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 1,252,761 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 MAD1L1, TCL1A, and ATP2A3 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.