Splicing QTL analysis focusing on coding sequences reveals pathogenicity of disease susceptibility loci-猫眼课题宝

DOI：

10.1101/2021.12.30.474578

发表时间：

2022-01

期刊：

bioRxiv

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

Kensuke Yamaguchi;K. Ishigaki;A. Suzuki;Y. Tsuchida;H. Tsuchiya;S. Sumitomo;Y. Nagafuchi;F. Miya;T. Tsunoda;Shoda Hirofumi;K. Fujio;Kazuhiko Yamamoto;Y. Kochi

剪接QTL（sQTL）是GWAS基因座的主要致病机制之一，但其在疾病发病机制中的作用尚不清楚。一个原因是可变剪接事件的巨大复杂性，产生许多未知的异构体。在这里，我们提出了两种新的方法，即整合和选择，这种复杂性，通过专注于蛋白质结构的异构体。首先，我们整合了具有相同编码序列（CDS）的异构体，并在6个免疫亚群中鉴定了369-601个整合异构体比率QTL（i2-rQTL），这些QTL改变了蛋白质结构。其次，我们选择了在GENCODE中注释的CDS不完全异构体，并鉴定了175-337异构体比率QTL（i-rQTL）。通过在这些不完整的异构体中进行全面的长读段捕获RNA-seq，我们发现了29种具有与GWAS性状相关的新型CDS的全长异构体。此外，我们已经表明，可以通过评估其trans-eQTL效应来识别致病sQTL基因。我们的方法突出了蛋白质改变sQTL的未充分研究的作用，并广泛适用于其他组织和疾病。

Splicing QTL (sQTL) are one of the major causal mechanisms in GWAS loci, but their role in disease pathogenesis is poorly understood. One reason is the huge complexity of alternative splicing events producing many unknown isoforms. Here, we proposed two novel approaches, namely integration and selection, for this complexity by focusing on protein-structure of isoforms. First, we integrated isoforms with the same coding sequence (CDS) and identified 369-601 integrated-isoform ratio QTLs (i2-rQTLs), which altered protein-structure, in six immune subsets. Second, we selected CDS incomplete isoforms annotated in GENCODE and identified 175-337 isoform-ratio QTL (i-rQTL). By comprehensive long-read capture RNA-seq among these incomplete isoforms, we revealed 29 full-length isoforms with novel CDSs associated with GWAS traits. Furthermore, we have shown that disease-causal sQTL genes can be identified by evaluating their trans-eQTL effects. Our approaches highlight the understudied role of protein-altering sQTLs and are broadly applicable to other tissues and diseases.

Splicing QTL analysis focusing on coding sequences reveals pathogenicity of disease susceptibility loci

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