{"doi":"10.4093/dmj.2025.0557","title":"Evaluation of Sex-Stratified Polygenic Risk Scores for Type 2 Diabetes Mellitus and Glycemic Traits in the Framingham Heart Study","abstract":"BACKGRUOUND: Diabetes is a multifactorial disease with significant genetic predisposition. Polygenic risk scores (PRS) have been developed to estimate an individual's genetic risk of a disease. Traditionally, PRS utilize sex-combined genome-wide association studies (GWAS) due to the limited availability of sex-stratified summary statistics. This study explores sex-dimorphic genetic effects and evaluates the potential benefits of incorporating sex-stratified effects in PRS for type 2 diabetes mellitus (T2DM) and glycemic traits by comparing PRS performance derived from sex-combined versus sex-stratified GWAS. METHODS: We performed a sex-heterogeneity test across sex-specific GWAS and identified nine signals with sex-dimorphic effects for T2DM. PRS[sex-combined] and PRS[sex-stratified] were developed using sex-combined and sex-stratified GWAS results for T2DM (41,444 cases and 354,539 controls), fasting glucose (n=120,595) and fasting insulin (n=98,210). We evaluated these PRS models in 8,379 participants (1,303 cases and 7,076 controls) from the Framingham Heart Study not included in the PRS derivation. RESULTS: Our findings suggest that sex-combined PRS currently offer better predictive performance for T2DM and glycemic traits. CONCLUSION: These results highlight the need for larger sex-stratified studies and the optimization of sex-stratified risk models for clinical practice.","journal":"Diabetes & Metabolism Journal","year":2025,"id":584762,"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":0.9555,"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":806375,"name":"Yixin Zhang","orcid":"0009-0008-2528-4624","position":1,"is_corresponding":false},{"id":707669,"name":"Philip Schroeder","orcid":"0000-0002-9885-7787","position":2,"is_corresponding":false},{"id":614898,"name":"Alicia Huerta‐Chagoya","orcid":"0000-0001-6218-3904","position":3,"is_corresponding":false},{"id":316845,"name":"Ravi Mandla","orcid":"0000-0002-0782-0138","position":4,"is_corresponding":false},{"id":1092,"name":"James B. Meigs","orcid":"0000-0002-2439-2657","position":5,"is_corresponding":false},{"id":16116,"name":"Alisa K. Manning","orcid":"0000-0003-0247-902X","position":6,"is_corresponding":false},{"id":22056,"name":"Ching‐Ti Liu","orcid":"0000-0002-0703-0742","position":7,"is_corresponding":false},{"id":1051,"name":"Josée Dupuis","orcid":"0000-0003-2871-3603","position":8,"is_corresponding":false},{"id":253982,"name":"Josep M. Mercader","orcid":"0000-0001-8494-3660","position":9,"is_corresponding":false},{"id":332064,"name":"N. Wang","orcid":"0009-0002-2192-5566","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:59:16.166424Z","pmid":"41360390","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":[]}