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Genetic regulation of RNA splicing in human pancreatic islets

Atla, Goutham ; Bonàs-Guarch, Silvia ; Cuenca-Ardura, Mirabai ; Beucher, Anthony ; Crouch, Daniel J. M. ; Garcia-Hurtado, Javier ; Moran, Ignasi ; Consortium, the T2DSystems ; Irimia, Manuel and Prasad, Rashmi B. LU , et al. (2022) In Genome Biology 23. p.1-28
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... (More)
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. (Less)
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LU orcid ; LU orcid ; LU and LU orcid
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Genome Biology
volume
23
article number
196
pages
1 - 28
publisher
BioMed Central (BMC)
external identifiers
  • scopus:85137930726
  • pmid:36109769
ISSN
1474-760X
DOI
10.1186/s13059-022-02757-0
language
English
LU publication?
yes
id
d1a3edfa-a90c-4412-8c03-e03b7f2d465a
date added to LUP
2022-09-17 16:57:25
date last changed
2024-04-04 09:02:50
@article{d1a3edfa-a90c-4412-8c03-e03b7f2d465a,
  abstract     = {{Background<br/>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.<br/><br/>Results<br/>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.<br/><br/>Conclusions<br/>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.}},
  author       = {{Atla, Goutham and Bonàs-Guarch, Silvia and Cuenca-Ardura, Mirabai and Beucher, Anthony and Crouch, Daniel J. M. and Garcia-Hurtado, Javier and Moran, Ignasi and Consortium, the T2DSystems and Irimia, Manuel and Prasad, Rashmi B. and Gloyn, Anna L. and Marselli, Lorella and Berney, Thierry and de Koning, Eelco J. P. and Kerr-Conte, Julie and Pattou, Francois and Todd, John A. and Piemonti, Lorenzo and Ferrer, Jorge}},
  issn         = {{1474-760X}},
  language     = {{eng}},
  pages        = {{1--28}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Genome Biology}},
  title        = {{Genetic regulation of RNA splicing in human pancreatic islets}},
  url          = {{http://dx.doi.org/10.1186/s13059-022-02757-0}},
  doi          = {{10.1186/s13059-022-02757-0}},
  volume       = {{23}},
  year         = {{2022}},
}