Abstract
BackgroundMosaic 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.ResultsWe 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.ConclusionsOur 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.
Highlights
Cells accumulate somatic mutations during normal growth and cellular division [36, 48], despite the presence of cellular mechanisms to prevent and repair genomic damage [19]
Genomic alterations can range in size from a single base pair change [16, 21, 22], to very large structural mosaic chromosomal alterations [20, 23, 28, 29, 34, 37, 42, 46]. Mosaic chromosomal alterations (mCAs) can be divided into different categories according to the location and span of these events, i.e. telomeric, centromeric, interstitial, and whole chromosome
Detectable mCAs in the UK Biobank population A total of 482,396 individuals were examined for mCAs, with a total of 17,113 (3.5%) having at least one detectable autosomal event and a total of 19,632 mosaic chromosomal alterations detected on the autosomes
Summary
Cells accumulate somatic mutations during normal growth and cellular division [36, 48], despite the presence of cellular mechanisms to prevent and repair genomic damage [19]. The chance of observing these subclones carrying genomic alterations increases with increasing age. These daughter cells eventually form a clonal subpopulation of cells with the somatic mutations offering potential cellular survival advantages. Genomic alterations can range in size from a single base pair change (e.g., somatic SNVs) [16, 21, 22], to very large structural mosaic chromosomal alterations (mCAs) [20, 23, 28, 29, 34, 37, 42, 46]. 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
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