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

Cell & Bioscience

Shu-Hong Lin¹  Derek W. Brown¹  Sairah M. Khan¹  Stephen J. Chanock¹  Olivia W. Lee¹  Jada Hislop¹  Mitchell J. Machiela¹  Felix Day²  John R. B. Perry²  Brandon Rose³ 

[1] Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, 20892, Rockville, MD, USA;MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK;University of Miami Miller School of Medicine, 33136, Miami, FL, USA;

关键词: Mosaic loss of Y;    Mosaic chromosomal alterations;    Phenome-wide association study;    PheWAS;    UK Biobank;   

DOI  :  10.1186/s13578-021-00651-z

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY