Tewhey Ryan, Kotliar Dylan, Park Daniel S, Liu Brandon, Winnicki Sarah, Reilly Steven K, Andersen Kristian G, Mikkelsen Tarjei S, Lander Eric S, Schaffner Stephen F, Sabeti Pardis C
Center for Systems Biology, Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA; Broad Institute, Cambridge, MA 02142, USA.
Center for Systems Biology, Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA; Broad Institute, Cambridge, MA 02142, USA.
Cell. 2016 Jun 2;165(6):1519-1529. doi: 10.1016/j.cell.2016.04.027.
Although studies have identified hundreds of loci associated with human traits and diseases, pinpointing causal alleles remains difficult, particularly for non-coding variants. To address this challenge, we adapted the massively parallel reporter assay (MPRA) to identify variants that directly modulate gene expression. We applied it to 32,373 variants from 3,642 cis-expression quantitative trait loci and control regions. Detection by MPRA was strongly correlated with measures of regulatory function. We demonstrate MPRA's capabilities for pinpointing causal alleles, using it to identify 842 variants showing differential expression between alleles, including 53 well-annotated variants associated with diseases and traits. We investigated one in detail, a risk allele for ankylosing spondylitis, and provide direct evidence of a non-coding variant that alters expression of the prostaglandin EP4 receptor. These results create a resource of concrete leads and illustrate the promise of this approach for comprehensively interrogating how non-coding polymorphism shapes human biology.
尽管已有研究确定了数百个与人类性状和疾病相关的基因座，但确定因果等位基因仍然很困难，尤其是对于非编码变异。为了应对这一挑战，我们采用了大规模平行报告基因检测法（MPRA）来识别直接调节基因表达的变异。我们将其应用于来自3642个顺式表达定量性状基因座和调控区域的32373个变异。MPRA检测结果与调控功能指标高度相关。我们展示了MPRA在确定因果等位基因方面的能力，利用它识别出842个在等位基因间表现出差异表达的变异，其中包括53个与疾病和性状相关的注释良好的变异。我们详细研究了其中一个，即强直性脊柱炎的一个风险等位基因，并提供了一个非编码变异改变前列腺素EP4受体表达的直接证据。这些结果创造了一个具体线索的资源，并说明了这种方法在全面探究非编码多态性如何塑造人类生物学方面的前景。
