Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Center for Data Sciences, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Nat Genet. 2024 Apr;56(4):569-578. doi: 10.1038/s41588-024-01684-z. Epub 2024 Mar 28.
Copy number variants (CNVs) are among the largest genetic variants, yet CNVs have not been effectively ascertained in most genetic association studies. Here we ascertained protein-altering CNVs from UK Biobank whole-exome sequencing data (n = 468,570) using haplotype-informed methods capable of detecting subexonic CNVs and variation within segmental duplications. Incorporating CNVs into analyses of rare variants predicted to cause gene loss of function (LOF) identified 100 associations of predicted LOF variants with 41 quantitative traits. A low-frequency partial deletion of RGL3 exon 6 conferred one of the strongest protective effects of gene LOF on hypertension risk (odds ratio = 0.86 (0.82-0.90)). Protein-coding variation in rapidly evolving gene families within segmental duplications-previously invisible to most analysis methods-generated some of the human genome's largest contributions to variation in type 2 diabetes risk, chronotype and blood cell traits. These results illustrate the potential for new genetic insights from genomic variation that has escaped large-scale analysis to date.
拷贝数变异（CNVs）是最大的遗传变异之一，但在大多数遗传关联研究中，CNVs 尚未得到有效确定。在这里，我们使用能够检测亚外显子 CNVs 和片段重复内变异的单倍型信息方法，从英国生物库全外显子测序数据（n=468570）中确定了蛋白质改变的 CNVs。将 CNVs 纳入对预测导致基因功能丧失（LOF）的稀有变异的分析中，鉴定出 100 个与 41 个数量性状相关的预测 LOF 变异的关联。RGL3 外显子 6 的低频部分缺失赋予了基因 LOF 对高血压风险的最强保护作用之一（优势比=0.86（0.82-0.90））。片段重复内快速进化基因家族的蛋白质编码变异——以前大多数分析方法都无法检测到——为 2 型糖尿病风险、生物钟和血细胞特征的变异产生了人类基因组的一些最大贡献。这些结果说明了从迄今为止尚未进行大规模分析的基因组变异中获得新遗传见解的潜力。
