1 Channing Division of Network Medicine.
2 Division of Pulmonary and Critical Care Medicine, and.
Am J Respir Crit Care Med. 2018 May 15;197(10):1275-1284. doi: 10.1164/rccm.201707-1434OC.
As the third leading cause of death in the United States, the impact of chronic obstructive pulmonary disease (COPD) makes identification of its molecular mechanisms of great importance. Genome-wide association studies (GWASs) have identified multiple genomic regions associated with COPD. However, genetic variation only explains a small fraction of the susceptibility to COPD, and sub-genome-wide significant loci may play a role in pathogenesis.
Regulatory annotation with epigenetic evidence may give priority for further investigation, particularly for GWAS associations in noncoding regions. We performed integrative genomics analyses using DNA methylation profiling and genome-wide SNP genotyping from lung tissue samples from 90 subjects with COPD and 36 control subjects.
We performed methylation quantitative trait loci (mQTL) analyses, testing for SNPs associated with percent DNA methylation and assessed the colocalization of these results with previous COPD GWAS findings using Bayesian methods in the R package coloc to highlight potential regulatory features of the loci.
We identified 942,068 unique SNPs and 33,996 unique CpG sites among the significant (5% false discovery rate) cis-mQTL results. The genome-wide significant and subthreshold (P < 10) GWAS SNPs were enriched in the significant mQTL SNPs (hypergeometric test P < 0.00001). We observed enrichment for sites located in CpG shores and shelves, but not CpG islands. Using Bayesian colocalization, we identified loci in regions near KCNK3, EEFSEC, PIK3CD, DCDC2C, TCERG1L, FRMD4B, and IL27.
Colocalization of mQTL and GWAS loci provides regulatory characterization of significant and subthreshold GWAS findings, supporting a role for genetic control of methylation in COPD pathogenesis.
慢性阻塞性肺疾病（COPD）是美国的第三大致死原因，因此明确其分子机制至关重要。全基因组关联研究（GWAS）已经确定了多个与 COPD 相关的基因组区域。然而，遗传变异仅能解释 COPD 易感性的一小部分，亚全基因组显著位点可能在发病机制中发挥作用。
具有表观遗传证据的调控注释可能优先进行进一步研究，特别是针对非编码区域的 GWAS 关联。我们使用来自 90 名 COPD 患者和 36 名对照者的肺组织样本的 DNA 甲基化谱和全基因组 SNP 基因分型进行了综合基因组学分析。
我们进行了甲基化数量性状基因座（mQTL）分析，检测与 DNA 甲基化百分比相关的 SNP，并使用 R 包 coloc 中的贝叶斯方法评估这些结果与先前 COPD GWAS 发现的共定位，以突出这些位点的潜在调控特征。
在显著（5%错误发现率）顺式-mQTL 结果中，我们鉴定了 942068 个独特的 SNP 和 33996 个独特的 CpG 位点。全基因组显著和亚阈值（P<10）GWAS SNP 在显著 mQTL SNP 中富集（超几何检验 P<0.00001）。我们观察到位于 CpG 潮岸和棚架而非 CpG 岛的位点富集。使用贝叶斯共定位，我们鉴定了 KCNK3、EEFSEC、PIK3CD、DCDC2C、TCERG1L、FRMD4B 和 IL27 附近区域的位点。
mQTL 和 GWAS 位点的共定位为显著和亚阈值 GWAS 发现提供了调控特征，支持遗传控制甲基化在 COPD 发病机制中的作用。
