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遗传变异影响 DNA 甲基化，为调节基因组功能的分子机制提供了新的见解。

Genetic variation influencing DNA methylation provides insights into molecular mechanisms regulating genomic function.

机构信息

Institute of Computational Biology, Deutsches Forschungszentrum für Gesundheit und Umwelt, Helmholtz Zentrum München, Neuherberg, Germany.

Department of Informatics, Technical University of Munich, Garching bei München, Germany.

出版信息

Nat Genet. 2022 Jan;54(1):18-29. doi: 10.1038/s41588-021-00969-x. Epub 2022 Jan 3.

DOI:10.1038/s41588-021-00969-x
PMID:34980917
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7617265/
Abstract

We determined the relationships between DNA sequence variation and DNA methylation using blood samples from 3,799 Europeans and 3,195 South Asians. We identify 11,165,559 SNP-CpG associations (methylation quantitative trait loci (meQTL), P < 10), including 467,915 meQTL that operate in trans. The meQTL are enriched for functionally relevant characteristics, including shared chromatin state, High-throuhgput chromosome conformation interaction, and association with gene expression, metabolic variation and clinical traits. We use molecular interaction and colocalization analyses to identify multiple nuclear regulatory pathways linking meQTL loci to phenotypic variation, including UBASH3B (body mass index), NFKBIE (rheumatoid arthritis), MGA (blood pressure) and COMMD7 (white cell counts). For rs6511961 , chromatin immunoprecipitation followed by sequencing (ChIP-seq) validates zinc finger protein (ZNF)333 as the likely trans acting effector protein. Finally, we used interaction analyses to identify population- and lineage-specific meQTL, including rs174548 in FADS1, with the strongest effect in CD8 T cells, thus linking fatty acid metabolism with immune dysregulation and asthma. Our study advances understanding of the potential pathways linking genetic variation to human phenotype.

摘要

我们使用来自 3799 名欧洲人和 3195 名南亚人的血液样本，确定了 DNA 序列变异与 DNA 甲基化之间的关系。我们确定了 11165559 个 SNP-CpG 关联（甲基化数量性状基因座（meQTL），P<10），包括 467915 个跨顺式作用的 meQTL。这些 meQTL 富含功能相关特征，包括共享染色质状态、高吞吐量染色体构象相互作用以及与基因表达、代谢变异和临床特征的关联。我们使用分子相互作用和共定位分析来识别将 meQTL 位置与表型变异联系起来的多个核调控途径，包括 UBASH3B（体重指数）、NFKBIE（类风湿关节炎）、MGA（血压）和 COMMD7（白细胞计数）。对于 rs6511961，染色质免疫沉淀测序（ChIP-seq）验证了锌指蛋白（ZNF）333 作为可能的跨作用效应蛋白。最后，我们使用相互作用分析鉴定了人群和谱系特异性的 meQTL，包括 FADS1 中的 rs174548，其在 CD8 T 细胞中的作用最强，从而将脂肪酸代谢与免疫失调和哮喘联系起来。我们的研究推进了对潜在途径的理解，这些途径将遗传变异与人类表型联系起来。

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