Distribution and clinical impact of functional variants in 50,726 whole-exome sequences from the DiscovEHR study

Frederick E. Dewey, Michael F. Murray, John D. Overton, Lukas Habegger, Joseph B. Leader, Samantha N. Fetterolf, Colm O'Dushlaine, Cristopher V. Van Hout, Jeffrey Staples, Claudia Gonzaga-Jauregui, Raghu Metpally, Sarah A. Pendergrass, Monica A. Giovanni, H. Lester Kirchner, Suganthi Balasubramanian, Noura S. Abul-Husn, Dustin N. Hartzel, Daniel R. Lavage, Korey A. Kost, Jonathan S. PackerAlexander E. Lopez, John Penn, Semanti Mukherjee, Nehal Gosalia, Manoj Kanagaraj, Alexander H. Li, Lyndon J. Mitnaul, Lance J. Adams, Thomas N. Person, Kavita Praveen, Anthony Marcketta, Matthew S. Lebo, Christina A. Austin-Tse, Heather M. Mason-Suares, Shannon Bruse, Scott Mellis, Robert Phillips, Neil Stahl, Andrew Murphy, Aris Economides, Kimberly A. Skelding, Christopher D. Still, James R. Elmore, Ingrid B. Borecki, George D. Yancopoulos, F. Daniel Davis, William A. Faucett, Omri Gottesman, Marylyn D. Ritchie, Alan R. Shuldiner, Jeffrey G. Reid, David H. Ledbetter, Aris Baras, David J. Carey

Research output: Contribution to journalArticlepeer-review

307 Scopus citations


The DiscovEHR collaboration between the Regeneron Genetics Center and Geisinger Health System couples high-throughput sequencing to an integrated health care system using longitudinal electronic health records (EHRs). We sequenced the exomes of 50,726 adult participants in the DiscovEHR study to identify ∼4.2 million rare single-nucleotide variants and insertion/deletion events, of which ∼176,000 are predicted to result in a loss of gene function. Linking these data to EHR-derived clinical phenotypes, we find clinical associations supporting therapeutic targets, including genes encoding drug targets for lipid lowering, and identify previously unidentified rare alleles associated with lipid levels and other blood level traits. About 3.5% of individuals harbor deleterious variants in 76 clinically actionable genes. The DiscovEHR data set provides a blueprint for large-scale precision medicine initiatives and genomics-guided therapeutic discovery.

Original languageEnglish (US)
Article numberaaf6814
Issue number6319
StatePublished - Dec 23 2016

All Science Journal Classification (ASJC) codes

  • General


Dive into the research topics of 'Distribution and clinical impact of functional variants in 50,726 whole-exome sequences from the DiscovEHR study'. Together they form a unique fingerprint.

Cite this