PT  - JOURNAL ARTICLE
AU  - Cristopher V. Van Hout
AU  - Ioanna Tachmazidou
AU  - Joshua D. Backman
AU  - Joshua X. Hoffman
AU  - Bin Ye
AU  - Ashutosh K. Pandey
AU  - Claudia Gonzaga-Jauregui
AU  - Shareef Khalid
AU  - Daren Liu
AU  - Nilanjana Banerjee
AU  - Alexander H. Li
AU  - O’Dushlaine Colm
AU  - Anthony Marcketta
AU  - Jeffrey Staples
AU  - Claudia Schurmann
AU  - Alicia Hawes
AU  - Evan Maxwell
AU  - Leland Barnard
AU  - Alexander Lopez
AU  - John Penn
AU  - Lukas Habegger
AU  - Andrew L. Blumenfeld
AU  - Ashish Yadav
AU  - Kavita Praveen
AU  - Marcus Jones
AU  - William J. Salerno
AU  - Wendy K. Chung
AU  - Ida Surakka
AU  - Cristen J. Willer
AU  - Kristian Hveem
AU  - Joseph B. Leader
AU  - David J. Carey
AU  - David H. Ledbetter
AU  - Geisinger-Regeneron DiscovEHR Collaboration
AU  - Lon Cardon
AU  - George D. Yancopoulos
AU  - Aris Economides
AU  - Giovanni Coppola
AU  - Alan R. Shuldiner
AU  - Suganthi Balasubramanian
AU  - Michael Cantor
AU  - Matthew R. Nelson
AU  - John Whittaker
AU  - Jeffrey G. Reid
AU  - Jonathan Marchini
AU  - John D. Overton
AU  - Robert A. Scott
AU  - Gonçalo Abecasis
AU  - Laura Yerges-Armstrong
AU  - Aris Baras
AU  - on behalf of the Regeneron Genetics Center
TI  - Whole exome sequencing and characterization of coding variation in 49,960 individuals in the UK Biobank
AID  - 10.1101/572347
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 572347
4099  - http://biorxiv.org/content/early/2019/03/09/572347.short
4100  - http://biorxiv.org/content/early/2019/03/09/572347.full
AB  - The UK Biobank is a prospective study of 502,543 individuals, combining extensive phenotypic and genotypic data with streamlined access for researchers around the world. Here we describe the first tranche of large-scale exome sequence data for 49,960 study participants, revealing approximately 4 million coding variants (of which ~98.4% have frequency < 1%). The data includes 231,631 predicted loss of function variants, a >10-fold increase compared to imputed sequence for the same participants. Nearly all genes (>97%) had ≥1 predicted loss of function carrier, and most genes (>69%) had ≥10 loss of function carriers. We illustrate the power of characterizing loss of function variation in this large population through association analyses across 1,741 phenotypes. In addition to replicating a range of established associations, we discover novel loss of function 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 significance in this population, finding that 2% of the population has a medically actionable variant. Additionally, we leverage the phenotypic data to characterize the relationship between rare BRCA1 and BRCA2 pathogenic variants and cancer risk. Exomes from the first 49,960 participants are now made accessible to the scientific community and highlight the promise offered by genomic sequencing in large-scale population-based studies.