Hematology and Transfusion Medicine, Department of Laboratory Medicine, BMC B13, 221 84, Lund, Sweden.
Broad Institute of Massachusetts Institute of Technology and Harvard University, 415 Main Street, Boston, MA, 02142, USA.
Nat Commun. 2022 Jan 10;13(1):151. doi: 10.1038/s41467-021-27666-x.
Thousands of non-coding variants have been associated with increased risk of human diseases, yet the causal variants and their mechanisms-of-action remain obscure. In an integrative study combining massively parallel reporter assays (MPRA), expression analyses (eQTL, meQTL, PCHiC) and chromatin accessibility analyses in primary cells (caQTL), we investigate 1,039 variants associated with multiple myeloma (MM). We demonstrate that MM susceptibility is mediated by gene-regulatory changes in plasma cells and B-cells, and identify putative causal variants at six risk loci (SMARCD3, WAC, ELL2, CDCA7L, CEP120, and PREX1). Notably, three of these variants co-localize with significant plasma cell caQTLs, signaling the presence of causal activity at these precise genomic positions in an endogenous chromosomal context in vivo. Our results provide a systematic functional dissection of risk loci for a hematologic malignancy.
数千种非编码变异与人类疾病的风险增加有关，但因果变异及其作用机制仍不清楚。在一项整合研究中，我们结合了大规模平行报告基因分析（MPRA）、表达分析（eQTL、meQTL、PCHiC）和原代细胞染色质可及性分析（caQTL），研究了与多发性骨髓瘤（MM）相关的 1039 个变异。我们证明，MM 的易感性是由浆细胞和 B 细胞中基因调控变化介导的，并在六个风险位点（SMARCD3、WAC、ELL2、CDCA7L、CEP120 和 PREX1）鉴定出潜在的因果变异。值得注意的是，其中三个变异与显著的浆细胞 caQTL 共定位，表明在体内内源性染色体环境中，这些精确基因组位置存在因果活性。我们的研究结果为血液恶性肿瘤的风险位点提供了系统的功能解析。
