英国阿斯利康公司Slavé Petrovski团队揭示281,104个英国生物银行（UKB）外显子组中罕见变体对人类疾病的贡献。相关论文于2021年8月10日在线发表在《自然》杂志上。

利用UKB中269,171名欧洲血统参与者的外显子测序数据，研究人员揭示了罕见蛋白质编码变异与17,361种二元表型和1,419种定量表型之间的关系。基于基因的折叠分析显示，二元性状有1703个具有统计学意义的基因-表型关联，中位数比值比为12.4。此外，这些关联中的83%通过单变体关联测试无法检测到，这强调了基于基因的折叠分析在高等位基因异质性背景下的能力。基因-表型关联在功能缺失介导的性状和获批的药物靶点上也明显富集。最后，研究人员利用来自非洲、东亚或南亚血统的11,933名UKB参与者的外显子组测序数据进行了特定血统和泛血统的折叠分析。

总之，这些结果突出了罕见变体对常见疾病的重大贡献。简要的统计数据可通过一个互动的门户网站（http://azphewas.com/）公开获得。

据悉，全基因组关联研究发现了数千种与人类疾病相关的常见变异，但罕见变异对常见疾病的贡献仍相对未被探究。UKB包含了与医疗记录相联系的约50万参与者的详细表型数据，为评估罕见变异对广泛的性状集合的影响提供了前所未有的机会。

附：英文原文

Title: Rare variant contribution to human disease in 281,104 UK Biobank exomes

Author: Wang, Quanli, Dhindsa, Ryan S., Carss, Keren, Harper, Andrew R., Nag, Abhishek, Tachmazidou, Ioanna, Vitsios, Dimitrios, Deevi, Sri V. V., Mackay, Alex, Muthas, Daniel, Hhn, Michael, Monkley, Sue, Olsson, Henric, Wasilewski, Sebastian, Smith, Katherine R., March, Ruth, Platt, Adam, Haefliger, Carolina, Petrovski, Slav

Issue&Volume: 2021-08-10

Abstract: Genome-wide association studies have uncovered thousands of common variants associated with human disease, but the contribution of rare variation to common disease remains relatively unexplored. The UK Biobank (UKB) contains detailed phenotypic data linked to medical records for approximately 500,000 participants, offering an unprecedented opportunity to evaluate the impact of rare variation on a broad collection of traits1,2. Here, we studied the relationships between rare protein-coding variants and 17,361 binary and 1,419 quantitative phenotypes using exome sequencing data from 269,171 UKB participants of European ancestry. Gene-based collapsing analyses revealed 1,703 statistically significant gene-phenotype associations for binary traits, with a median odds ratio of 12.4. Furthermore, 83% of these associations were undetectable via single variant association tests, emphasizing the power of gene-based collapsing analysis in the setting of high allelic heterogeneity. Gene-phenotype associations were also significantly enriched for loss-of-function-mediated traits and approved drug targets. Finally, we performed ancestry-specific and pan-ancestry collapsing analyses using exome sequencing data from 11,933 UKB participants of African, East Asian, or South Asian ancestry. Together, our results highlight a significant contribution of rare variants to common disease. Summary statistics are publicly available through an interactive portal (http://azphewas.com/).

DOI: 10.1038/s41586-021-03855-y

Source: https://www.nature.com/articles/s41586-021-03855-y