Identification of novel type 1 and type 2 diabetes genes by co-localization of human islet eQTL and GWAS variants with colocRedRibbon

Anthony Piron¹, Florian Szymczak², Lise Folon³, Daniel J M Crouch⁴, Theodora Papadopoulou³, Maria Lytrivi³, Yue Tong³, Maria Inês Alvelos³, Maikel L Colli³, Xiaoyan Yi³, Marcin L Pekalski⁵, Konstantinos Hatzikotoulas⁶, Alicia Huerta-Chagoya⁷, Henry J Taylor⁸; Type 2 Diabetes Global Genomics Initiative; Matthieu Defrance⁹, John A Todd⁴, Décio L Eizirik³, Josep M Mercader¹⁰, Miriam Cnop¹¹

Affiliations

¹ ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, 1070 Brussels, Belgium; Pharmacognosy, Bioanalysis and Drug Discovery, Pharmacy Faculty, Université Libre de Bruxelles, 1050 Brussels, Belgium; Interuniversity Institute of Bioinformatics in Brussels (IB2), 1050 Brussels, Belgium; JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK. Electronic address: anthony.piron@ulb.be.
² ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, 1070 Brussels, Belgium; Interuniversity Institute of Bioinformatics in Brussels (IB2), 1050 Brussels, Belgium.
³ ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, 1070 Brussels, Belgium.
⁴ JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK.
⁵ JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK; Military Institute of Medicine, National Research Institute Warsaw, Warsaw, Poland.
⁶ Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
⁷ Diabetes Unit, Massachusetts General Hospital, Boston, MA 02144, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
⁸ Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-2152, USA; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB2 0BB, UK; Heart and Lung Research Institute, University of Cambridge, Cambridge CB2 0BB, UK.
⁹ Interuniversity Institute of Bioinformatics in Brussels (IB2), 1050 Brussels, Belgium.
¹⁰ Diabetes Unit, Massachusetts General Hospital, Boston, MA 02144, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹¹ ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, 1070 Brussels, Belgium; Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, 1070 Brussels, Belgium; WEL Research Institute, 1300 Wavre, Belgium. Electronic address: miriam.cnop@ulb.be.

PMID: 40961947
DOI: 10.1016/j.xgen.2025.101004

Free article

Identification of novel type 1 and type 2 diabetes genes by co-localization of human islet eQTL and GWAS variants with colocRedRibbon

Anthony Piron et al. Cell Genom. 2025.

Free article

. 2025 Nov 12;5(11):101004.

doi: 10.1016/j.xgen.2025.101004. Epub 2025 Sep 16.

Authors

Affiliations

¹ ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, 1070 Brussels, Belgium; Pharmacognosy, Bioanalysis and Drug Discovery, Pharmacy Faculty, Université Libre de Bruxelles, 1050 Brussels, Belgium; Interuniversity Institute of Bioinformatics in Brussels (IB2), 1050 Brussels, Belgium; JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK. Electronic address: anthony.piron@ulb.be.
² ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, 1070 Brussels, Belgium; Interuniversity Institute of Bioinformatics in Brussels (IB2), 1050 Brussels, Belgium.
³ ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, 1070 Brussels, Belgium.
⁴ JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK.
⁵ JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK; Military Institute of Medicine, National Research Institute Warsaw, Warsaw, Poland.
⁶ Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
⁷ Diabetes Unit, Massachusetts General Hospital, Boston, MA 02144, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
⁸ Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-2152, USA; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB2 0BB, UK; Heart and Lung Research Institute, University of Cambridge, Cambridge CB2 0BB, UK.
⁹ Interuniversity Institute of Bioinformatics in Brussels (IB2), 1050 Brussels, Belgium.
¹⁰ Diabetes Unit, Massachusetts General Hospital, Boston, MA 02144, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹¹ ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, 1070 Brussels, Belgium; Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, 1070 Brussels, Belgium; WEL Research Institute, 1300 Wavre, Belgium. Electronic address: miriam.cnop@ulb.be.

PMID: 40961947
DOI: 10.1016/j.xgen.2025.101004

Abstract

Over 1,000 genetic variants have been associated with diabetes by genome-wide association studies (GWASs), but for most, their functional impact is unknown; only 7% alter gene expression in pancreatic islets in expression quantitative trait locus (eQTL) studies. To fill this gap, we developed a co-localization pipeline, colocRedRibbon, that prefilters eQTLs by the direction of effect on gene expression and shortlists overlapping eQTL and GWAS variants prior to co-localization. Applying colocRedRibbon to recent diabetes and glycemic trait GWASs, we identified 292 co-localizing gene regions, including 24 co-localizations for type 1 diabetes and 268 for type 2 diabetes and glycemic traits, representing a 4-fold increase. A low-frequency type 2 diabetes protective variant increases islet MYO5C expression, and a type 1 diabetes protective variant increases FUT2 expression. These novel co-localizations advance the understanding of diabetes genetics and its impact on human islet biology. colocRedRibbon has broad applicability to co-localize GWASs and various QTLs.

Keywords: GWAS; co-localization; colocRedRibbon; diabetes; eQTL; genetics; glycemic traits; insulin; meQTL; multi-ancestry; pQTL; pancreatic islets; β cells.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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Identification of novel type 1 and type 2 diabetes genes by co-localization of human islet eQTL and GWAS variants with colocRedRibbon

Affiliations

Identification of novel type 1 and type 2 diabetes genes by co-localization of human islet eQTL and GWAS variants with colocRedRibbon

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

LinkOut - more resources

Full Text Sources

Miscellaneous