美国再生元遗传学中心Aris Baras、Cristopher V. Van Hout团队取得一项新突破。他们揭示了UK Biobank中49,960名个体的外显子组测序数据和特征。这一研究成果于2020年10月21日在线发表在国际学术期刊《自然》上。

研究人员报道了UK Biobank中前期49,960名参与者的外显子组序列数据并揭示了大约400万个编码变体（其中约98.6％的频率小于1％）。该数据包括198,269个可能的常染色体功能丧失（LOF）变体，与推算序列相比，增加了14倍以上。几乎所有基因（超过97％）带有至少一个LOF变体，大多数基因（超过69％）具有至少十个LOF变体。

通过对1,730个表型的关联分析，研究人员表明了该群体中LOF变异的特征。除了复制已建立的关联外，研究人员还发现了对疾病特征有重大影响的新型LOF变体，包括与静脉曲张有关的PIEZO1、与角膜抵抗有关的COL6A1、影响骨密度的MEPE和对血细胞特征有影响的IQGAP2和GMPR。通过探究在临床上具有重要功能的病原体变异致病率，研究人员进一步证明了外显子组测序的价值，并表明该人群中有2％具有医学上可操作的变异。

此外,研究人员还表征了致病性BRCA1和BRCA2变异携带者中癌症的发生率。该前期49,960名参与者的外显子组测序数据突显了在基于人群的大型研究中进行基因组测序的前景，并且该数据库现已对全球开放。

研究人员介绍，UK Biobank是一项针对502,543名个体的前瞻性研究，包涵了广泛的表型和基因型数据，并对全球人员开放。

附：英文原文

Title: Exome sequencing and characterization of 49,960 individuals in the UK Biobank

Author: Cristopher V. Van Hout, Ioanna Tachmazidou, Joshua D. Backman, Joshua D. Hoffman, Daren Liu, Ashutosh K. Pandey, Claudia Gonzaga-Jauregui, Shareef Khalid, Bin Ye, Nilanjana Banerjee, Alexander H. Li, Colm ODushlaine, Anthony Marcketta, Jeffrey Staples, Claudia Schurmann, Alicia Hawes, Evan Maxwell, Leland Barnard, Alexander Lopez, John Penn, Lukas Habegger, Andrew L. Blumenfeld, Xiaodong Bai, Sean OKeeffe, Ashish Yadav, Kavita Praveen, Marcus Jones, William J. Salerno, Wendy K. Chung, Ida Surakka, Cristen J. Willer, Kristian Hveem, Joseph B. Leader, David J. Carey, David H. Ledbetter, Lon Cardon, George D. Yancopoulos, Aris Economides, Giovanni Coppola, Alan R. Shuldiner, Suganthi Balasubramanian, Michael Cantor, Matthew R. Nelson, John Whittaker, Jeffrey G. Reid, Jonathan Marchini, John D. Overton, Robert A. Scott, Gonalo R. Abecasis, Laura Yerges-Armstrong, Aris Baras

Issue&Volume: 2020-10-21

Abstract: The UK Biobank is a prospective study of 502,543 individuals, combining extensive phenotypic and genotypic data with streamlined access for researchers around the world1. Here we describe the release of exome-sequence data for the first 49,960 study participants, revealing approximately 4 million coding variants (of which around 98.6% have a frequency of less than 1%). The data include 198,269 autosomal predicted loss-of-function (LOF) variants, a more than 14-fold increase compared to the imputed sequence. Nearly all genes (more than 97%) had at least one carrier with a LOF variant, and most genes (more than 69%) had at least ten carriers with a LOF variant. We illustrate the power of characterizing LOF variants in this population through association analyses across 1,730 phenotypes. In addition to replicating established associations, we found novel LOF variants with large effects on disease traits, including PIEZO1 on varicose veins, COL6A1 on corneal resistance, MEPE on bone density, and IQGAP2 and GMPR on blood cell traits. We further demonstrate the value of exome sequencing by surveying the prevalence of pathogenic variants of clinical importance, and show that 2% of this population has a medically actionable variant. Furthermore, we characterize the penetrance of cancer in carriers of pathogenic BRCA1 and BRCA2 variants. Exome sequences from the first 49,960 participants highlight the promise of genome sequencing in large population-based studies and are now accessible to the scientific community.

DOI: 10.1038/s41586-020-2853-0

Source: https://www.nature.com/articles/s41586-020-2853-0