2022,
Genome Biology.
DOI:
10.1186/s13059-022-02757-0
Genetic regulation of RNA splicing in human pancreatic islets
Abstract:
Background
Non-coding genetic variants that influence gene transcription in pancreatic islets play a major role in the susceptibility to type 2 diabetes (T2D), and likely also contribute to type 1 diabetes (T1D) risk. For many loci, however, the mechanisms through which non-coding variants influence diabetes susceptibility are unknown.
Results
We examine splicing QTLs (sQTLs) in pancreatic islets from 399 human donors and observe that common genetic variation has a widespread influence on the splicing of genes with established roles in islet biology and diabetes. In parallel, we profile expression QTLs (eQTLs) and use transcriptome-wide association as well as genetic co-localization studies to assign islet sQTLs or eQTLs to T2D and T1D susceptibility signals, many of which lack candidate effector genes. This analysis reveals biologically plausible mechanisms, including the association of T2D with an sQTL that creates a nonsense isoform in ERO1B , a regulator of ER-stress and proinsulin biosynthesis. The expanded list of T2D risk effector genes reveals overrepresented pathways, including regulators of G-protein-mediated cAMP production. The analysis of sQTLs also reveals candidate effector genes for T1D susceptibility such as DCLRE1B , a senescence regulator, and lncRNA MEG3 .
Conclusions
These data expose widespread effects of common genetic variants on RNA splicing in pancreatic islets. The results support a role for splicing variation in diabetes susceptibility, and offer a new set of genetic targets with potential therapeutic benefit.
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2022-09-22 22:58:00
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#paper doi: 10.1186/s13059-022-02757-0 Genome Biology, 2022, Genetic regulation of RNA splicing in human pancreatic islets。在胰岛细胞中存在的非编码编译影响了细胞转录组，从而在I型和II型糖尿病发病过程中可能扮演重要角色。本文在由399名患者组成的队列中分析了一类特殊的常见基因组变异（sQTL，splicing QTL，那些能可变剪接事件的QTL）。sQTL 的靶基因不同于eQTL，暗示着两类QTL可能独立发挥作用。作者识别了一批新的与sQTL关联的I型和II型糖尿病风险基因。作者据此认为胰岛细胞中的可变剪接事件是重要的糖尿病风险因素。