Expanded chromatin accessibility mapping explains genetic variation associated with complex traits in liver

Genome-wide association studies (GWAS) have identified thousands of genomic loci associated with a variety of common, complex human traits. The contribution of genetic variants to gene expression regulation has been well studied, supporting the idea that gene expression plays a causal role at some complex trait-associated loci. However, many current studies have not comprehensively investigated the impact of genetic variation on chromatin accessibility at a large scale within a single tissue. Genetic variants associated with differences in chromatin accessibility, known as chromatin accessibility quantitative trait loci (caQTLs), are major contributors to gene expression differences and GWAS signals. We assessed chromatin accessibility in 189 human liver tissue samples using ATAC-seq and identified over two million accessible chromatin regions enriched for gene regulatory characteristics. We integrated chromatin accessibility and genotype data from 175 samples and identified 14,076 caQTLs. Using publicly available blood lipid GWAS data, we found 157 loci where the colocalization of caQTLs, expression quantitative trait loci (eQTLs), and GWAS signals generated specific molecular hypotheses about causal regulatory elements, affected genes, and, in some cases, transcription factors, resolving these associations to single-nucleotide resolution. We performed a comprehensive analysis of the GWAS signals that remain without a proposed mechanism beyond liver caQTLs and eQTLs. After incorporating additional potential regulatory mechanism data, we found that approximately 26% of blood lipid GWAS signals remain without a proposed mechanism. Overall, our results demonstrate the benefits of integrating multiple datasets to improve our understanding of GWAS signals while emphasizing the need for additional experiments to fully characterize them. Overall design: ATAC-seq was performed on biopsies from normal human liver samples and consensus peaks were called across all samples.

全基因组关联研究（Genome-wide association studies, GWAS）已鉴定出数千个与多种常见人类复杂性状相关的基因组位点。遗传变异对基因表达调控的贡献已得到充分研究，支持了基因表达在部分复杂性状相关位点发挥因果作用的观点。然而，当前多数研究尚未在单一组织内大规模、全面地探究遗传变异对染色质开放性的影响。与染色质开放性差异相关的遗传变异被称为染色质开放性数量性状位点（chromatin accessibility quantitative trait loci, caQTLs），是基因表达差异和GWAS信号的主要贡献因素。本研究利用ATAC-seq技术对189份人类肝脏组织样本的染色质开放性进行了检测，鉴定出超过200万个具备基因调控特征的开放染色质区域。我们整合了175份样本的染色质开放性与基因型数据，共鉴定出14076个caQTLs。利用公开的血脂GWAS数据，我们发现了157个位点：在这些位点中，caQTLs、表达数量性状位点（expression quantitative trait loci, eQTLs）与GWAS信号的共定位为因果调控元件、受影响基因，以及部分情况下的转录因子，提供了具体的分子假说，将这些关联解析至单核苷酸分辨率。我们对目前仅通过肝脏caQTLs和eQTLs无法提出明确作用机制的GWAS信号开展了全面分析。在纳入额外的潜在调控机制数据后，我们发现约26%的血脂GWAS信号仍未找到明确的作用机制。总体而言，本研究结果证实了整合多组数据集有助于加深对GWAS信号的理解，同时也强调了需要开展更多实验以完全解析这些信号。整体实验设计：对正常人类肝脏组织活检样本进行ATAC-seq测序，并在所有样本中统一鉴定共识峰。