Poster Presentation 39th Annual Lorne Genome Conference 2018

Fine-mapping reveals complex genetic architecture underlying DNA methylation (#125)

Vignesh Kartik Chundru 1 , Riccardo E Marioni 2 , Ian J Deary 2 , Naomi R Wray 1 , Peter M Visscher 1 , Allan F McRae 1
  1. Institute for Molecular Biosciences, University of Queensland, Brisbane, QLD, Australia
  2. Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom

The genetic contribution to DNA methylation has been studied through identifying methylation quantitative trait loci (mQTL). A trivial example of an mQTL is a SNP at the CpG site (CpG-SNP) which will change the C or G in the CpG sequence, and consequently the DNA methylation. Such sites have a known causal variant with a large effect and thus are potential model traits to test fine-mapping methodology. Using DNA methylation data from the Lothian Birth Cohorts of 1921 and 1936 (n=1366), we compare two methods never previously used for fine-mapping (the J-test and BSLMM) with the widely used BIMBAM method by constructing a 95% credible set of causal SNPs for mQTL with a CpG-SNP. All three methods failed to capture the CpG-SNP with the expected 95% probability. Simulations confirmed the three methods performed as expected under ideal conditions.  The influence of multiple, independent signals underlying the mQTL was also excluded. Comparing the CpG-SNP, and the most associated SNP (top-SNP), we found that often the effect of the top-SNP was masking the effect of the CpG-SNP. This was shown to be more evident in CpG islands, where the fine-mapping methods captured the CpG-SNP less often than in non-island regions (OR=1.6, p=2×10-3). This indicates that methylation sites within a CpG island and the surrounding region can share common genetic control, providing potential insight into the mechanisms underlying the maintenance of DNA methylation at CpG islands.