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

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.

Citation

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 O'Dushlaine, Anthony Marcketta, Jeffrey Staples, Claudia Schurmann, Alicia Hawes, Evan Maxwell, Leland Barnard, Alexander Lopez, John Penn, Lukas Habegger, Andrew L Blumenfeld, Xiaodong Bai, Sean O'Keeffe, 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, Geisinger-Regeneron DiscovEHR Collaboration, Lon Cardon, George D Yancopoulos, Aris Economides, Giovanni Coppola, Alan R Shuldiner, Suganthi Balasubramanian, Michael Cantor, Regeneron Genetics Center, Matthew R Nelson, John Whittaker, Jeffrey G Reid, Jonathan Marchini, John D Overton, Robert A Scott, Gonçalo R Abecasis, Laura Yerges-Armstrong, Aris Baras. Exome sequencing and characterization of 49,960 individuals in the UK Biobank. Nature. 2020 Oct;586(7831):749-756

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PMID: 33087929

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