Investigating potential causal relationships between SNPs, DNA methylation and HDL.

Using data on 680 patients from the GAW20 real data set, we conducted Mendelian randomization (MR) studies to explore the causal relationships between methylation levels at selected probes (cytosine-phosphate-guanine sites [CpGs]) and high-density lipoprotein (HDL) changes (Δ) using single-nucleotide polymorphisms (SNPs) as instrumental variables. Several methods were used to estimate the causal effects at CpGs of interest on Δ, including a newly developed method that we call (CIV). CIV performs automatic SNP selection while providing estimates of causal effects adjusted for possible pleiotropy, when the potentially-pleiotropic phenotypes are measured. For CpGs in or near the 10 genes identified as associated with Δ using a family-based VC-score test, we compared CIV to Egger regression and the two-stage least squares (TSLS) method. All 3 approaches selected at least 1CpG in 2 genes- and -as showing a causal relationship with Δ.