{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T13:43:09Z","timestamp":1765546989662,"version":"3.37.3"},"reference-count":51,"publisher":"Oxford University Press (OUP)","issue":"8","funder":[{"name":"Intramural Research Program of National Institute of Diabetes and Digestive and Kidney Diseases","award":["ZIA DK043304\u201324"],"award-info":[{"award-number":["ZIA DK043304\u201324"]}]},{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000093","name":"Center for Information Technology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000093","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1ZIA HG200362"],"award-info":[{"award-number":["1ZIA HG200362"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,4,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>How ancestry-associated genetic variance affects disparities in the risk of polygenic diseases and influences the identification of disease-associated genes warrants a deeper understanding. We hypothesized that the discovery of genes associated with polygenic diseases may be limited by the overreliance on single-nucleotide polymorphism (SNP)-based genomic investigation, as most significant variants identified in genome-wide SNP association studies map to introns and intergenic regions of the genome. To overcome such potential limitations, we developed a gene-constrained, function-based analytical method centered on high-risk variants (hrV) that encode frameshifts, stopgains or splice site disruption. We analyzed the total number of hrV per gene in populations of different ancestry, representing a total of 185\u2009934 subjects. Using this analysis, we developed a quantitative index of hrV (hrVI) across 20\u2009428 genes within each population. We then applied hrVI analysis to the discovery of genes associated with type 2 diabetes mellitus (T2DM), a polygenic disease with ancestry-related disparity. HrVI profiling and gene-to-gene comparisons of ancestry-specific hrV between the case (20\u2009781 subjects) and control (24\u2009440 subjects) populations in the T2DM national repository identified 57 genes associated with T2DM, 40 of which were discoverable only by ancestry-specific analysis. These results illustrate how a function-based, ancestry-specific analysis of genetic variations can accelerate the identification of genes associated with polygenic diseases. Besides T2DM, such analysis may facilitate our understanding of the genetic basis for other polygenic diseases that are also greatly influenced by environmental and behavioral factors, such as obesity, hypertension and Alzheimer\u2019s disease.<\/jats:p>","DOI":"10.1093\/hmg\/ddac255","type":"journal-article","created":{"date-parts":[[2022,10,18]],"date-time":"2022-10-18T15:47:38Z","timestamp":1666108058000},"page":"655-666","source":"Crossref","is-referenced-by-count":2,"title":["Ancestry-specific high-risk gene variant profiling unmasks diabetes-associated genes"],"prefix":"10.1093","volume":"33","author":[{"given":"Jianhua","family":"Zhang","sequence":"first","affiliation":[{"name":"Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases , Bethesda, MD 20892 , United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weiping","family":"Chen","sequence":"additional","affiliation":[{"name":"Genomic Core, National Institute of Diabetes and Digestive and Kidney Diseases , Bethesda, MD 20892 , United States"},{"name":"Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases , Bethesda, MD 20892 , United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5745-5618","authenticated-orcid":false,"given":"Guanjie","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Research on Genomics and Global Health, National Human Genome Research Institute , Bethesda, MD 20892 , United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason","family":"Flannick","sequence":"additional","affiliation":[{"name":"Metabolism Program, Broad Institute , Cambridge, MA 02142 , United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma","family":"Fikse","sequence":"additional","affiliation":[{"name":"Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases , Bethesda, MD 20892 , United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Glenda","family":"Smerin","sequence":"additional","affiliation":[{"name":"Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases , Bethesda, MD 20892 , United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katherine","family":"Degner","sequence":"additional","affiliation":[{"name":"Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases , Bethesda, MD 20892 , United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanqin","family":"Yang","sequence":"additional","affiliation":[{"name":"Laboratory of Transplantation Genomics, National Heart Lung and Blood Institute; National Institutes of Health , Bethesda, MD 20892 , United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine","family":"Xu","sequence":"additional","affiliation":[{"name":"Genomic Core, National Institute of Diabetes and Digestive and Kidney Diseases , Bethesda, MD 20892 , United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"Consortium AMP-T2D-GENES","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yulong","family":"Li","sequence":"additional","affiliation":[{"name":"Milton S. 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