The resources generated by the GTEx consortium offer unprecedented opportunities to advance our understanding of the biology of human diseases. Here, we present an in-depth examination of the phenotypic consequences of transcriptome regulation and a blueprint for the functional interpretation of genome-wide association study-discovered loci. Across a broad set of complex traits and diseases, we demonstrate widespread dose-dependent effects of RNA expression and splicing. We develop a data-driven framework to benchmark methods that prioritize causal genes and find no single approach outperforms the combination of multiple approaches. Using colocalization and association approaches that take into account the observed allelic heterogeneity of gene expression, we propose potential target genes for 47% (2,519 out of 5,385) of the GWAS loci examined. Our results demonstrate the translational relevance of the GTEx resources and highlight the need to increase their resolution and breadth to further our understanding of the genotype-phenotype link.

中文翻译：

---

利用GTEx资源来解密GWAS位点的机制

GTEx联盟产生的资源提供了前所未有的机会，可以增进我们对人类疾病生物学的理解。在这里，我们介绍了转录组调控的表型后果的深入检查，以及对全基因组关联研究发现的基因座进行功能解释的蓝图。在广泛的复杂性状和疾病中，我们证明了RNA表达和剪接的广泛剂量依赖性效应。我们开发了一个数据驱动的框架来对优先考虑因果基因的方法进行基准测试，发现没有任何一种方法能胜过多种方法的组合。使用考虑到观察到的基因表达等位基因异质性的共定位和关联方法，我们提出了47％（5,385个中的2,519个）GWAS基因座的潜在靶基因。