{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T16:15:16Z","timestamp":1783700116905,"version":"3.55.0"},"posted":{"date-parts":[[2026,7,8]]},"group-title":"Genetic and Genomic Medicine","reference-count":35,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:00:00Z","timestamp":1783468800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["1RO1HL092577"],"award-info":[{"award-number":["1RO1HL092577"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["K24HL105780"],"award-info":[{"award-number":["K24HL105780"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01HL157635"],"award-info":[{"award-number":["R01HL157635"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"crossref","award":["18SFRN34110082"],"award-info":[{"award-number":["18SFRN34110082"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"crossref","award":["961045"],"award-info":[{"award-number":["961045"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Integrating human genetics into therapeutic discovery accelerates drug development. However, ancestral biases in historical cohorts have left critical functional variation largely uncharted. Here, we leverage the diverse NIH\n                  <jats:italic>All of Us<\/jats:italic>\n                  Research Program to conduct comprehensive common- and rare-variant association analyses for 624 quantitative traits across 369,655 ancestrally diverse individuals. We identified 6,181 genome-wide significant locus-trait associations (526 novel) and 416 gene-trait associations (105 novel) via rare-variant burden testing. By integrating fine-mapping with computational variant-effect predictors, we systematically prioritized rare, likely causal variants driving these signals. Jointly modeling common and rare variation with protein-class annotations significantly improved the identification of known drug targets compared to common-variant analysis alone. Notably, we identified\n                  <jats:italic>NRG4<\/jats:italic>\n                  as a high-confidence candidate therapeutic target for preserving kidney function. Our findings demonstrate that characterization of rare and common variation across diverse populations enhances causal gene discovery and identifies novel, actionable therapeutic targets.\n                <\/jats:p>","DOI":"10.64898\/2026.06.25.26356239","type":"posted-content","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T17:05:25Z","timestamp":1783530325000},"source":"Crossref","is-referenced-by-count":0,"title":["Integrating multi-ancestry common and rare variant mapping accelerates therapeutic target discovery"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3899-4405","authenticated-orcid":false,"given":"Nobuyuki","family":"Enzan","sequence":"first","affiliation":[{"name":"Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"name":"Heart and Vascular Institute, Mass General Brigham, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1605-9782","authenticated-orcid":false,"given":"Sean J.","family":"Jurgens","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"name":"Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Cardiomyopathy & Arrhythmias, Amsterdam UMC location University of Amsterdam, Amsterdam, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung Hoan","family":"Choi","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"name":"Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsushi","family":"Nakao","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"name":"Heart and Vascular Institute, Mass General Brigham, Boston, MA, USA"},{"name":"Division of Cardiovascular Medicine, Brigham and Women\u2019s Hospital, Boston, MA, USA"},{"name":"Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9286-0360","authenticated-orcid":false,"given":"Satoshi","family":"Koyama","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"name":"Heart and Vascular Institute, Mass General Brigham, Boston, MA, USA"},{"name":"Harvard Medical School, Boston, MA, USA"},{"name":"Personalized Medicine, Mass General Brigham, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick T.","family":"Ellinor","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"name":"Heart and Vascular Institute, Mass General Brigham, Boston, MA, USA"},{"name":"Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026071008400863000_2026.06.25.26356239v1.1","doi-asserted-by":"crossref","first-page":"2408","DOI":"10.1038\/s41588-025-02335-7","article-title":"Pan-UK Biobank genome-wide association analyses enhance discovery and resolution of ancestry-enriched effects","volume":"57","year":"2025","journal-title":"Nature Genetics"},{"key":"2026071008400863000_2026.06.25.26356239v1.2","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1038\/s41586-025-09272-9","article-title":"Whole-genome sequencing of 490,640 UK Biobank participants","volume":"645","year":"2025","journal-title":"Nature"},{"key":"2026071008400863000_2026.06.25.26356239v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1310-4"},{"key":"2026071008400863000_2026.06.25.26356239v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06957-x"},{"key":"2026071008400863000_2026.06.25.26356239v1.5","unstructured":"Moore, J.E. et al. An expanded registry of candidate cis-regulatory elements. Nature (2026)."},{"key":"2026071008400863000_2026.06.25.26356239v1.6","doi-asserted-by":"crossref","unstructured":"Cheng, J. et al. Accurate proteome-wide missense variant effect prediction with AlphaMissense. Science 381(2023).","DOI":"10.1126\/science.adg7492"},{"key":"2026071008400863000_2026.06.25.26356239v1.7","unstructured":"Gao, H. et al. The landscape of tolerated genetic variation in humans and primates. Science 380(2023)."},{"key":"2026071008400863000_2026.06.25.26356239v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.08.016"},{"key":"2026071008400863000_2026.06.25.26356239v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-025-02400-1"},{"key":"2026071008400863000_2026.06.25.26356239v1.10","unstructured":"Verma, A. et al. Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program. 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