Genetic effects on liver chromatin accessibility identify disease regulatory variants
Genetic effects on liver chromatin accessibility identify disease regulatory variants
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DOI：
10.1016/j.ajhg.2021.05.001
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发表时间：
2021-07-01
影响因子：
9.8
通讯作者：
Mohlke, Karen L.
中科院分区：
文献类型：
--
作者：
Currin, Kevin W.;Erdos, Chael R.;Mohlke, Karen L.
确定全基因组关联研究（GWAS）位点影响性状的分子机制仍然具有挑战性。染色质可及性数量性状基因座（caQTL）有助于鉴定可能通过调节染色质结构而改变GWAS性状的GWAS基因座，但caQTL已在有限的人类组织中鉴定。在这里，我们在20个肝脏样本中定位了人类肝脏组织中的caQTL，并确定了3，123个caQTL。caQTL变体在肝组织启动子和增强子状态中富集，并且经常破坏在肝中表达的转录因子的结合基序。我们预测了861个caQTL峰值的靶基因，使用邻近性，染色质相互作用，与启动子可及性或基因表达的相关性，以及与表达QTL的共定位。使用GWAS信号的19个肝功能和/或心脏代谢性状，我们确定了110个共定位的caQTL和GWAS信号，其中56个包含预测的caPeak靶基因。在LITAF LDL-胆固醇GWAS位点，我们验证了caQTL变体在蛋白质结合和转录活性方面表现出等位基因差异。这些caQTL有助于人类肝脏的表观基因组表征，并有助于鉴定GWAS位点的分子机制和基因。
Identifying the molecular mechanisms by which genome-wide association study (GWAS) loci influence traits remains challenging. Chromatin accessibility quantitative trait loci (caQTLs) help identify GWAS loci that may alter GWAS traits by modulating chromatin structure, but caQTLs have been identified in a limited set of human tissues. Here we mapped caQTLs in human liver tissue in 20 liver samples and identified 3,123 caQTLs. The caQTL variants are enriched in liver tissue promoter and enhancer states and frequently disrupt binding motifs of transcription factors expressed in liver. We predicted target genes for 861 caQTL peaks using proximity, chromatin interactions, correlation with promoter accessibility or gene expression, and colocalization with expression QTLs. Using GWAS signals for 19 liver function and/or cardiometabolic traits, we identified 110 colocalized caQTLs and GWAS signals, 56 of which contained a predicted caPeak target gene. At the LITAF LDL-cholesterol GWAS locus, we validated that a caQTL variant showed allelic differences in protein binding and transcriptional activity. These caQTLs contribute to the epigenomic characterization of human liver and help identify molecular mechanisms and genes at GWAS loci.