MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
Nat Genet. 2021 Sep;53(9):1311-1321. doi: 10.1038/s41588-021-00923-x. Epub 2021 Sep 6.
Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.
描述 DNA 甲基化（DNAm）的遗传影响，为理解基因调控和疾病的机制提供了机会。在本研究中，我们描述了对 32851 名参与者进行 DNAm 数量性状基因座（mQTL）分析的结果，鉴定了与血液中 420509 个 DNAm 位点的 DNAm 相关的遗传变异。我们提供了一个包含超过 270000 个独立 mQTL 的数据库，其中 8.5% 包含长程（trans）关联。鉴定的 mQTL 关联解释了 DNAm 加性遗传变异的 15-17%。我们表明，DNAm 水平的遗传结构高度多基因。利用远端 DNAm 位点之间的共享遗传控制，我们构建了网络，确定了 405 个离散的基因组社区，这些社区富含基因组注释和复杂性状。共享的遗传变异与 DNAm 水平和复杂疾病都有关联，但在这些关联中，只有少数情况下反映了 DNAm 对性状或反之的因果关系，这表明基因型-表型图谱比预期的更为复杂。
