Integrating Whole Genome and Transcriptome Sequencing to Characterize the Genetic Architecture of Isoform Variation and its Implications for Health and Disease.

Chunyu Liu, Roby Joehanes, Jiantao Ma, Jiuyong Xie, Jian Yang, Mengyao Wang, Tianxiao Huan, Shih-Jen Hwang, Jia Wen, Quan Sun, Demirkale Y Cumhur, Nancy L Heard-Costa, Peter Orchard, April P Carson, Laura M Raffield, Alexander Reiner, Yun Li, George O'Connor, Joanne M Murabito, Peter Munson, Daniel Levy
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Abstract

We created a comprehensive whole blood splice variation quantitative trait locus (sQTL) resource by analyzing isoform expression ratio (isoform-to-gene) in Framingham Heart Study (FHS) participants (discovery: n=2,622; validation: n=1,094) with whole genome (WGS) and transcriptome sequencing (RNA-seq) data. External replication was conducted using WGS and RNA-seq from the Jackson Heart Study (JHS, n=1,020). We identified over 3.5 million cis -sQTL-isoform pairs ( p <5e-8), comprising 1,176,624 cis -sQTL variants and 10,883 isoform transcripts from 4,971 sGenes, with significant change in isoform-to-gene ratio due to allelic variation. We validated 61% of these pairs in the FHS validation sample ( p <1e-4). External validation ( p <1e-4) in JHS for the top 10,000 and 100,000 most significant cis -sQTL-isoform pairs was 88% and 69%, respectively, while overall pairs validated at 23%. For 20% of cis -sQTLs in the FHS discovery sample, allelic variation did not significantly correlate with overall gene expression. sQTLs are enriched in splice donor and acceptor sites, as well as in GWAS SNPs, methylation QTLs, and protein QTLs. We detailed several sentinel cis -sQTLs influencing alternative splicing, with potential causal effects on cardiovascular disease risk. Notably, rs12898397 (T>C) affects splicing of ULK3 , lowering levels of the full-length transcript ENST00000440863.7 and increasing levels of the truncated transcript ENST00000569437.5, encoding proteins of different lengths. Mendelian randomization analysis demonstrated that a lower ratio of the full-length isoform is causally associated with lower diastolic blood pressure and reduced lymphocyte percentages. This sQTL resource provides valuable insights into how transcriptomic variation may influence health outcomes.

整合全基因组和转录组测序,描述同工酶变异的遗传结构及其对健康和疾病的影响。
我们利用全基因组(WGS)和转录组测序(RNA-seq)数据分析了弗雷明汉心脏研究(FHS)参与者(发现:n=2,622;验证:n=1,094)的同工酶表达比(同工酶-基因),从而创建了一个全面的全血剪接变异定量性状位点(sQTL)资源。利用杰克逊心脏研究(JHS,n=1,020)的 WGS 和 RNA-seq 数据进行了外部复制。我们发现了 350 多万个顺式 -sQTL - 同工酶对(p 顺式 -sQTL 变异和来自 4,971 个 s 基因的 10,883 个同工酶转录物,由于等位基因变异,同工酶与基因的比例发生了显著变化。我们在 FHS 验证样本中验证了 61% 的这些配对(顺式 -sQTL - 同工酶配对的验证率分别为 88% 和 69%,而整体配对的验证率为 23%)。在 FHS 发现样本中,有 20% 的顺式 -sQTL 的等位基因变异与整体基因表达没有显著相关性。sQTL 在剪接供体和受体位点以及 GWAS SNP、甲基化 QTL 和蛋白质 QTL 中富集。我们详细研究了几个影响替代剪接的前哨顺式-sQTLs,它们对心血管疾病风险具有潜在的因果效应。值得注意的是,rs12898397(T>C)会影响 ULK3 的剪接,降低全长转录本 ENST00000440863.7 的水平,增加截短转录本 ENST00000569437.5 的水平,编码不同长度的蛋白质。孟德尔随机分析表明,较低的全长异构体比例与较低的舒张压和较低的淋巴细胞百分比有因果关系。这一 sQTL 资源为了解转录组变异如何影响健康结果提供了宝贵的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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