{"doi":"10.1101/2025.05.05.25326880","title":"Unravelling the molecular mechanisms causal to type 2 diabetes across global populations and disease-relevant tissues","abstract":"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.","journal":"medRxiv","year":2025,"id":557843,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.6145,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1193410,"name":"Ana Luiza Arruda","orcid":"0000-0002-6550-9794","position":1,"is_corresponding":false},{"id":908958,"name":"Satoshi Yoshiji","orcid":"0000-0001-8863-2413","position":2,"is_corresponding":false},{"id":1218618,"name":"Chi Zhao","orcid":"0000-0002-1051-8386","position":3,"is_corresponding":false},{"id":813238,"name":"Chen‐Yang Su","orcid":"0000-0001-6071-4660","position":4,"is_corresponding":false},{"id":11253,"name":"Xianyong Yin","orcid":"0000-0001-6454-2384","position":5,"is_corresponding":false},{"id":989332,"name":"Davis Cammann","orcid":"0009-0008-2202-5790","position":6,"is_corresponding":false},{"id":991167,"name":"Henry J. Taylor","orcid":"0000-0003-2088-5240","position":7,"is_corresponding":false},{"id":519422,"name":"Jingchun Chen","orcid":"0000-0001-9408-0117","position":8,"is_corresponding":false},{"id":1457909,"name":"K. Suzuki","orcid":"0000-0002-1546-1657","position":9,"is_corresponding":false},{"id":316845,"name":"Ravi Mandla","orcid":"0000-0002-0782-0138","position":10,"is_corresponding":false},{"id":614898,"name":"Alicia Huerta‐Chagoya","orcid":"0000-0001-6218-3904","position":11,"is_corresponding":false},{"id":1211047,"name":"Ta‐Yu Yang","orcid":"0000-0002-5379-5340","position":12,"is_corresponding":false},{"id":318524,"name":"Fumihiko Matsuda","orcid":"0000-0003-4557-4553","position":13,"is_corresponding":false},{"id":253982,"name":"Josep M. Mercader","orcid":"0000-0001-8494-3660","position":14,"is_corresponding":false},{"id":557682,"name":"Jason Flannick","orcid":"0000-0002-3618-795X","position":15,"is_corresponding":false},{"id":1092,"name":"James B. Meigs","orcid":"0000-0002-2439-2657","position":16,"is_corresponding":false},{"id":291141,"name":"Alexis C. Wood","orcid":"0000-0001-7616-2119","position":17,"is_corresponding":false},{"id":253978,"name":"Marijana Vujković","orcid":"0000-0003-4924-5714","position":18,"is_corresponding":false},{"id":45188,"name":"Benjamin F. Voight","orcid":"0000-0002-6205-9994","position":19,"is_corresponding":false},{"id":108737,"name":"Cassandra N. Spracklen","orcid":"0000-0003-3590-7182","position":20,"is_corresponding":false},{"id":11276,"name":"Jerome I. Rotter","orcid":"0000-0001-7191-1723","position":21,"is_corresponding":false},{"id":16092,"name":"Andrew P. 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