Background: Carotid intima‐media thickness (IMT) is a measure of atherosclerosis and a predictor of vascular diseases. Traditional vascular risk factors and genetic variants do not completely explain the variation in carotid IMT. We sought to identify epigenetic factors that may contribute to the remaining carotid IMT variability. Methods and Results: An epigenome‐wide association study was performed in 61 Dominican families with 769 individuals. A cytosine nucleotide that precedes a guanine nucleotide methylation in blood‐derived DNA was measured using the Human MethylationEPIC BeadChip. Linear mixed model analyses were performed regressing bifurcation carotid IMT (bIMT) on beta values for cytosine nucleotide that precedes a guanine nucleotide sites, adjusting for covariates, followed by differentially methylated region (DMR) analysis. One‐sample Mendelian randomization analysis was conducted to investigate causal associations between DMRs and bIMT. Twenty‐five DMRs were associated with bIMT (Sidak P <0.05), with the strongest DMR (Sidak P =2.45×10 ⁻¹⁷ ) overlapping with the promoter of PM20D1 . All 11 cytosine nucleotides that precede a guanine nucleotide within the PM20D1 DMR were positively associated with bIMT ( P =0.0007–0.00006). Methylation of the PM20D1 DMR was associated with cis variants, including rs823154 (β=0.26; P =1.1×10 ⁻¹²¹ ). As reported in GTEx (Genotype‐Tissue Expression project), rs823154 is an expression quantitative trait locus for PM20D1 in multiple tissues, including the aorta ( P =2.3×10 ⁻⁶⁰ ) and blood ( P =4.0×10 ⁻⁷³ ), suggesting that hypermethylation of the PM20D1 DMR directs lower expression of the gene. Mendelian randomization analysis supported a causal role for PM20D1 DMR in bIMT ( P =0.049). Conclusions: Our study and previous expression quantitative trait locus studies provide converging evidence that reduced PM20D1 expression via hypermethylation of the promoter is associated with increased atherosclerosis.

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