Zhang Xu, Moen Erika L, Liu Cong, Mu Wenbo, Gamazon Eric R, Delaney Shannon M, Wing Claudia, Godley Lucy A, Dolan M Eileen, Zhang Wei
Section of Hematology/Oncology, Department of Medicine.
Committee on Cancer Biology.
Hum Mol Genet. 2014 Nov 15;23(22):5893-905. doi: 10.1093/hmg/ddu313. Epub 2014 Jun 18.
Interindividual variation in cytosine modifications could contribute to heterogeneity in disease risks and other complex traits. We assessed the genetic architecture of cytosine modifications at 283,540 CpG sites in lymphoblastoid cell lines (LCLs) derived from independent samples of European and African descent. Our study suggests that cytosine modification variation was primarily controlled in local by single major modification quantitative trait locus (mQTL) and additional minor loci. Local genetic epistasis was detectable for a small proportion of CpG sites, which were enriched by more than 9-fold for CpG sites mapped to population-specific mQTL. Genetically dependent CpG sites whose modification levels negatively (repressive sites) or positively (facilitative sites) correlated with gene expression levels significantly co-localized with transcription factor binding, with the repressive sites predominantly associated with active promoters whereas the facilitative sites rarely at active promoters. Genetically independent repressive or facilitative sites preferentially modulated gene expression variation by influencing local chromatin accessibility, with the facilitative sites primarily antagonizing H3K27me3 and H3K9me3 deposition. In comparison with expression quantitative trait loci (eQTL), mQTL detected from LCLs were enriched in associations for a broader range of disease categories including chronic inflammatory, autoimmune and psychiatric disorders, suggesting that cytosine modification variation, while possesses a degree of cell linage specificity, is more stably inherited over development than gene expression variation. About 11% of unique single-nucleotide polymorphisms reported in the Genome-Wide Association Study Catalog were annotated, 78% as mQTL and 31% as eQTL in LCLs, which covered 37% of the investigated diseases/traits and provided insights to the biological mechanisms.
胞嘧啶修饰的个体间差异可能导致疾病风险和其他复杂性状的异质性。我们评估了来自欧洲和非洲血统独立样本的淋巴母细胞系（LCL）中283,540个CpG位点的胞嘧啶修饰的遗传结构。我们的研究表明，胞嘧啶修饰变异主要由单个主要修饰数量性状位点（mQTL）和其他次要位点在局部进行控制。对于一小部分CpG位点可检测到局部基因上位性，映射到群体特异性mQTL的CpG位点富集了9倍以上。修饰水平与基因表达水平呈负相关（抑制位点）或正相关（促进位点）的遗传依赖性CpG位点与转录因子结合显著共定位，抑制位点主要与活性启动子相关，而促进位点很少位于活性启动子处。遗传独立的抑制或促进位点通过影响局部染色质可及性优先调节基因表达变异，促进位点主要拮抗H3K27me3和H3K9me3沉积。与表达数量性状位点（eQTL）相比，从LCL中检测到的mQTL在更广泛的疾病类别（包括慢性炎症、自身免疫和精神疾病）的关联中富集，这表明胞嘧啶修饰变异虽然具有一定程度的细胞谱系特异性，但在发育过程中比基因表达变异更稳定地遗传。在全基因组关联研究目录中报告的约11%的独特单核苷酸多态性被注释，在LCL中78%为mQTL，31%为eQTL，这些多态性涵盖了37%的研究疾病/性状，并为生物学机制提供了见解。
