Abstract
Epigenome association studies that test a large number of methylation sites suffer from stringent multiple-testing corrections. This study’s goals were to investigate region-based associations between DNA methylation sites and lipid-level changes in response to the treatment with fenofibrate in the GAW20 data and to investigate whether improvements in power could be obtained by taking into account correlations between DNA methylation at neighboring cytosine-phosphate-guanine (CpG) sites. To this end, we applied both a recently developed block-based data-dimension-reduction approach and a region-based variance-component (VC) linear mixed model to GAW20 data. We compared analyses of unrelated individuals with familial data. The region-based VC approach using unrelated (independent) individuals identified the gene LGALS9C as significantly associated with changes in triglycerides. However, univariate tests of individual CpG sites yielded no valid statistically significant results.
Highlights
Lipid levels can be influenced by drug therapy or lifestyle factors such as diet, physical activity, alcohol consumption, and smoking [1]
principal components of explained variation (PCEV) approach PCEV is a dimension-reduction technique that searches for a linear combination of the columns of Y, ypcev = Y w (w is ap × 1 vector), that maximizes h2(w), the ratio of the variance in Y explained by x to the total variance of Y, while taking into account the confounding factors, C
The VC-score approach using unrelated subjects identified the gene LGALS9C as significantly associated with TG changes
Summary
Lipid levels can be influenced by drug therapy or lifestyle factors such as diet, physical activity, alcohol consumption, and smoking [1]. Lipid levels are associated with inherited genetic variants (single-nucleotide polymorphisms [SNPs]), as revealed by several genome-wide association studies [2]. DNA sequence variation explains only a small proportion of lipid-level variance [2]. Through regulation of lipid levels, epigenetic mechanisms may contribute to cardiovascular risk profiles [3, 4]. Irvin et al [3] identified strong association of 4 cytosine-phosphate-guanine (CpG) sites within the CPT1A gene on chromosome 11 with both triglycerides (TGs) and very-low-density lipoprotein C (VLDL-C). Because their analysis examined phenotype associations at each CpG site, a substantial correction for multiple testing was required
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