{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T17:18:43Z","timestamp":1780593523485,"version":"3.54.1"},"posted":{"date-parts":[[2025,11,28]]},"group-title":"Genetic and Genomic Medicine","reference-count":46,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,11,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Polygenic risk scores (PRSs) can improve type 2 diabetes (T2D) risk prediction beyond clinical risk factors, but most exclude low-frequency, rare, and population-specific variants. We hypothesized that incorporation of rare variants via large-scale, well-imputed or whole-genome sequence-based genome-wide association (GWAS) meta-analyses and expanded linkage disequilibrium (LD) reference panels would improve risk prediction for T2D. We constructed a GWAS meta-analysis (230,675 T2D cases and 991,401 T2D controls), enabling the inclusion of rare variants (minor allele frequency [MAF] range= 1\u00d710\n                  <jats:sup>\u22125<\/jats:sup>\n                  - 0.01) to construct three T2D PRSs: (i) CTSLEB, which utilizes a custom ancestry-matched LD panel of 79.5 million variants and 83K participants to specifically model LD of rare variants; (ii) PRS-CS (TAGIT), using a reference panel expanded to 2.3 million variants to better capture low-frequency and population specific variants (population-specific MAF \u2265 0.01); (iii) PRS-CS (HM3), using a standard LD panel with HapMap3 variants (1.2 million variants). Performance was evaluated in the All of Us Research Program (20,301 T2D cases; 30,617 T2D controls) and compared to a benchmark multi-ancestry PRS (MAF\u22650.01), developed by the D-PRISM consortium and derived from a significantly larger set of ancestry-specific meta-analyses (totaling 359,891 T2D cases and 1,825,792 controls). Expanding variant coverage with PRS-CS (TAGIT) and CTSLEB improved risk prediction relative to PRS-CS (HM3). While PRS-CS (TAGIT) showed greater prediction accuracy in the overall population, CTSLEB uniquely captured risk driven by rare variants, showing greater prediction accuracy for carriers of rare and low-frequency variants compared to PRS-CS (TAGIT) (AUC = 0.832 vs. 0.823 p(DeLong test) = 7.9\u00d710\n                  <jats:sup>\u22125<\/jats:sup>\n                  ) and PRS-CS (HM3) (AUC = 0.832 vs 0.818, p(DeLong test) = 2.39\u00d710\n                  <jats:sup>\u22127<\/jats:sup>\n                  ). The benchmark D-PRISM PRS showed the highest predictive performance for all ancestries except in African ancestry populations, where CTSLEB performed similarly for the overall population (CTSLEB AUC = 0.786 vs. D-PRISM AUC = 0.784, p(DeLong test) = 0.57) and significantly better for rare variant carriers (CSTLEB AUC = 0.775 vs. D-PRISM AUC = 0.768, p(DeLong test) = 8.71\u00d710\n                  <jats:sup>\u22123<\/jats:sup>\n                  ). These results demonstrate the value in incorporating rare and population-specific variants into PRS construction, improving genetic risk prediction in diverse populations.\n                <\/jats:p>","DOI":"10.1101\/2025.11.24.25340878","type":"posted-content","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T19:35:17Z","timestamp":1764358517000},"source":"Crossref","is-referenced-by-count":1,"title":["Improving type 2 diabetes polygenic risk scores by incorporating rare, low-frequency, and population-specific variants"],"prefix":"10.64898","author":[{"given":"Katie","family":"Taylor","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Huerta-Chagoya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maheak","family":"Vora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7006-1285","authenticated-orcid":false,"given":"Jiang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lehte","family":"Turk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teng Hiang","family":"Heng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joohyun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andres","family":"Moreno-Estrada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Tusie-Luna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Aguilar-Salinas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maggie","family":"Ng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilary C.","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0637-2265","authenticated-orcid":false,"given":"David A","family":"van Heel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Genes & Health Research Team","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0247-902X","authenticated-orcid":false,"given":"Alisa","family":"Manning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Carey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9320-7008","authenticated-orcid":false,"given":"Priit","family":"Palta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitja I.","family":"Kurki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Finer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Ge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4972-5451","authenticated-orcid":false,"given":"Uyenlinh L.","family":"Mirshahi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8494-3660","authenticated-orcid":false,"given":"Josep M","family":"Mercader","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025120100500839000_2025.11.24.25340878v1.1","unstructured":"Magliano, D. 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