespread associations between DNA methylation and race in 388 individuals (365 African American and 23 Caucasian). We subsequently evaluate the performance of our PC-based approaches and other methods in adjusting for confounding due to population stratification. Our simulations show that (1) all of the methods considered are effective at removing inflation due to population stratification, and (2) maximum power can be obtained with single-nucleotide polymorphism (SNP)-based PCs, followed by methylation-based PCs, which outperform both surrogate variable analysis and genomic control. Among our different approaches to computing methylation-based PCs, we find that PCs based on CpG sites chosen for their potential to proxy nearby SNPs can provide a powerful and computationally efficient approach to adjust for population stratification in DNA methylation studies when genome-wide SNP data are unavailable.

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http://dx.doi.org/10.1002/gepi.21789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4090102PMC
April 2014
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References

(Supplied by CrossRef)
Racial differences in gene-specific DNA methylation levels are present at birth
Adkins et al.
Birth Defects Res A Clin Mol Teratol 2011
The power of genomic control
Bacanu et al.
Am J Hum Genet 2000
Controlling the false discovery rate: a practical and powerful approach to multiple testing
Benjamini et al.
J R Stat Soc. Series B 1995
Remarks on parallel analysis
Buja et al.
Multivar Behav Res 1992

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