Genetic regulation of RNA splicing in human pancreatic islets

Atla, G.; Bonas-Guarch, S.; Cuenca, M.; Beucher, A.; Garcia-Hurtado, J.; Moran, I.; Irimia, M.; Prasad, R. B.; Gloyn, A. L.; Marselli, l.; Suleiman, M.; Berney, T.; de Koning, E. J. P.; Kerr-Conte, J.; Pattou, F.; Piemonti, L.; Ferrer, J.

doi:10.1101/2021.11.11.468254

bioRxiv · 10.1101/2021.11.11.468254

Genetic regulation of RNA splicing in human pancreatic islets

Atla, G.·Bonas-Guarch, S.·Cuenca, M.·Beucher, A.·Garcia-Hurtado, J.·Moran, I.·Irimia, M.·Prasad, R. B.·Gloyn, A. L.·Marselli, l.·Suleiman, M.·Berney, T.·de Koning, E. J. P.·Kerr-Conte, J.·Pattou, F.·Piemonti, L.·Ferrer, J.

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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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Atla, G., Bonas-Guarch, S., Cuenca, M., Beucher, A., Garcia-Hurtado, J., Moran, I., Irimia, M., Prasad, R. B., Gloyn, A. L., Marselli, l., Suleiman, M., Berney, T., de Koning, E. J. P., Kerr-Conte, J., Pattou, F., Piemonti, L., Ferrer, J.. 2021-11-13. Genetic regulation of RNA splicing in human pancreatic islets. https://doi.org/10.1101/2021.11.11.468254

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