Detecting Master Regulators in Methylation QTL Studies

• Activity Number: 311
• Type: Contributed
• Date/Time: Tuesday, August 6, 2013 : 8:30 AM to 10:20 AM
• Sponsor: Section on Statistics in Epidemiology
• Author(s): Jianxin Shi*+
• Keywords: Master regulator ; Epigenetics ; Methylation QTL

Abstract

DNA methylation is an important epigenetic mechanism involved in gene regulation and complex diseases. Genetic control of DNA methylation remains largely unknown. Methylation quantitative trait loci (meQTL) studies allow the detection of SNPs regulating methylations of approximately half million CpG sites. Detecting master regulators (MR), i.e. SNPs that trans-regulate the methylation of many distal CpG sites, is biologically particularly important. However, detecting MR is statistically very difficult because of relatively small sample sizes and weak signals in trans-acting associations. We show that the long range correlation among methylation traits further complicates the analysis and makes no power to reject the null hypothesis. We have developed a statistical method for detecting MR by correcting empirical null distribution appropriately. We demonstrate through extensive simulations that the proposed method has a power comparable to the situation with independent traits. We applied our methods to a meQTL study with 210 normal lung tissue samples and identified 4 MRs that are further replicated in an independent data set in The Cancer Genome Atlas.