Genetic regulation of RNA splicing in human pancreatic islets.
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
Journal
Genome biology
ISSN: 1474-760X
Titre abrégé: Genome Biol
Pays: England
ID NLM: 100960660
Informations de publication
Date de publication:
15 09 2022
15 09 2022
Historique:
received:
24
12
2021
accepted:
23
08
2022
entrez:
15
9
2022
pubmed:
16
9
2022
medline:
20
9
2022
Statut:
epublish
Résumé
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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 36109769
doi: 10.1186/s13059-022-02757-0
pii: 10.1186/s13059-022-02757-0
pmc: PMC9479353
doi:
Substances chimiques
Protein Isoforms
0
RNA, Long Noncoding
0
Proinsulin
9035-68-1
DCLRE1B protein, human
EC 3.1.-
Exodeoxyribonucleases
EC 3.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
196Subventions
Organisme : Medical Research Council
ID : MC_PC_17228
Pays : United Kingdom
Organisme : Wellcome Trust
ID : WT101033
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L02036X/1
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 200837/Z/16/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_QA137853
Pays : United Kingdom
Investigateurs
Miriam Cnop
(M)
Lena Eliasson
(L)
Jonathan Lou S Esguerra
(JLS)
Décio L Eizirik
(DL)
Leif Groop
(L)
Thomas S Jensen
(TS)
Torben Hansen
(T)
Piero Marchetti
(P)
Josep M Mercader
(JM)
Hindrik Mulder
(H)
Chris R Stabile-Barnett
(CR)
Christian Thirion
(C)
David Torrents
(D)
Informations de copyright
© 2022. The Author(s).
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