Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Nat Commun. 2020 Mar 6;11(1):1237. doi: 10.1038/s41467-020-15022-4.
Genome-wide association studies have associated thousands of genetic variants with complex traits and diseases, but pinpointing the causal variant(s) among those in tight linkage disequilibrium with each associated variant remains a major challenge. Here, we use seven experimental assays to characterize all common variants at the multiple disease-associated TNFAIP3 locus in five disease-relevant immune cell lines, based on a set of features related to regulatory potential. Trait/disease-associated variants are enriched among SNPs prioritized based on either: (1) residing within CRISPRi-sensitive regulatory regions, or (2) localizing in a chromatin accessible region while displaying allele-specific reporter activity. Of the 15 trait/disease-associated haplotypes at TNFAIP3, 9 have at least one variant meeting one or both of these criteria, 5 of which are further supported by genetic fine-mapping. Our work provides a comprehensive strategy to characterize genetic variation at important disease-associated loci, and aids in the effort to identify trait causal genetic variants.
全基因组关联研究已经将数千种遗传变异与复杂性状和疾病联系起来，但在与每个相关变异紧密连锁的遗传变异中确定因果变异仍然是一个主要挑战。在这里，我们使用七种实验方法，根据与调节潜能相关的一系列特征，在五个与疾病相关的免疫细胞系中对与多种疾病相关的 TNFAIP3 基因座的所有常见变异进行了特征描述。基于以下两种方法之一，优先考虑的 SNP 中富集了与性状/疾病相关的变异：（1）位于 CRISPRi 敏感的调节区域内，或（2）位于染色质可及区域中，同时显示等位基因特异性报告基因活性。在 TNFAIP3 的 15 个与性状/疾病相关的单倍型中，有 9 个至少有一个符合上述一个或两个标准的变异，其中 5 个进一步得到遗传精细映射的支持。我们的工作提供了一种全面的策略来描述重要疾病相关基因座的遗传变异，并有助于识别性状因果遗传变异。
