National Health and Environmental Effects Laboratory, US Environmental Protection Agency, Chapel Hill, NC, United States of America.
Department of Environmental Sciences and Engineering, Gillings School of Public Health, University of North Carolina, Chapel Hill, NC, United States of America.
PLoS One. 2019 Apr 19;14(4):e0207834. doi: 10.1371/journal.pone.0207834. eCollection 2019.
DNA methylation age (DNAm age) has become a widely utilized epigenetic biomarker for the aging process. The Horvath method for determining DNAm age is perhaps the most widely utilized and validated DNA methylation age assessment measure. Horvath DNAm age is calculated based on methylation measurements at 353 loci, present on Illumina's 450k and 27k DNA methylation microarrays. With increasing use of the more recently developed Illumina MethylationEPIC (850k) microarray, it is worth revisiting this aging measure to evaluate estimation differences due to array design. Of the requisite 353 loci, 17 are missing from the 850k microarray. Similarly, an alternate, 71 loci DNA methylation age assessment measure created by Hannum et al. is missing 6 requisite loci. Using 17 datasets with 27k, 450k, and/or 850k methylation data, we compared each sample's epigenetic age estimated from all 353 loci required by the Horvath DNAm age calculator, and using only the 336 loci available on the 850k array. In 450k/27k data, removing loci not on the 850k array resulted in underestimation of Horvath's DNAm age. Underestimation of Horvath DNAm age increased from ages 0 to ~20, remaining stable thereafter (mean deviation = -3.46 y, SD = 1.13 for individuals ≥20 years). Underestimation of Horvath's DNAm age by the reduced 450k/27k data was similar to the underestimation observed in the 850k data indicating it is driven by missing probes. In analogous examination of Hannum's DNAm age, the magnitude and direction of epigenetic age misestimation varied with chronological age. In conclusion, inter-array deviations in DNAm age estimations may be largely driven by missing probes between arrays, despite default probe imputation procedures. Though correlations and associations based on Horvath's DNAm age may be unaffected, researchers should exercise caution when interpreting results based on absolute differences in DNAm age or when mixing samples assayed on different arrays.
DNA 甲基化年龄（DNAm 年龄）已成为广泛用于评估衰老过程的表观遗传生物标志物。用于确定 DNAm 年龄的 Horvath 方法可能是应用最广泛和最有效的 DNA 甲基化年龄评估方法。Horvath DNAm 年龄是基于 Illumina 450k 和 27k DNA 甲基化微阵列上 353 个位点的甲基化测量值计算得出的。随着最近开发的 Illumina MethylationEPIC（850k）微阵列的广泛应用，有必要重新评估这种衰老指标，以评估由于阵列设计而导致的估计差异。在必需的 353 个位点中，有 17 个缺失于 850k 微阵列中。同样，Hannum 等人创建的另一种替代的 71 个位点的 DNA 甲基化年龄评估方法缺少 6 个必需的位点。我们使用了 17 个数据集，其中包含 27k、450k 和/或 850k 甲基化数据，比较了使用 Horvath DNAm 年龄计算器所需的所有 353 个位点以及仅使用 850k 阵列上可用的 336 个位点计算的每个样本的表观遗传年龄。在 450k/27k 数据中，去除不在 850k 阵列上的位点会导致 Horvath DNAm 年龄的低估。Horvath DNAm 年龄的低估从 0 岁到~20 岁增加，此后保持稳定（年龄≥20 岁的个体平均偏差= -3.46 岁，标准差= 1.13）。用减少的 450k/27k 数据进行的 Horvath DNAm 年龄低估与在 850k 数据中观察到的低估相似，表明这是由缺失的探针引起的。在对 Hannum 的 DNAm 年龄进行类似的检查时，表观遗传年龄的估算偏差的大小和方向随年龄而变化。总之，尽管存在默认的探针插补程序，但 DNAm 年龄估计值在不同阵列之间的差异可能主要由探针缺失引起。尽管基于 Horvath DNAm 年龄的相关性和关联可能不受影响，但研究人员在基于 DNAm 年龄的绝对差异或在混合不同阵列上检测的样本时，应谨慎解释结果。
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