Atla, GouthamBonàs-Guarch, SilviaCuenca-Ardura, MirabaiBeucher, AnthonyCrouch, Daniel J.M.García-Hurtado, JavierMoran, IgnasiT2DSystems ConsortiumIrimia Martínez, ManuelPrasad, Rashmi B.Gloyn, Anna L.Marselli, LorellaSuleiman, MaraBerney, ThierryKoning, Eelco J.P. deKerr-Conte, JuliePattou, FrancoisTodd, John A.Piemonti, LorenzoFerrer, Jorge2022-10-282022-10-282022Atla G, Bonàs-Guarch S, Cuenca-Ardura M, Beucher A, Crouch DJM, Garcia-Hurtado J, Moran I; T2DSystems Consortium, Irimia M, Prasad RB, Gloyn AL, Marselli L, Suleiman M, Berney T, de Koning EJP, Kerr-Conte J, Pattou F, Todd JA, Piemonti L, Ferrer J. Genetic regulation of RNA splicing in human pancreatic islets. Genome Biol. 2022 Sep 15;23(1):196. DOI: 10.1186/s13059-022-02757-01474-7596http://hdl.handle.net/10230/54636Background: 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.application/pdfeng© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1186/s13059-022-02757-0Beta cellsCTRB2Diabetes pathophysiologyG-protein signalingPancreatic beta-cellsPancreatic isletsQuantitative trait lociRNA splicingSenescenceTWASType 1 diabetesType 2 diabetesinfo:eu-repo/semantics/openAccess