Identification of novel type 1 and type 2 diabetes genes by co-localization of human islet eQTL and GWAS variants with colocRedRibbon
Year: 2025
Type: article
Abstract: 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.
Source: Cell Genomics
Authors: Anthony Piron, Florian Szymczak, Lise Folon, Daniel J.M. Crouch, Theodora Papadopoulou, Maria Lytrivi, Yue Tong, Maria Inês Alvelos, Maikel L. Colli, Xiaoyan Yi, Marcin L. Pekalski, Konstantinos Hatzikotoulas, Alicia Huerta-Chagoya, Henry J. Taylor, Matthieu Defrance, John A. Todd, Décio L. Eizirik, Josep M. Mercader, Miriam Cnop
Institutions: Université Libre de Bruxelles, Centre for Human Genetics, University of Oxford, Helmholtz Munich, Harvard University, Massachusetts General Hospital, National Institutes of Health, University of Cambridge, British Heart Foundation, National Human Genome Research Institute, Broad Institute, Massachusetts Institute of Technology, Erasmus Hospital
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $8,900
Funders: American Diabetes Association, Leona M. and Harry B. Helmsley Charitable Trust, European Federation of Pharmaceutical Industries and Associations, Human Islet Research Network, Innovative Health Initiative, European Commission, Fonds De La Recherche Scientifique - FNRS, Fonds Wetenschappelijk Onderzoek, Fondation Philippe Wiener - Maurice Anspach, Ministerstwo Edukacji i Nauki, Università di Pisa, Fonds Alice et David van Buuren, Innovative Medicines Initiative, Uniwersytet Medyczny w Białymstoku, Walloon excellence in life sciences and biotechnology, National Institutes of Health, Horizon 2020 Framework Programme, National Human Genome Research Institute, National Institute of Diabetes and Digestive and Kidney Diseases, H2020 Health, JDRF
Awards: G1029617247, G1769912367, iPLA2beta-mediated alternative splicing and beta-cell death in type 1 diabetes, GENOMIC, PHYSIOLOGICAL AND PHARMACOLOGICAL CHARACTERIZATION OF GENETIC VARIATION ASSOCIATED WITH TYPE 2 DIABETES IN LATIN AMERICANS, G2959005975, Translational approaches to disease modifying therapy of type 1 diabetes - HARVESTing the fruits of INNODIA, Development of a systems biomedicine approach for risk identification, prevention and treatment of type 2 diabetes, G3544627429, G4052596415, G4077097149, Development of a systems biomedicine approach for risk identification, prevention and treatment of type 2 diabetes, Translational approaches to disease modifying therapy of type 1 diabetes: an innovative approach towards understanding and arresting type 1 diabetes – Sofia ref.: 115797, G7360159043, G7696965656, G8312218698, Identification of mechanistic pathways driving type 2 diabetes risk in Latin American populations, Interferon Signaling in the T1D Islet Microenvironment, Development of Polygenic Risk Scores for Diabetes and Complications across the Life-Span in Populations of Multiple Ancestries, GEneration and assessment of Multi-omic informed Subtypes of Type 2 Diabetes in Diverse Populations (GEMS-T2D), Cataloging multi-ancestry 'omic readouts of the environmental and genetic determinants of type 2 diabetes, Implications of Changes in Islet Exosomal Cargo in Type 1 Diabetes, G973953574
OpenAlex ID: W4414301431