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

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, 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 (), Gonçalo R. Abecasis, Laura Yerges-Armstrong () and Aris Baras ()
Additional contact information
Cristopher V. Van Hout: Regeneron Genetics Center
Ioanna Tachmazidou: GlaxoSmithKline
Joshua D. Backman: Regeneron Genetics Center
Joshua D. Hoffman: GlaxoSmithKline
Daren Liu: Regeneron Genetics Center
Ashutosh K. Pandey: GlaxoSmithKline
Claudia Gonzaga-Jauregui: Regeneron Genetics Center
Shareef Khalid: Regeneron Genetics Center
Bin Ye: Regeneron Genetics Center
Nilanjana Banerjee: Regeneron Genetics Center
Alexander H. Li: Regeneron Genetics Center
Colm O’Dushlaine: Regeneron Genetics Center
Anthony Marcketta: Regeneron Genetics Center
Jeffrey Staples: Regeneron Genetics Center
Claudia Schurmann: Regeneron Genetics Center
Alicia Hawes: Regeneron Genetics Center
Evan Maxwell: Regeneron Genetics Center
Leland Barnard: Regeneron Genetics Center
Alexander Lopez: Regeneron Genetics Center
John Penn: Regeneron Genetics Center
Lukas Habegger: Regeneron Genetics Center
Andrew L. Blumenfeld: Regeneron Genetics Center
Xiaodong Bai: Regeneron Genetics Center
Sean O’Keeffe: Regeneron Genetics Center
Ashish Yadav: Regeneron Genetics Center
Kavita Praveen: Regeneron Genetics Center
Marcus Jones: Regeneron Pharmaceuticals
William J. Salerno: Regeneron Genetics Center
Wendy K. Chung: Columbia University Irving Medical Center
Ida Surakka: University of Michigan
Cristen J. Willer: University of Michigan
Kristian Hveem: Norwegian University of Science and Technology
Joseph B. Leader: Geisinger
David J. Carey: Geisinger
David H. Ledbetter: Geisinger
Lon Cardon: GlaxoSmithKline
George D. Yancopoulos: Regeneron Pharmaceuticals
Aris Economides: Regeneron Pharmaceuticals
Giovanni Coppola: Regeneron Genetics Center
Alan R. Shuldiner: Regeneron Genetics Center
Suganthi Balasubramanian: Regeneron Genetics Center
Michael Cantor: Regeneron Genetics Center
Matthew R. Nelson: GlaxoSmithKline
John Whittaker: GlaxoSmithKline
Jeffrey G. Reid: Regeneron Genetics Center
Jonathan Marchini: Regeneron Genetics Center
John D. Overton: Regeneron Genetics Center
Robert A. Scott: GlaxoSmithKline
Gonçalo R. Abecasis: Regeneron Genetics Center
Laura Yerges-Armstrong: GlaxoSmithKline
Aris Baras: Regeneron Genetics Center

Nature, 2020, vol. 586, issue 7831, 749-756

Abstract: 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.

Date: 2020
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Citations: View citations in EconPapers (8)

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DOI: 10.1038/s41586-020-2853-0

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