{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T06:35:43Z","timestamp":1785825343340,"version":"3.56.0"},"update-to":[{"DOI":"10.1371\/journal.pgen.1011889","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:00:00Z","timestamp":1759968000000}}],"reference-count":108,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T00:00:00Z","timestamp":1759190400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM008307-30, GM139534-01"],"award-info":[{"award-number":["GM008307-30, GM139534-01"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Gulf Coast Consortia","award":["GM139801-03\/-02"],"award-info":[{"award-number":["GM139801-03\/-02"]}]},{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["BC220523"],"award-info":[{"award-number":["BC220523"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007863","name":"Rice University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007863","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["CA268380"],"award-info":[{"award-number":["CA268380"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AG074009-04, U01 AG068214-02"],"award-info":[{"award-number":["R01 AG074009-04, U01 AG068214-02"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["2344149"],"award-info":[{"award-number":["2344149"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>\n                    Type 2 diabetes mellitus (T2DM) risk is heavily influenced by genetics, yet current association tests have explained only parts of its heritability. We developed MEVA (Meta-Evolutionary Action), a meta-analytic framework that integrates three complementary methods\u2014EAML, Sigma-Diff, and GeneEMBED\u2014to assess the functional burden of protein-coding variants using evolutionary data. MEVA was applied to exome data from 28,115 T2DM cases and 28,115 controls in the UK Biobank (UKB), identifying 101 genes (p\u2009&lt;\u20091e-5). MEVA outperformed its component methods, each of which substantially outperformed a conventional burden test (MAGMA), in recovering known T2DM genes (AUROC\u2009=\u20090.925) and maintaining robustness in progressively smaller cohorts (AUROC\u2009=\u20090.917). MEVA showed significant enrichment for T2DM-related loci (p\u2009=\u20096.8e-10, p\u2009=\u20092.0e-34), protein interactions (z\u2009=\u20094.6, z\u2009=\u20094.2), pathways (p\u2009=\u20091.3e-6, z\u2009=\u20092.0), phenotypes (p\u2009=\u20091.3e-21, z\u2009=\u20099.1), and literature mentions (z\u2009=\u20097.2). Replication in 16,915 T2DM cases and 16,915 controls from All of Us (AoU) yielded 99 genes (p\u2009&lt;\u20091e-5), 23 of which were also recovered in the UKB cohort \u2013 far exceeding random chance. These included established genes (\n                    <jats:italic>SLC30A8, WFS1, HNF1A<\/jats:italic>\n                    ) and less-characterized candidates (\n                    <jats:italic>NRIP1, ADAM30, CALCOCO2, TUBB1, ZFP36L2, WDR90<\/jats:italic>\n                    ). Notably,\n                    <jats:italic>NRIP1<\/jats:italic>\n                    loss-of-function variants were associated with increased T2DM risk in both the UKB (OR = 1.09, FDR\u2009=\u20095.4e-4) and AoU (OR = 1.09, FDR\u2009=\u20090.046), and\n                    <jats:italic>TUBB1<\/jats:italic>\n                    and\n                    <jats:italic>CALCOCO2<\/jats:italic>\n                    gain-of-function variants showed consistent risk effects (FDR\u2009&lt;\u20090.05). Pathway analyses revealed convergence on endoplasmic reticulum chaperone complexes (FDR\u2009=\u20090.02) and Hippo signaling (FDR\u2009=\u20098.5e-4). Finally, all 177 candidate genes were functionally prioritized using ten orthogonal criteria to guide experimental follow-up. These results demonstrate that combining complementary, impact-aware association tests increases sensitivity, improves replication, and expands the catalog of genetic risk factors for T2DM.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1011889","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T17:47:38Z","timestamp":1759254458000},"page":"e1011889","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Meta-evolutionary exome analysis identifies novel type 2 diabetes mellitus genes in the UK Biobank and All of Us"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2686-0976","authenticated-orcid":true,"given":"Kevin","family":"Wilhelm","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9280-0333","authenticated-orcid":true,"given":"Jennifer","family":"Asmussen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwanghyuk","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam","family":"Samieinasab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5779-9740","authenticated-orcid":true,"given":"Emmanuel","family":"Asante","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marek","family":"Kimmel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4057-7122","authenticated-orcid":true,"given":"Olivier","family":"Lichtarge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,9,30]]},"reference":[{"key":"pgen.1011889.ref001","doi-asserted-by":"crossref","first-page":"107843","DOI":"10.1016\/j.diabres.2019.107843","article-title":"Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition","volume":"157","author":"P Saeedi","year":"2019","journal-title":"Diabetes Res Clin Pract"},{"issue":"10027","key":"pgen.1011889.ref002","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1016\/S0140-6736(16)00618-8","article-title":"Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants","volume":"387","author":"NCD Risk Factor Collaboration (NCD-RisC).","year":"2016","journal-title":"Lancet"},{"issue":"6","key":"pgen.1011889.ref003","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1212\/WNL.0000000000002950","article-title":"Type 2 diabetes mellitus is associated with brain atrophy and hypometabolism in the ADNI cohort","volume":"87","author":"W Li","year":"2016","journal-title":"Neurology"},{"issue":"1","key":"pgen.1011889.ref004","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1186\/s12916-017-0901-x","article-title":"Environmental\/lifestyle factors in the pathogenesis and prevention of type 2 diabetes","volume":"15","author":"H Kolb","year":"2017","journal-title":"BMC Med"},{"issue":"11","key":"pgen.1011889.ref005","doi-asserted-by":"crossref","first-page":"2811","DOI":"10.1007\/s00125-011-2267-5","article-title":"Heritability and familiality of type 2 diabetes and related quantitative traits in the Botnia Study","volume":"54","author":"P Almgren","year":"2011","journal-title":"Diabetologia"},{"issue":"10138","key":"pgen.1011889.ref006","doi-asserted-by":"crossref","first-page":"2463","DOI":"10.1016\/S0140-6736(18)31132-2","article-title":"Genomic insights into the causes of type 2 diabetes","volume":"391","author":"C Langenberg","year":"2018","journal-title":"Lancet"},{"issue":"5","key":"pgen.1011889.ref007","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1007\/s11892-022-01462-3","article-title":"Genetics of Type 2 Diabetes: Implications from Large-Scale Studies","volume":"22","author":"N DeForest","year":"2022","journal-title":"Curr Diab Rep"},{"issue":"18","key":"pgen.1011889.ref008","article-title":"Emerging Targets in Type 2 Diabetes and Diabetic Complications","volume":"8","author":"S Demir","year":"2021","journal-title":"Adv Sci (Weinh)"},{"key":"pgen.1011889.ref009","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkae1070","article-title":"The NHGRI-EBI GWAS Catalog: standards for reusability, sustainability and diversity","volume":"53","author":"M Cerezo","year":"2025","journal-title":"Nucleic Acids Res"},{"key":"pgen.1011889.ref010","doi-asserted-by":"crossref","unstructured":"Wessel J, Majarian TD, Highland HM, Raghavan S, Szeto MD, Hasbani NR, et al. 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