Genetic regulation of RNA splicing in human pancreatic islets

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• dc.contributor.author Atla, Goutham
• dc.contributor.author Bonàs-Guarch, Silvia
• dc.contributor.author Cuenca-Ardura, Mirabai
• dc.contributor.author Beucher, Anthony
• dc.contributor.author Crouch, Daniel J.M.
• dc.contributor.author García-Hurtado, Javier
• dc.contributor.author Moran, Ignasi
• dc.contributor.author T2DSystems Consortium
• dc.contributor.author Irimia Martínez, Manuel
• dc.contributor.author Prasad, Rashmi B.
• dc.contributor.author Gloyn, Anna L.
• dc.contributor.author Marselli, Lorella
• dc.contributor.author Suleiman, Mara
• dc.contributor.author Berney, Thierry
• dc.contributor.author Koning, Eelco J.P. de
• dc.contributor.author Kerr-Conte, Julie
• dc.contributor.author Pattou, Francois
• dc.contributor.author Todd, John A.
• dc.contributor.author Piemonti, Lorenzo
• dc.contributor.author Ferrer, Jorge
• dc.date.accessioned 2022-10-28T06:50:21Z
• dc.date.available 2022-10-28T06:50:21Z
• dc.date.issued 2022
• dc.description.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.
• dc.description.sponsorship This research was supported by Ministerio de Ciencia e Innovación (BFU2014-54284-R, RTI2018-095666-B-I00), Medical Research Council (MR/L02036X/1), a Wellcome Trust Senior Investigator Award (WT101033), European Research Council Advanced Grant (789055), EU Horizon 2020 TDSystems (667191), ESPACE (874710), and Marie Sklodowska-Curie (643062, ZENCODE). S.B.G was supported by a Juan de la Cierva postdoctoral fellowship (MINECO; FJCI-2017-32090). M.C.A was supported by a Boehringer Ingelheim Fonds PhD fellowship. Work in CRG was supported by the CERCA Programme, Generalitat de Catalunya, Centro de Excelencia Severo Ochoa (CEX2020-001049), and support of the Spanish Ministry of Science and Innovation to the EMBL partnership. Work in Imperial College was supported by NIHR Imperial Biomedical Research Centre. M.I. was supported by a European Research Council consolidator award (101002275). D.J.M.C. and J.A.T. were supported by JDRF grants 9-2011-253, 5-SRA-2015-130-A-N, 4- SRA-2017-473-A-N, and Wellcome grants 091157/Z/10/Z and 107212/Z/15/Z, to the Diabetes and Inflammation Laboratory, Oxford, as well as the Oxford Biomedical Research Computing (BMRC) facility, a joint development between the Wellcome Centre for Human Genetics and the Big Data Institute supported by Health Data Research UK and NIHR Oxford Biomedical Research Centre, and Wellcome Trust Core Award grant 203141/Z/16/Z. D.M.J.C analysis with the UK Biobank Resource was conducted under Application 31295. A.L.G. is a Wellcome Senior Fellow in Basic Biomedical Science and was supported by the Wellcome Trust (095101, 200837, 106130, 203141), the NIDDK (U01DK105535 and UM1 DK126185), and the Oxford NIHR Biomedical Research Centre.
• dc.format.mimetype application/pdf
• dc.identifier.citation Atla 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/s13059-022-02757-0
• dc.identifier.doi http://dx.doi.org/10.1186/s13059-022-02757-0
• dc.identifier.issn 1474-7596
• dc.identifier.uri http://hdl.handle.net/10230/54636
• dc.language.iso eng
• dc.publisher BioMed Central
• dc.relation.ispartof Genome Biol. 2022 Sep 15;23(1):196
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/789055
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2014-54284-R
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-095666-B-I00
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/667191
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/874710
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/643062
• dc.rights © 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.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Beta cells
• dc.subject.keyword CTRB2
• dc.subject.keyword Diabetes pathophysiology
• dc.subject.keyword G-protein signaling
• dc.subject.keyword Pancreatic beta-cells
• dc.subject.keyword Pancreatic islets
• dc.subject.keyword Quantitative trait loci
• dc.subject.keyword RNA splicing
• dc.subject.keyword Senescence
• dc.subject.keyword TWAS
• dc.subject.keyword Type 1 diabetes
• dc.subject.keyword Type 2 diabetes
• dc.title Genetic regulation of RNA splicing in human pancreatic islets
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion