Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
University of Exeter Medical School, Exeter, UK.
Genome Biol. 2023 Jul 31;24(1):176. doi: 10.1186/s13059-023-03011-x.
Pinpointing genetic impacts on DNA methylation can improve our understanding of pathways that underlie gene regulation and disease risk.
We report heritability and methylation quantitative trait locus (meQTL) analysis at 724,499 CpGs profiled with the Illumina Infinium MethylationEPIC array in 2358 blood samples from three UK cohorts. Methylation levels at 34.2% of CpGs are affected by SNPs, and 98% of effects are cis-acting or within 1 Mbp of the tested CpG. Our results are consistent with meQTL analyses based on the former Illumina Infinium HumanMethylation450 array. Both SNPs and CpGs with meQTLs are overrepresented in enhancers, which have improved coverage on this platform compared to previous approaches. Co-localisation analyses across genetic effects on DNA methylation and 56 human traits identify 1520 co-localisations across 1325 unique CpGs and 34 phenotypes, including in disease-relevant genes, such as USP1 and DOCK7 (total cholesterol levels), and ICOSLG (inflammatory bowel disease). Enrichment analysis of meQTLs and integration with expression QTLs give insights into mechanisms underlying cis-meQTLs (e.g. through disruption of transcription factor binding sites for CTCF and SMC3) and trans-meQTLs (e.g. through regulating the expression of ACD and SENP7 which can modulate DNA methylation at distal sites).
Our findings improve the characterisation of the mechanisms underlying DNA methylation variability and are informative for prioritisation of GWAS variants for functional follow-ups. The MeQTL EPIC Database and viewer are available online at https://epicmeqtl.kcl.ac.uk .
精确定位对 DNA 甲基化的遗传影响可以增进我们对基因调控和疾病风险相关通路的理解。
我们报告了在三个英国队列的 2358 个血液样本中，使用 Illumina Infinium MethylationEPIC 阵列进行的 724,499 个 CpG 的遗传力和甲基化数量性状基因座（meQTL）分析。34.2%的 CpG 的甲基化水平受到 SNP 的影响，98%的影响是顺式作用或在测试的 CpG 附近 1 Mbp 内。我们的结果与基于先前的 Illumina Infinium HumanMethylation450 阵列的 meQTL 分析一致。具有 meQTL 的 SNP 和 CpG 在增强子中更为常见，与以前的方法相比，该平台在增强子上的覆盖度得到了提高。对 DNA 甲基化遗传效应和 56 个人类特征的共定位分析，在 1325 个独特的 CpG 和 34 个表型中鉴定出 1520 个共定位，包括在疾病相关基因中，如 USP1 和 DOCK7（总胆固醇水平）和 ICOSLG（炎症性肠病）。meQTL 的富集分析和与表达 QTL 的整合为 cis-meQTL（例如通过破坏 CTCF 和 SMC3 的转录因子结合位点）和 trans-meQTL（例如通过调节 ACD 和 SENP7 的表达，从而可以调节远端位点的 DNA 甲基化）的机制提供了深入的见解。
我们的研究结果改善了对 DNA 甲基化变异性潜在机制的描述，并为 GWAS 变体的功能后续研究提供了优先排序的信息。MeQTL EPIC 数据库和查看器可在 https://epicmeqtl.kcl.ac.uk 在线获取。
