Imperial College London
Alternate

ProfessorJorgeFerrer

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Chair in Medicine and Genetics
 
 
 
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Contact

 

+44 (0)20 7594 0968j.ferrer

 
 
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Location

 

535ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Atla:2022:10.1186/s13059-022-02757-0,
author = {Atla, G and Bonas-Guarch, S and Cuenca-Ardura, M and Beucher, A and Crouch, DJM and Garcia-Hurtado, J and Moran, I and the, T2DSystems Consortium and Irimia, M and Prasad, RB and Gloyn, AL and Marselli, L and Suleiman, M and Berney, T and de, Koning EJP and Kerr-Conte, J and Pattou, F and Todd, JA and Piemonti, L and Ferrer, J},
doi = {10.1186/s13059-022-02757-0},
journal = {Genome Biology},
pages = {1--28},
title = {Genetic regulation of RNA splicing in human pancreatic islets},
url = {http://dx.doi.org/10.1186/s13059-022-02757-0},
volume = {23},
year = {2022}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Background: Noncoding 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 noncoding variants influence diabetes susceptibility are unknown. Results: We examine splicing QTLs (sQTLs) in pancreatic islets from 399 human donors and observe that genetic variation has a widespread influence on splicing of genes with established roles in islet biology and diabetes. In parallel, we profile expression QTLs (eQTLs) and use transcriptomewide association as well as genetic colocalization 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 ERstress and proinsulin biosynthesis. The expanded list of T2D risk effector genes reveals overrepresented pathways, including regulators of Gproteinmediated cAMP production. The analysis of sQTLs also reveals candidate effector genesfor 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.
AU  - Atla,G
AU  - Bonas-Guarch,S
AU  - Cuenca-Ardura,M
AU  - Beucher,A
AU  - Crouch,DJM
AU  - Garcia-Hurtado,J
AU  - Moran,I
AU  - the,T2DSystems Consortium
AU  - Irimia,M
AU  - Prasad,RB
AU  - Gloyn,AL
AU  - Marselli,L
AU  - Suleiman,M
AU  - Berney,T
AU  - de,Koning EJP
AU  - Kerr-Conte,J
AU  - Pattou,F
AU  - Todd,JA
AU  - Piemonti,L
AU  - Ferrer,J
DO  - 10.1186/s13059-022-02757-0
EP  - 28
PY  - 2022///
SN  - 1474-7596
SP  - 1
TI  - Genetic regulation of RNA splicing in human pancreatic islets
T2  - Genome Biology
UR  - http://dx.doi.org/10.1186/s13059-022-02757-0
UR  - https://genomebiology.biomedcentral.com/articles/10.1186/s13059-022-02757-0
UR  - http://hdl.handle.net/10044/1/99574
VL  - 23
ER  -
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