Type 2 diabetes (T2D) is a prevalent disease that arises from complex molecular mechanisms. Here, we leverage T2D multi-ancestry genetic associations to identify causal molecular mechanisms in an ancestry- and tissue-aware manner. Using two-sample Mendelian Randomization corroborated by colocalization across four global ancestries, we analyze 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, including novel associations such as CPXM1, PTGES2 and FAM20B. Causal effects are mostly shared across ancestries, but highly heterogeneous across tissues. Our findings provide insights in cross-ancestry and tissue-informed multi-omics causal inference analysis approaches and demonstrate their power in uncovering molecular processes driving T2D.

The authors have declared no competing interest.

OB has received funding from the European Union Horizon 2020 research and innovation programme under Grant Agreement No 101017802 (OPTOMICS). SY has received funding from the Japan Society for the Promotion of Science (202460267) and Canadian Institutes of Health Research (AD6-200177). This work is supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung, and Blood Institute (NHLBI) grant R01HL105756. The TIGER data have been generated by the T2DSystems Consortium, and downloaded from the TIGER Data Portal - http://tiger.bsc.es. CNS was supported by the National Institutes of Health (R01DK118011 and R01DK136671) and the American Diabetes Association (11-22-JDFPM-06).

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

All contributing cohorts have ethical approval from their institutional ethics review boards. All data used in the study, except for the Kyoto cohort (EAS pQTL), are publicly available with reference to the corresponding studies summarized in Supplemental Table 1. The Kyoto Nagahama cohort study was approved by the ethics committees of Kyoto University Graduate School of Medicine and the Nagahama Municipal Review Board (No. 278). The Kyoto Nagahama cohort study data will be available after publication of the study at https://www.hgvd.genome.med.kyoto-u.ac.jp/.

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All contributing cohorts have ethical approval from their institutional ethics review boards. All data used in the study, except for the Kyoto cohort (EAS pQTL), are publicly available with reference to the corresponding studies summarized in Supplemental Table 1. The Kyoto Nagahama cohort study data will be available after publication of the study at https://www.hgvd.genome.med.kyoto-u.ac.jp/.