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Atla, G.; Bonas-Guarch, S.; Cuenca-Ardura, M.; Beucher, A.; Crouch, D.J.M.; Garcia-Hurtado, J.; ... ; T2DSyst Consortium (2022)

Genetic regulation of RNA splicing in human pancreatic islets

Article / Letter to editor
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...Show moreBackground: 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.Show less
RNA splicing
Type 1 diabetes
Type 2 diabetes
TWAS
G-protein signaling
Pancreatic islets
Beta cells
Senescence
CTRB2
Pancreatic beta-cells
Diabetes pathophysiology
Quantitative trait loci
All authors
Atla, G.; Bonas-Guarch, S.; Cuenca-Ardura, M.; Beucher, A.; Crouch, D.J.M.; Garcia-Hurtado, J.; Moran, I.; Irimia, M.; Prasad, R.B.; Gloyn, A.L.; Marselli, L.; Suleiman, M.; Berney, T.; Koning, E.J.P. de; Kerr-Conte, J.; Pattou, F.; Todd, J.A.; Piemonti, L.; Ferrer, J.; T2DSyst Consortium
Date
2022-09-15
Journal
Genome Biology
Volume
23
Issue
1
DOI
doi:10.1186/s13059-022-02757-0