Genetic regulation of RNA splicing in human pancreatic islets

Goutham Atla, Silvia Bonàs-Guarch, Mirabai Cuenca-Ardura, Anthony Beucher, Daniel J. M. Crouch, Javier Garcia-Hurtado, Ignasi Moran, the T2DSystems Consortium, Manuel Irimia, Rashmi B. Prasad, Anna L. Gloyn, Lorella Marselli, Mara Suleiman, Thierry Berney, Eelco J. P. de Koning, Julie Kerr-Conte, Francois Pattou, John A. Todd, Lorenzo Piemonti & Jorge Ferrer.
Genome Biol. 2022-09-15;23(1):196.
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. Keywords: Beta cells; CTRB2; Diabetes pathophysiology; G-protein signaling; Pancreatic beta-cells; Pancreatic islets; Quantitative trait loci; RNA splicing; Senescence; TWAS; Type 1 diabetes; Type 2 diabetes.