{"doi":"10.1101/2025.06.09.25329166","title":"Development and validation of a Trans-Ancestry polygenic risk score for Type 1 Diabetes","abstract":"Abstract Objectives The high heritability of type 1 diabetes has enabled the development of polygenic risk scores (PRS) as disease risk screening tools. PRS can identify individuals at the highest genetic risk in a population, who can benefit from autoantibody and metabolic surveillance, to avoid ketoacidosis at diagnosis and access preventive therapies. However, PRS for type 1 diabetes developed from European data perform less well in non-European ancestries. We aimed to develop a PRS with comparable performance among different ancestries. Methods Using a the PRS-CSx method, and data from large European, East-Asian, African-American and Hispanic type 1 diabetes GWAS (N total_cases =29,469), we developed a trans-ancestry PRS (TA-PS), combining a non- HLA component incorporating over a million variants, with the HLA component of a published European PRS (GRS2x). We tested the performance of the PRS using AUROC, sensitivity and specificity in a multi-ancestry T1D case-control cohort (N total = 4,657; N non-European =556) from Montreal, Canada. We validated our results in two independent T1D case-control cohorts (CHOP-CAG and GRACE) and two population-based cohorts (All of Us and UK Biobank). Results In our multi-ancestry Montreal-based cohort, TA-PS showed an AUROC of 0.89 which was significantly higher from the AUROC of 0.85 of GRS2x. At a 90th percentile cut-off, in African-Americans, the sensitivity of GRS2x was 0.32, compared to 0.56 in Europeans. For TA-PS, we obtained overall better sensitivities, ranging from 0.71 in Europeans to 0.77 in South Asians. TA-PS demonstrated slightly lower albeit acceptable specificity compared to that of GRS2x (> 0.83 across all ancestries). These results were validated in the four independent cohorts. Conclusion We developed a trans-ancestry PRS that outperformed the European-based GRS2x. Importantly, TA-PS provides a comparable prediction in various ancestries, which supports its use in population-wide screening programs. Research in context What is already known about this subject? - Polygenic risk scores (PRS) for type 1 diabetes are primarily developed using data from individuals of European ancestry. - The widely used, European-based GRS2 score shows reduced performance in non-European populations, particularly among individuals of African descent. - There are concerns regarding the equity of genetic risk prediction in population-based screening programs for T1D. What is the key question? - Can a trans-ancestry PRS provide accurate and equitable type 1 diabetes risk prediction across ancestries? What are the new findings? - A new trans-ancestry score, TA-PS, was developed by integrating an optimized non- HLA PRS to GRS2. - Compared to GRS2, in multi ancestry case-control and population-based cohorts, TA-PS improves sensitivity across all ancestry groups while maintaining high specificity. How might this impact on clinical practice in the foreseeable future? - TA-PS could provide equitable genetic risk stratification in population-wide screening programs for type 1 diabetes.","journal":"medRxiv","year":2025,"id":567897,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9529,"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":51488,"name":"Hui‐Qi Qu","orcid":"0000-0001-9317-4488","position":1,"is_corresponding":false},{"id":269890,"name":"Tianyuan Lu","orcid":"0000-0002-5664-5698","position":2,"is_corresponding":false},{"id":1220367,"name":"Kai Liu","orcid":"0000-0003-3633-1226","position":3,"is_corresponding":false},{"id":400514,"name":"Erica L. Kleinbrink","orcid":"0000-0002-8565-207X","position":4,"is_corresponding":false},{"id":351016,"name":"Kathleen Klein","orcid":"0000-0001-8652-6502","position":5,"is_corresponding":false},{"id":1472431,"name":"Wiame Belbellaj","orcid":null,"position":6,"is_corresponding":false},{"id":1119746,"name":"Isabel Gamache","orcid":"0000-0002-0613-0979","position":7,"is_corresponding":false},{"id":25375,"name":"Lauric Ferrat","orcid":"0000-0002-3166-9685","position":8,"is_corresponding":false},{"id":267234,"name":"Guillaume Butler‐Laporte","orcid":"0000-0001-5388-0396","position":9,"is_corresponding":false},{"id":1472082,"name":"Yangxi Li","orcid":"0000-0003-4579-1080","position":10,"is_corresponding":false},{"id":37445,"name":"Håkon Håkonarson","orcid":"0000-0003-2814-7461","position":11,"is_corresponding":false},{"id":1472083,"name":"Wei Wu","orcid":"0000-0002-9020-9339","position":12,"is_corresponding":false},{"id":610985,"name":"Constantin Polychronakos","orcid":"0000-0002-7624-6635","position":13,"is_corresponding":false},{"id":304553,"name":"Celia M.T. Greenwood","orcid":"0000-0002-2427-5696","position":14,"is_corresponding":false},{"id":663909,"name":"Despoina Manousaki","orcid":"0000-0002-4133-0618","position":15,"is_corresponding":false},{"id":1472430,"name":"Basile Jumentier","orcid":null,"position":0,"is_corresponding":true}],"reference_count":26,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:56:48.183032Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}