{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T03:11:47Z","timestamp":1791256307671,"version":"4.1.0"},"posted":{"date-parts":[[2025,3,6]]},"group-title":"Genetic and Genomic Medicine","reference-count":44,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,3,6]],"date-time":"2025-03-06T00:00:00Z","timestamp":1741219200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Mosaic chromosomal alterations of the autosomes (aut-mCAs) are large structural somatic mutations which cause clonal hematopoiesis and increase cancer risk. Here, we detected aut-mCAs in 1,252,761 participants across four biobanks. Through integrative analysis of the minimum critical region and inherited genetic variation, we nominated candidate driver genes for each aut-mCA, prioritizing proto-oncogenes within recurrently gained regions and tumor suppressors within recurrently lost regions. We identified three novel inherited risk loci in\n                  <jats:italic>MAD1L1<\/jats:italic>\n                  ,\n                  <jats:italic>TCL1A<\/jats:italic>\n                  , and\n                  <jats:italic>ATP2A3<\/jats:italic>\n                  that modulate aut-mCA risk and four novel aut-mCA- specific loci. We found specific aut-mCAs are associated with cardiovascular, cerebrovascular, or kidney disease incidence. High-risk aut-mCAs were associated with elevated plasma protein levels of therapeutically actionable targets: NPM1, PARP1, and TACI. Participants with multiple high-risk features such as high clonal fraction, more than one aut-mCA, and abnormal red cell morphology had a 50% cumulative incidence of blood count abnormalities over 2 years. Leveraging inherited variation, we provide evidence supporting a role for specific autosomal mCAs in chronic lymphocytic leukemia development. Together, our findings provide a framework integrating somatic mosaicism, germline genetics, and clinical phenotypes to identify individuals who could benefit from preventative interventions.\n                <\/jats:p>","DOI":"10.1101\/2025.03.05.25323443","type":"posted-content","created":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T07:31:50Z","timestamp":1741332710000},"source":"Crossref","is-referenced-by-count":11,"title":["Genetic drivers and clinical consequences of mosaic chromosomal alterations in 1 million individuals"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2811-4419","authenticated-orcid":false,"given":"Kun","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, US"},{"name":"Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, 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