Unravelling the molecular mechanisms causal to type 2 diabetes across global populations and disease-relevant tissues

Type 2 diabetes (T2D) is a prevalent disease arising from complex molecular mechanisms. Here we leverage T2D genetic associations to identify causal molecular mechanisms in an ancestry-aware and tissue-aware manner. Using two-sample Mendelian randomization corroborated by colocalization across four global ancestries, we analyse 20,307 gene and 1,630 protein expression levels using blood-derived cis-quantitative trait loci (QTLs). We detect causal effects of genetically predicted levels of 335 genes and 46 proteins on T2D risk, with 16.4% and 50% replication in independent cohorts, respectively. Using gene expression cis-QTLs derived from seven T2D-relevant tissues, we identify causal links between the expression of 676 genes and T2D risk, refining known associations such as BAK1 and describing additional ones like CPXM1. Causal effects are mostly shared across ancestries but are highly heterogeneous across tissues. Our findings provide insights into cross-ancestry and tissue-informed multi-omics causal inference approaches and demonstrate their power in uncovering molecular processes driving T2D.

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Publication Details

Journal
Nature Metabolism
Published
2026-01-27
DOI
https://doi.org/10.1038/s42255-025-01444-1
Primary Topic
Genetic Associations and Epidemiology
Type
article
Field-Weighted Citation Impact
0.00

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article

Unravelling the molecular mechanisms causal to type 2 diabetes across global populations and disease-relevant tissues

Henry J. Taylor, Ken Suzuki, Ta-Yu Yang, Ravi Mandla et al.
Nature Metabolism
Genetic Associations and Epidemiology
article

Unravelling the molecular mechanisms causal to type 2 diabetes across global populations and disease-relevant tissues

Henry J. Taylor, Ken Suzuki, Ta-Yu Yang, Ravi Mandla, James B. Meigs, Satoshi Yoshiji, Chi Zhao, Benjamin F. Voight, Fumihiko Matsuda, Alicia Huerta-Chagoya, Ozvan Bocher, Eleftheria Zeggini, Alexis C. Wood, Cassandra N. Spracklen, Xianyong Yin, Marijana Vujkovic, Josep M. Mercader, Chen-Yang Su, Jingchun Chen, Andrew P. Morris, Davis Cammann, Ana Luiza Arruda, Jason Flannick, Jerome I. Rotter
article en

Abstract

Type 2 diabetes (T2D) is a prevalent disease arising from complex molecular mechanisms. Here we leverage T2D genetic associations to identify causal molecular mechanisms in an ancestry-aware and tissue-aware manner. Using two-sample Mendelian randomization corroborated by colocalization across four global ancestries, we analyse 20,307 gene and 1,630 protein expression levels using blood-derived cis-quantitative trait loci (QTLs). We detect causal effects of genetically predicted levels of 335 genes and 46 proteins on T2D risk, with 16.4% and 50% replication in independent cohorts, respectively. Using gene expression cis-QTLs derived from seven T2D-relevant tissues, we identify causal links between the expression of 676 genes and T2D risk, refining known associations such as BAK1 and describing additional ones like CPXM1. Causal effects are mostly shared across ancestries but are highly heterogeneous across tissues. Our findings provide insights into cross-ancestry and tissue-informed multi-omics causal inference approaches and demonstrate their power in uncovering molecular processes driving T2D.

Nature MetabolismVol. 8(2)
Broad Institute (US), Boston Children's Hospital (US), National Institutes of Health (US), University of Nevada, Las Vegas (US), Harvard University (US), Inserm (FR), Université de Bretagne Occidentale (FR), Kyoto University (JP), University of Cambridge (GB), University of Massachusetts Amherst (US), University of Michigan (US), UCLA Medical Center (US), University of Manchester (GB), Helmholtz Zentrum München (DE), British Heart Foundation (GB), Massachusetts General Hospital (US), National Human Genome Research Institute (US), Manchester University NHS Foundation Trust (GB), Arthritis UK (GB), McGill Genome Centre (CA), Translational Therapeutics (United States) (US), Centre Hospitalier Régional Universitaire de Brest (FR), Philadelphia VA Medical Center (US), Children's Nutrition Research Center at Baylor College of Medicine (US), Statistical Research (United States) (US), MRC Epidemiology Unit (GB), NIHR Manchester Biomedical Research Centre (GB), Harbor–UCLA Medical Center (US), McGill University (CA), Technical University of Munich (DE), The University of Tokyo (JP), University of Pennsylvania (US), Nanjing Medical University (CN), Medical Research Council (GB)
American Diabetes Association, TD Bank, National Institute for Health and Care Research, European Commission, Versus Arthritis, National Institutes of Health, Manchester Biomedical Research Centre, Canadian Institutes of Health Research, Medical Research Council, Japan Society for the Promotion of Science, Helmholtz Zentrum München, National Heart, Lung, and Blood Institute
Openalex Percentile: Top 72%
Genetic Associations and Epidemiology
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