Identifying genetic variants associated with chromatin looping and genome function

Here we present a comprehensive HiChIP dataset on naïve CD4 T cells (nCD4) from 30 donors and identify QTLs that associate with genotype-dependent and/or allele-specific variation of HiChIP contacts defining loops between active regulatory regions (iQTLs). We observe a substantial overlap between iQTLs and previously defined eQTLs and histone QTLs, and an enrichment for fine-mapped QTLs and GWAS variants. Furthermore, we describe a distinct subset of nCD4 iQTLs, for which the significant variation of chromatin contacts in nCD4 are translated into significant eQTL trends in CD4 T cell memory subsets. Finally, we define connectivity-QTLs as iQTLs that are significantly associated with concordant genotype-dependent changes in chromatin contacts over a broad genomic region (e.g., GWAS SNP in the RNASET2 locus). Our results demonstrate the importance of chromatin contacts as a complementary modality for QTL mapping and their power in identifying novel classes of QTLs linked to cell-specific gene expression and connectivity.

This repository contains the source code, supplementary datasets for the manuscript (Nature Communications 2024).

本研究公开了一套覆盖30名供体的初始CD4阳性T细胞（naïve CD4 T cells, nCD4）的完整HiChIP数据集，并鉴定出与活性调控区域之间形成染色质环的HiChIP互作的基因型依赖式/等位基因特异性变异相关的数量性状位点（Quantitative Trait Locus, QTL），即iQTLs。研究发现iQTLs与已报道的表达数量性状位点（expression Quantitative Trait Locus, eQTL）及组蛋白数量性状位点存在大量重叠，同时富集精细定位的QTL与全基因组关联分析（Genome-Wide Association Study, GWAS）变异。此外，本研究还鉴定出一类独特的nCD4 iQTL亚群：该类位点在初始CD4阳性T细胞中染色质互作的显著变异，可转化为记忆性CD4阳性T细胞亚群中显著的eQTL调控趋势。最后，本研究将连接性数量性状位点（connectivity-QTLs）定义为：与大范围基因组区域内染色质互作的一致性基因型依赖式变化显著相关的iQTLs（例如RNASET2基因座中的GWAS SNP）。本研究结果证实，染色质互作作为QTL定位的互补研究手段具有重要价值，同时证明其在鉴定与细胞特异性基因表达及染色质连接相关的新型QTL类别方面的效能。

本开源代码仓库包含该2024年发表于《Nature Communications》的论文的源代码与补充数据集。