Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Nat Commun. 2024 May 6;15(1):3786. doi: 10.1038/s41467-024-48244-x.
Expression quantitative trait loci (eQTL) studies typically consider exon expression of genes and discard intronic RNA sequencing reads despite their information on RNA metabolism. Here, we quantify genetic effects on exon and intron levels of genes and their ratio in lymphoblastoid cell lines, revealing thousands of cis-QTLs of each type. While genetic effects are often shared between cis-QTL types, 7814 (47%) are not detected as top cis-QTLs at exon levels. We show that exon levels preferentially capture genetic effects on transcriptional regulation, while exon-intron-ratios better detect those on co- and post-transcriptional processes. Considering all cis-QTL types substantially increases (by 71%) the number of colocalizing variants identified by genome-wide association studies (GWAS). It further allows dissecting the potential gene regulatory processes underlying GWAS associations, suggesting comparable contributions by transcriptional (50%) and co- and post-transcriptional regulation (46%) to complex traits. Overall, integrating intronic RNA sequencing reads in eQTL studies expands our understanding of genetic effects on gene regulatory processes.
表达数量性状基因座（eQTL）研究通常考虑基因的外显子表达，并丢弃内含子 RNA 测序读数，尽管它们提供了有关 RNA 代谢的信息。在这里，我们定量研究了基因的外显子和内含子水平及其在淋巴母细胞系中的比值的遗传效应，揭示了数千种每种类型的顺式-QTL。虽然遗传效应通常在顺式-QTL 类型之间共享，但有 7814 个（47%）在exon 水平上未被检测为顶级顺式-QTL。我们表明，exon 水平优先捕获对转录调控的遗传效应，而 exon-intron-ratio 则更好地检测对共转录和转录后过程的遗传效应。考虑所有顺式-QTL 类型可大大增加（增加 71%）全基因组关联研究（GWAS）中鉴定的共定位变体数量。它进一步允许剖析 GWAS 关联背后潜在的基因调控过程，表明转录（50%）和共转录和转录后调节（46%）对复杂性状的贡献相当。总体而言，在 eQTL 研究中整合内含子 RNA 测序读数扩展了我们对基因调控过程中遗传效应的理解。
