Institute of Genetic Epidemiology.
Hum Mol Genet. 2014 Jan 15;23(2):534-45. doi: 10.1093/hmg/ddt430. Epub 2013 Sep 6.
Previously, we reported strong influences of genetic variants on metabolic phenotypes, some of them with clinical relevance. Here, we hypothesize that DNA methylation may have an important and potentially independent effect on human metabolism. To test this hypothesis, we conducted what is to the best of our knowledge the first epigenome-wide association study (EWAS) between DNA methylation and metabolic traits (metabotypes) in human blood. We assess 649 blood metabolic traits from 1814 participants of the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) population study for association with methylation of 457 004 CpG sites, determined on the Infinium HumanMethylation450 BeadChip platform. Using the EWAS approach, we identified two types of methylome-metabotype associations. One type is driven by an underlying genetic effect; the other type is independent of genetic variation and potentially driven by common environmental and life-style-dependent factors. We report eight CpG loci at genome-wide significance that have a genetic variant as confounder (P = 3.9 × 10(-20) to 2.0 × 10(-108), r(2) = 0.036 to 0.221). Seven loci display CpG site-specific associations to metabotypes, but do not exhibit any underlying genetic signals (P = 9.2 × 10(-14) to 2.7 × 10(-27), r(2) = 0.008 to 0.107). We further identify several groups of CpG loci that associate with a same metabotype, such as 4-vinylphenol sulfate and 4-androsten-3-beta,17-beta-diol disulfate. In these cases, the association between CpG-methylation and metabotype is likely the result of a common external environmental factor, including smoking. Our study shows that analysis of EWAS with large numbers of metabolic traits in large population cohorts are, in principle, feasible. Taken together, our data suggest that DNA methylation plays an important role in regulating human metabolism.
先前，我们报告了遗传变异对代谢表型的强烈影响，其中一些具有临床相关性。在这里，我们假设 DNA 甲基化可能对人类代谢有重要且潜在独立的影响。为了验证这一假设，我们进行了据我们所知首次在人类血液中 DNA 甲基化与代谢特征（代谢表型）之间的全基因组关联研究（EWAS）。我们评估了来自科罗地区奥格斯堡合作健康研究（KORA）人群研究的 1814 名参与者的 649 种血液代谢特征与 457004 个 CpG 位点的甲基化之间的关联，这些 CpG 位点是在 Infinium HumanMethylation450 BeadChip 平台上确定的。使用 EWAS 方法，我们确定了两种甲基化-代谢表型关联类型。一种类型是由潜在的遗传效应驱动的；另一种类型与遗传变异无关，可能由共同的环境和生活方式相关因素驱动。我们报告了在全基因组范围内具有遗传变异作为混杂因素的 8 个 CpG 位点（P = 3.9×10(-20) 至 2.0×10(-108)，r(2) = 0.036 至 0.221）。7 个位点显示出与代谢表型的特定 CpG 位点关联，但没有显示出任何潜在的遗传信号（P = 9.2×10(-14) 至 2.7×10(-27)，r(2) = 0.008 至 0.107）。我们进一步确定了一些与同一代谢表型相关的 CpG 位点群，例如 4-乙烯基苯酚硫酸盐和 4-雄烯-3-β,17-β-二醇二硫酸盐。在这些情况下，CpG 甲基化与代谢表型之间的关联可能是共同外部环境因素的结果，包括吸烟。我们的研究表明，在大型人群队列中分析大量代谢特征的 EWAS 在原则上是可行的。总之，我们的数据表明，DNA 甲基化在调节人类代谢中起着重要作用。
