Massively Parallel Reporter Assay Confirms Regulatory Potential of hQTLs and Reveals Important Variants in Lupus and Other Autoimmune Diseases.
Massively Parallel Reporter Assay Confirms Regulatory Potential of hQTLs and Reveals Important Variants in Lupus and Other Autoimmune Diseases.
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大规模平行报告基因检测证实了 hQTL 的调控潜力，并揭示了狼疮和其他自身免疫性疾病的重要变异。
DOI：
10.1101/2023.08.17.553722
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Gaffney,PatrickM
中科院分区：
文献类型：
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作者：
Fu,Yao;Kelly,JenniferA;Gopalakrishnan,Jaanam;Pelikan,RichardC;Tessneer,KandiceL;Pasula,Satish;Grundahl,Kiely;Murphy,DavidA;Gaffney,PatrickM
我们在EB病毒转化的B细胞系中设计了大规模平行报告基因测定（MPRA），以直接表征组蛋白翻译后修饰的潜力，即，组蛋白数量性状基因座（hQTL）、表达QTL（eQTL）和系统性红斑狼疮（SLE）和自身免疫性（AI）疾病风险单倍型上的变体以等位基因依赖性方式调节调节活性。我们的研究表明，与其他测试的变体类别相比，hQTL作为一个组更有可能调节MPRA中的调节活性，包括一组先前显示与hQTL相互作用的eQTL和测试的AI风险变体。此外，我们提名了17个变体（包括11个以前未报道的）作为SLE的假定因果变体，另外14个用于各种其他AI疾病，优先考虑这些变体用于未来在原代和永生化B细胞中的功能研究。因此，我们揭示了SLE和AI疾病表型中基因型、表观遗传学和基因表达之间的机制关系的重要见解。
We designed a massively parallel reporter assay (MPRA) in an Epstein-Barr virus transformed B cell line to directly characterize the potential for histone post-translational modifications, i.e., histone quantitative trait loci (hQTLs), expression QTLs (eQTLs), and variants on systemic lupus erythematosus (SLE) and autoimmune (AI) disease risk haplotypes to modulate regulatory activity in an allele-dependent manner. Our study demonstrates that hQTLs, as a group, are more likely to modulate regulatory activity in an MPRA compared with other variant classes tested, including a set of eQTLs previously shown to interact with hQTLs and tested AI risk variants. In addition, we nominate 17 variants (including 11 previously unreported) as putative causal variants for SLE and another 14 for various other AI diseases, prioritizing these variants for future functional studies in primary and immortalized B cells. Thus, we uncover important insights into the mechanistic relationships among genotype, epigenetics, and gene expression in SLE and AI disease phenotypes.