Over 1,000 distinct genetic variants have been associated with diabetes risk by genome-wide association studies (GWAS) but for most their functional impact is unknown and less than 15% of the diabetes GWAS variants have been shown in expression quantitative trait locus (eQTL) studies to alter gene expression in pancreatic islets. To fill this gap, we developed a new co-localization pipeline, called colocRedRibbon, that prefilters eQTL variants by direction of effect on gene expression, shortlists overlapping eQTL and GWAS variants and then runs the co-localization. Applying colocRedRibbon to diabetes and glycemic trait GWAS, we identified 292 co-localizing gene regions - 236 of which are new - including 24 co-localizations for type 1 diabetes and 268 for type 2 diabetes and glycemic traits. We achieved a four-fold increase in co-localizations, with the novel pipeline and updated GWAS each contributing two-fold. Among the co-localizations are a low frequency variant increasing MYO5C expression that reduces type 2 diabetes risk and a type 1 diabetes protective variant that increases FUT2 and decreases RASIP1 expression. These novel co-localizations represent a significant step forward to understand polygenic diabetes genetics and its impact on human islet gene expression.

The authors have declared no competing interest.

This work has been supported by the European Union's Horizon 2020 research and innovation program T2DSystems under grant agreement no. 667191, the Fonds National de la Recherche Scientifique (FNRS), the Walloon Region SPW-EER Win2Wal project BetaSource, Belgium, the FWO and FRS-FNRS under the Excellence of Science (EOS) programme (Pandarome project 40007487), the Walloon Region strategic axis FRFS-WELBIO, and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement 115797 (INNODIA) and 945268 (INNODIA HARVEST). This latter Joint Undertaking received support from the Union's Horizon 2020 research and innovation programme and the European Federation of Pharmaceutical Industries and Associations, JDRF, and The Leona M. and Harry B. Helmsley Charitable Trust. A.P. is supported by Fonds David et Alice Van Buuren, Fondation Jaumotte-Demoulin, Fondation Héger-Masson, Fondation Wiener-Anspach and FNRS. F.S. is supported by a Research Fellow FNRS fellowship. D.L.E. is supported by grants from the JDRF International (now T1D Breakthrough) (3-SRA-2022-1201-S-B and 3-SRA-2022-1201-S-B); the National Institutes of Health Human Islet Research Network Consortium on Beta Cell Death & Survival from Pancreatic β-Cell Gene Networks to Therapy (HIRN-CBDS) (grant U01 DK127786); and the National Institutes of Health NIDDK grants RO1DK126444 and RO1DK133881-01. J.M.M. is supported by American Diabetes Association grant #11-22-ICTSPM-16, NHGRI U01HG011723, the National Institute Of Diabetes And Digestive And Kidney Diseases of the National Institutes of Health under Award Number R01DK137993 and U01DK140757, and a Medical University of Bialystok (MUB) grant from the Ministry of Science and Higher Education (Poland).

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