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Incident disease associations with mosaic chromosomal alterations on autosomes, X and Y chromosomes: insights from a phenome-wide association study in the UK Biobank.

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Lin, Shu-Hong 
Brown, Derek W 
Rose, Brandon 
Day, Felix 
Lee, Olivia W 


BACKGROUND: Mosaic chromosomal alterations (mCAs) are large chromosomal gains, losses and copy-neutral losses of heterozygosity (LOH) in peripheral leukocytes. While many individuals with detectable mCAs have no notable adverse outcomes, mCA-associated gene dosage alterations as well as clonal expansion of mutated leukocyte clones could increase susceptibility to disease. RESULTS: We performed a phenome-wide association study (PheWAS) using existing data from 482,396 UK Biobank (UKBB) participants to investigate potential associations between mCAs and incident disease. Of the 1290 ICD codes we examined, our adjusted analysis identified a total of 50 incident disease outcomes associated with mCAs at PheWAS significance levels. We observed striking differences in the diseases associated with each type of alteration, with autosomal mCAs most associated with increased hematologic malignancies, incident infections and possibly cancer therapy-related conditions. Alterations of chromosome X were associated with increased lymphoid leukemia risk and, mCAs of chromosome Y were linked to potential reduced metabolic disease risk. CONCLUSIONS: Our findings demonstrate that a wide range of diseases are potential sequelae of mCAs and highlight the critical importance of careful covariate adjustment in mCA disease association studies.



Mosaic chromosomal alterations, Mosaic loss of Y, PheWAS, Phenome-wide association study, UK Biobank

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Cell Biosci

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Springer Science and Business Media LLC
MRC (MC_UU_00006/2)
Medical Research Council (MC_UU_12015/2)