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. 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. 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.

中文翻译：

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事件疾病与常染色体、X 和 Y 染色体镶嵌染色体改变的关联：来自英国生物银行全表型关联研究的见解

镶嵌染色体改变 (mCA) 是外周白细胞中大量的染色体获得、丢失和杂合性复制中性丢失​​ (LOH)。虽然许多可检测到 mCA 的个体没有明显的不良后果，但 mCA 相关基因剂量的改变以及突变白细胞克隆的克隆扩张可能会增加对疾病的易感性。我们利用 482,396 名英国生物银行 (UKBB) 参与者的现有数据进行了一项全表型关联研究 (PheWAS)，以调查 mCA 与突发疾病之间的潜在关联。在我们检查的 1290 个 ICD 代码中，我们的调整后分析总共确定了 50 种与 PheWAS 显着性水平的 mCA 相关的事件疾病结果。我们观察到与每种类型的改变相关的疾病存在显着差异，其中常染色体 mCA 与血液恶性肿瘤、感染事件以及可能的癌症治疗相关病症的增加最相关。X 染色体的改变与淋巴白血病风险增加相关，Y 染色体的 mCA 与潜在的代谢性疾病风险降低相关。我们的研究结果表明，多种疾病是 mCA 的潜在后遗症，并强调了 mCA 疾病关联研究中仔细协变量调整的至关重要性。