Chromatin accessibility variation provides insights into missing regulation underlying immune-mediated diseases.
Chromatin accessibility variation provides insights into missing regulation underlying immune-mediated diseases.
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染色质可及性变异提供了对免疫介导疾病背后调控缺失的见解。
DOI：
10.1101/2024.04.12.589213
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Bulyk,MarthaL
中科院分区：
文献类型：
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作者：
Jeong,Raehoon;Bulyk,MarthaL
通过全基因组关联研究（GWAS），大多数与复杂性状和疾病相关的遗传位点是非编码的，这表明致病变异可能具有基因调控作用。然而，目前检测到的与表达量性状基因座（eQTL）连锁的位点很少。为了更好地理解许多性状相关位点缺乏eQTL共定位的潜在原因，我们调查了类淋巴母细胞系（LCL）中的染色质可及性QTL（caQTL）是否能解释LCL中eQTL不能解释的免疫介导的疾病关联。caQTL的检测能力大于eQTL，受相关基因转录起始位点距离的影响较小。荟萃分析LCL eQTL数据，以增加样本量超过1000导致额外的位点与eQTL共定位，表明统计能力不足仍然可能是一个因素。此外，通过调查其他免疫细胞类型的eQTL，发现了更多的eQTL共定位位点。总而言之，eQTL的功效不足和环境特异性都有助于“缺失调控”。
Most genetic loci associated with complex traits and diseases through genome-wide association studies (GWAS) are noncoding, suggesting that the causal variants likely have gene regulatory effects. However, only a small number of loci have been linked to expression quantitative trait loci (eQTLs) detected currently. To better understand the potential reasons for many trait-associated loci lacking eQTL colocalization, we investigated whether chromatin accessibility QTLs (caQTLs) in lymphoblastoid cell lines (LCLs) explain immune-mediated disease associations that eQTLs in LCLs did not. The power to detect caQTLs was greater than that of eQTLs and was less affected by the distance from the transcription start site of the associated gene. Meta-analyzing LCL eQTL data to increase the sample size to over a thousand led to additional loci with eQTL colocalization, demonstrating that insufficient statistical power is still likely to be a factor. Moreover, further eQTL colocalization loci were uncovered by surveying eQTLs of other immune cell types. Altogether, insufficient power and context-specificity of eQTLs both contribute to the ‘missing regulation.’