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  • Atla, GouthamCIBER Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) (author)

Genetic regulation of RNA splicing in human pancreatic islets

  • Article/chapterEnglish2022

Publisher, publication year, extent ...

  • 2022-09-15
  • Springer Science and Business Media LLC,2022

Numbers

  • LIBRIS-ID:oai:lup.lub.lu.se:d1a3edfa-a90c-4412-8c03-e03b7f2d465a
  • https://lup.lub.lu.se/record/d1a3edfa-a90c-4412-8c03-e03b7f2d465aURI
  • https://doi.org/10.1186/s13059-022-02757-0DOI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:art swepub-publicationtype
  • Subject category:ref swepub-contenttype

Notes

  • BackgroundNon-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.ResultsWe 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.ConclusionsThese 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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Added entries (persons, corporate bodies, meetings, titles ...)

  • Bonàs-Guarch, SilviaBarcelona Institute of Science and Technology (author)
  • Cuenca-Ardura, MirabaiCIBER Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) (author)
  • Beucher, AnthonyBarcelona Institute of Science and Technology (author)
  • Crouch, Daniel J. M.University of Oxford (author)
  • Garcia-Hurtado, JavierCIBER Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) (author)
  • Moran, IgnasiImperial College London (author)
  • Consortium, the T2DSystems (author)
  • Irimia, ManuelBarcelona Institute of Science and Technology (author)
  • Prasad, Rashmi B.Lund University,Lunds universitet,Genomik, diabetes och endokrinologi,Forskargrupper vid Lunds universitet,Genomics, Diabetes and Endocrinology,Lund University Research Groups,Skåne University Hospital(Swepub:lu)med-rpa (author)
  • Gloyn, Anna L.University of Oxford (author)
  • Marselli, LorellaUniversity of Pisa (author)
  • Berney, Thierry (author)
  • de Koning, Eelco J. P. (author)
  • Kerr-Conte, Julie (author)
  • Pattou, Francois (author)
  • Todd, John A. (author)
  • Piemonti, Lorenzo (author)
  • Ferrer, Jorge (author)
  • Eliasson, LenaLund University,Lunds universitet,Diabetes - öcellsexocytos,Forskargrupper vid Lunds universitet,Diabetes - Islet Cell Exocytosis,Lund University Research Groups,Skåne University Hospital(Swepub:lu)mphy-lel (creator_code:cre_t)
  • Esguerra, Jonathan Lou S.Lund University,Lunds universitet,Diabetes - öcellsexocytos,Forskargrupper vid Lunds universitet,Diabetes - Islet Cell Exocytosis,Lund University Research Groups(Swepub:lu)med-jer (creator_code:cre_t)
  • Groop, LeifLund University,Lunds universitet,Genomik, diabetes och endokrinologi,Forskargrupper vid Lunds universitet,Genomics, Diabetes and Endocrinology,Lund University Research Groups(Swepub:lu)endo-lgr (creator_code:cre_t)
  • Mulder, HindrikLund University,Lunds universitet,Diabetes - molekylär metabolism,Forskargrupper vid Lunds universitet,Diabetes - Molecular Metabolism,Lund University Research Groups(Swepub:lu)medk-hmu (creator_code:cre_t)
  • CIBER Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)Barcelona Institute of Science and Technology (creator_code:org_t)

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  • In:Genome Biology: Springer Science and Business Media LLC23, s. 1-281474-760X

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