Department of Biomedical Data Science, School of Medicine, Stanford University, Stanford, CA 94305, USA; Department of Pediatrics, School of Medicine, Stanford University, Stanford, CA 94305, USA.
Department of Biomedical Data Science, School of Medicine, Stanford University, Stanford, CA 94305, USA.
Am J Hum Genet. 2019 Aug 1;105(2):373-383. doi: 10.1016/j.ajhg.2019.07.001. Epub 2019 Jul 25.
Copy-number variations (CNVs) represent a significant proportion of the genetic differences between individuals and many CNVs associate causally with syndromic disease and clinical outcomes. Here, we characterize the landscape of copy-number variation and their phenome-wide effects in a sample of 472,228 array-genotyped individuals from the UK Biobank. In addition to population-level selection effects against genic loci conferring high mortality, we describe genetic burden from potentially pathogenic and previously uncharacterized CNV loci across more than 3,000 quantitative and dichotomous traits, with separate analyses for common and rare classes of variation. Specifically, we highlight the effects of CNVs at two well-known syndromic loci 16p11.2 and 22q11.2, previously uncharacterized variation at 9p23, and several genic associations in the context of acute coronary artery disease and high body mass index. Our data constitute a deeply contextualized portrait of population-wide burden of copy-number variation, as well as a series of dosage-mediated genic associations across the medical phenome.
拷贝数变异（CNVs）代表了个体之间遗传差异的重要组成部分，许多 CNVs 与综合征疾病和临床结果有因果关系。在这里，我们在来自英国生物银行的 472,228 个基因分型个体的样本中描述了拷贝数变异及其表型全基因组效应的特征。除了针对导致高死亡率的基因座的群体水平选择效应外，我们还描述了来自超过 3000 个定量和二分性状的潜在致病性和以前未表征的 CNV 位点的遗传负担，对常见和稀有变异类别的分析是分开进行的。具体来说，我们强调了两个众所周知的综合征位点 16p11.2 和 22q11.2 的 CNV 效应、以前未表征的 9p23 上的变异，以及急性冠状动脉疾病和高体重指数背景下的几个基因关联。我们的数据构成了人群范围内拷贝数变异负担的深度情境化描述，以及整个医学表型中一系列剂量介导的基因关联。
