Genetic regulation of RNA splicing in human pancreatic islets

Goutham Atla; Sílvia Bonàs‐Guarch; Mirabai Cuenca-Ardura; Anthony Beucher; Daniel J. M. Crouch; Javier García-Hurtado; Ignasi Morán; Miriam Cnop; Lena Eliasson; Jonathan L.S. Esguerra; Decio Laks Eizirik; Leif Groop; Thomas Skøt Jensen; Torben F. Hansen; Piero Marchetti; Josep Maria Mercader; Hindrik Mulder; Chris R. Stabile-Barnett; Christian Thirion; David Torrents; Manuel Irimia; Rashmi B. Prasad; Anna L. Gloyn; Lorella Marselli; Mara Suleiman; Thierry Berney; Eelco J.P. de Koning; Julie A. Kerr-Conte; François N. Pattou; John A. Todd

doi:10.1186/s13059-022-02757-0

GeneticsGenome biologySep 15, 2022

Peer-reviewed journal article

Genetic regulation of RNA splicing in human pancreatic islets

Goutham Atla iD, Sílvia Bonàs‐Guarch iD, Mirabai Cuenca-Ardura iD, Anthony Beucher iD, Daniel J. M. Crouch iD, Javier García-Hurtado iD, Ignasi Morán iD, Miriam Cnop iD, Lena Eliasson iD, Jonathan L.S. Esguerra iD, Decio Laks Eizirik iD, Leif Groop iD, Thomas Skøt Jensen iD, Torben F. Hansen iD, Piero Marchetti iD, Josep Maria Mercader iD, Hindrik Mulder iD, Chris R. Stabile-Barnett, Christian Thirion iD, David Torrents iD, Manuel Irimia iD, Rashmi B. Prasad iD, Anna L. Gloyn iD, Lorella Marselli iD, Mara Suleiman iD, , Jorge P. Ferrer iD

Abstract

Genetic variants that influence transcriptional regulation in pancreatic islets play a major role in the susceptibility to type 2 diabetes (T2D). For many susceptibility loci, however, the mechanisms are unknown. We examined splicing QTLs (sQTLs) in islets from 399 donors and observed that genetic variation has a widespread influence on splicing of genes with important functions in islet biology. In parallel, we profiled expression QTLs, and used transcriptome-wide association and co-localization studies to assign islet sQTLs or eQTLs to T2D susceptibility signals that lacked candidate effector genes. We found novel T2D associations, including an sQTL that creates a nonsense isoform in ERO1B, a regulator of ER-stress and proinsulin biosynthesis. The expanded list of T2D risk effectors revealed overrepresented pathways, including regulators of G-protein-mediated cAMP production. This data exposes an underappreciated layer of genetic regulation in pancreatic islets, and nominates molecular mediators of T2D susceptibility.

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