Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Am J Hum Genet. 2021 Jul 1;108(7):1169-1189. doi: 10.1016/j.ajhg.2021.05.001. Epub 2021 May 25.
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.
确定全基因组关联研究（GWAS）基因座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）有助于识别可能通过调节染色质结构改变 GWAS 性状的 GWAS 基因座，但 caQTL 仅在有限数量的人类组织中被鉴定出来。在这里，我们在 20 个肝组织样本中绘制了人类肝组织中的 caQTL，并鉴定了 3123 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，预测了 861 个 caQTL 峰的靶基因。使用 19 个肝功能和/或心脏代谢特征的 GWAS 信号，我们鉴定了 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 胆固醇 LDL GWAS 基因座，我们验证了一个 caQTL 变体在蛋白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特征描述，并有助于确定 GWAS 基因座的分子机制和基因。
