{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:12:48Z","timestamp":1785413568957,"version":"3.56.0"},"posted":{"date-parts":[[2026,5,27]]},"group-title":"Cardiovascular Medicine","reference-count":27,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T00:00:00Z","timestamp":1779840000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100000862","name":"Doris Duke Charitable Foundation","doi-asserted-by":"crossref","award":["Award 2023-0224"],"award-info":[{"award-number":["Award 2023-0224"]}],"id":[{"id":"10.13039\/100000862","id-type":"DOI","asserted-by":"crossref"}]},{"award":["IK2-BX006551"],"award-info":[{"award-number":["IK2-BX006551"]}],"id":[{"id":"https:\/\/ror.org\/05rsv9s98","id-type":"ROR","asserted-by":"publisher"}]},{"award":["I01-BX003362"],"award-info":[{"award-number":["I01-BX003362"]}],"id":[{"id":"https:\/\/ror.org\/05rsv9s98","id-type":"ROR","asserted-by":"publisher"}]},{"award":["VA ORD 24-D4V-02"],"award-info":[{"award-number":["VA ORD 24-D4V-02"]}],"id":[{"id":"https:\/\/ror.org\/05rsv9s98","id-type":"ROR","asserted-by":"publisher"}]},{"award":["1K08HL153937"],"award-info":[{"award-number":["1K08HL153937"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01HL174912"],"award-info":[{"award-number":["R01HL174912"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,27]]},"abstract":"Abstract<\/jats:title>\n \n Importance<\/jats:title>\n \n Dilated cardiomyopathy (DCM) is a major cause of heart failure that disproportionately affects individuals of African genetic ancestry (AFR), among whom familial clustering of disease is also more pronounced relative to those of European ancestry (EUR). However, established monogenic DCM genes, identified primarily in EUR populations, explain a smaller proportion of DCM cases in AFR populations. A recent study identified a common AFR-specific nonsense variant in\n CD36<\/jats:italic>\n that accounts for a substantial burden of DCM in AFR. How the risk and population impact of this variant compare with those of established genetic causes of DCM is unknown.\n <\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n \n To compare the contribution of a\n CD36<\/jats:italic>\n nonsense variant to DCM risk with that of truncating variants in\n TTN<\/jats:italic>\n and pathogenic or likely pathogenic (P\/LP) variants in other established DCM genes.\n <\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n Multicohort genetic association study including AFR and EUR participants with exome or genome sequence and DCM case status from four datasets: All of Us, Million Veteran Program, Penn Medicine Biobank, and the DCM Precision Medicine Study.<\/jats:p>\n <\/jats:sec>\n \n Exposure<\/jats:title>\n \n Carrier status for\n TTN<\/jats:italic>\n truncating variants, P\/LP variants in 11 high confidence DCM genes, and the\n CD36<\/jats:italic>\n nonsense variant (Y325*; 0, 1, or 2 copies).\n <\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n Odds of DCM; prevalence of risk-variant carriers among DCM cases; and population attributable fraction (PAF) for DCM.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Among 82,623 AFR individuals across four studies, the mean age was 53.4 years and 1,625 had DCM.\n CD36<\/jats:italic>\n Y325* risk-allele homozygotes had 4.8-fold (95% CI, 3.1-7.3) increased odds of DCM, and\n CD36<\/jats:italic>\n Y325* heterozygotes had 1.4-fold (95% CI, 1.2-1.7) increased odds.\n TTN<\/jats:italic>\n truncating variants also conferred elevated risk of DCM in AFR participants (OR, 8.46; 95% CI, 5.3-12.3). Among AFR DCM cases, 2.5% were\n CD36<\/jats:italic>\n homozygotes, second only to\n TTN<\/jats:italic>\n truncating variants (4.3%) and exceeding all other high-confidence DCM genes combined (1.5%). In population-level analyses incorporating both heterozygous and homozygous\n CD36<\/jats:italic>\n Y325* carriers, the population-attributable fraction for\n CD36<\/jats:italic>\n (9.0%) surpassed that of\n TTN<\/jats:italic>\n truncating variants (3.6%).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n \n An ancestry-specific\n CD36<\/jats:italic>\n variant contributes more to DCM burden in AFR ancestry than established DCM genes, including\n TTN<\/jats:italic>\n truncating variants, typically considered the most common genetic cause of DCM. These findings reshape the known genetic architecture of DCM in individuals of African ancestry and highlight the importance of representation in genomic research.\n <\/jats:p>\n <\/jats:sec>\n \n Key Points<\/jats:title>\n \n Question<\/jats:title>\n \n To what extent does a common, African ancestry-specific nonsense variant in\n CD36<\/jats:italic>\n contribute to the genetic architecture of dilated cardiomyopathy (DCM) in individuals of African ancestry in the United States?\n <\/jats:p>\n <\/jats:sec>\n \n Findings<\/jats:title>\n \n In an analysis of African ancestry individuals from multiple U.S.-based cohorts, a\n CD36<\/jats:italic>\n nonsense variant accounted for a greater population burden of DCM than\n TTN<\/jats:italic>\n truncating variants and pathogenic or likely pathogenic variants in other established DCM genes.\n <\/jats:p>\n <\/jats:sec>\n \n Meaning<\/jats:title>\n \n A single ancestry-specific\n CD36<\/jats:italic>\n variant substantially alters current understanding of DCM genetic architecture in individuals of African ancestry and underscores the importance of including ancestral diversity in all genetic studies.\n <\/jats:p>\n <\/jats:sec>\n <\/jats:sec>","DOI":"10.64898\/2026.05.26.26353838","type":"posted-content","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T17:45:15Z","timestamp":1779903915000},"source":"Crossref","is-referenced-by-count":0,"title":["A Common\n CD36<\/i>\n Variant and the Genetic Landscape of Dilated Cardiomyopathy in Individuals of African Ancestry"],"prefix":"10.64898","author":[{"given":"Saketh","family":"Challa","sequence":"first","affiliation":[{"name":"Cardiovascular Disease Initiative, The Broad Institute of MIT & Harvard, Cambridge, MA, USA"},{"name":"Heart and Vascular Institute, Mass General Brigham, Boston, MA, USA"},{"name":"Massachusetts Veterans Epidemiology Research and Information Collaborative (MAVERIC), VA Boston Healthcare System, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiran","family":"Biddinger","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative, The Broad Institute of MIT & Harvard, Cambridge, MA, USA"},{"name":"Heart and Vascular Institute, Mass General Brigham, Boston, MA, USA"},{"name":"Massachusetts Veterans Epidemiology Research and Information Collaborative (MAVERIC), VA Boston Healthcare System, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Abramowitz","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA"},{"name":"Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell, Hempstead, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Zheng","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative, The Broad Institute of MIT & Harvard, Cambridge, MA, USA"},{"name":"Heart and Vascular Institute, Mass General Brigham, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan O.","family":"Mead","sequence":"additional","affiliation":[{"name":"Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA"},{"name":"The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA"},{"name":"The Ohio Colleges of Medicine Government Resource Center, The Ohio State University, Columbus, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renae L.","family":"Judy","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA"},{"name":"Corporal Michael J. 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