Genetic drivers and clinical consequences of mosaic chromosomal alterations in 1 million individuals

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 1,011,269 participants across four biobanks. Through integrative analysis of the minimum critical region and inherited genetic variation, we found that proto-oncogenes exclusively drive chromosomal gains, tumor suppressors drive losses, and copy-neutral events can be driven by either. We identified three novel inherited risk loci in CHI3L2, HLA class II, and TERT that modulate aut-mCA risk and ten 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 causally established aut-mCAs as premalignant lesions for chronic lymphocytic leukemia. Together, our findings provide a framework integrating somatic mosaicism, germline genetics, and clinical phenotypes to identify individuals who could benefit from preventative interventions.