title: Distribution and clinical impact of functional variants in 50,726 whole-exome sequences from the DiscovEHR study.
abstract: 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.
authors.affiliation: Regeneron Genetics Center, Tarrytown, NY 10591, USA. djcarey@geisinger.edu frederick.dewey@regeneron.com.
authors.forename: Frederick E
authors.initials: FE
authors.lastname: Dewey
authors.affiliation: Geisinger Health System, Danville, PA 17822, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Murray
authors.affiliation: Regeneron Genetics Center, Tarrytown, NY 10591, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Overton
authors.affiliation: Regeneron Genetics Center, Tarrytown, NY 10591, USA.
authors.forename: Lukas
authors.initials: L
authors.lastname: Habegger
authors.affiliation: Geisinger Health System, Danville, PA 17822, USA.
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Leader
authors.affiliation: Geisinger Health System, Danville, PA 17822, USA.
authors.forename: Samantha N
authors.initials: SN
authors.lastname: Fetterolf
authors.affiliation: Regeneron Genetics Center, Tarrytown, NY 10591, USA.
authors.forename: Colm
authors.initials: C
authors.lastname: O'Dushlaine
authors.affiliation: Regeneron Genetics Center, Tarrytown, NY 10591, USA.
authors.forename: Cristopher V
authors.initials: CV
authors.lastname: Van Hout
authors.affiliation: Regeneron Genetics Center, Tarrytown, NY 10591, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Staples
authors.affiliation: Regeneron Genetics Center, Tarrytown, NY 10591, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Gonzaga-Jauregui
authors.affiliation: Geisinger Health System, Danville, PA 17822, USA.
authors.forename: Raghu
authors.initials: R
authors.lastname: Metpally
authors.affiliation: Geisinger Health System, Danville, PA 17822, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Pendergrass
authors.affiliation: Geisinger Health System, Danville, PA 17822, USA.
authors.forename: Monica A
authors.initials: MA
authors.lastname: Giovanni
authors.affiliation: Geisinger Health System, Danville, PA 17822, USA.
authors.forename: H Lester
authors.initials: HL
authors.lastname: Kirchner
authors.affiliation: Regeneron Genetics Center, Tarrytown, NY 10591, USA.
authors.forename: Suganthi
authors.initials: S
authors.lastname: Balasubramanian
authors.affiliation: Regeneron Genetics Center, Tarrytown, NY 10591, USA.
authors.forename: Noura S
authors.initials: NS
authors.lastname: Abul-Husn
authors.affiliation: Geisinger Health System, Danville, PA 17822, USA.
authors.forename: Dustin N
authors.initials: DN
authors.lastname: Hartzel
authors.affiliation: Geisinger Health System, Danville, PA 17822, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Lavage
authors.affiliation: Geisinger Health System, Danville, PA 17822, USA.
authors.forename: Korey A
authors.initials: KA
authors.lastname: Kost
authors.affiliation: Regeneron Genetics Center, Tarrytown, NY 10591, USA.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Packer
authors.affiliation: Regeneron Genetics Center, Tarrytown, NY 10591, USA.
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Lopez
authors.affiliation: Regeneron Genetics Center, Tarrytown, NY 10591, USA.
authors.forename: John
authors.initials: J
authors.lastname: Penn
authors.affiliation: Regeneron Genetics Center, Tarrytown, NY 10591, USA.
authors.forename: Semanti
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Regeneron Genetics Center, Tarrytown, NY 10591, USA.
authors.forename: Nehal
authors.initials: N
authors.lastname: Gosalia
authors.affiliation: Regeneron Genetics Center, Tarrytown, NY 10591, USA.
authors.forename: Manoj
authors.initials: M
authors.lastname: Kanagaraj
authors.affiliation: Regeneron Genetics Center, Tarrytown, NY 10591, USA.
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Li
authors.affiliation: Regeneron Genetics Center, Tarrytown, NY 10591, USA.
authors.forename: Lyndon J
authors.initials: LJ
authors.lastname: Mitnaul
authors.affiliation: Geisinger Health System, Danville, PA 17822, USA.
authors.forename: Lance J
authors.initials: LJ
authors.lastname: Adams
authors.affiliation: Geisinger Health System, Danville, PA 17822, USA.
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Person
authors.affiliation: Regeneron Genetics Center, Tarrytown, NY 10591, USA.
authors.forename: Kavita
authors.initials: K
authors.lastname: Praveen
authors.affiliation: Regeneron Genetics Center, Tarrytown, NY 10591, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Marcketta
authors.affiliation: Laboratory for Molecular Medicine, Cambridge, MA 02139, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Lebo
authors.affiliation: Laboratory for Molecular Medicine, Cambridge, MA 02139, USA.
authors.forename: Christina A
authors.initials: CA
authors.lastname: Austin-Tse
authors.affiliation: Laboratory for Molecular Medicine, Cambridge, MA 02139, USA.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Mason-Suares
authors.affiliation: Regeneron Genetics Center, Tarrytown, NY 10591, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Bruse
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Mellis
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Phillips
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Stahl
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Murphy
authors.affiliation: Regeneron Genetics Center, Tarrytown, NY 10591, USA.
authors.forename: Aris
authors.initials: A
authors.lastname: Economides
authors.affiliation: Geisinger Health System, Danville, PA 17822, USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Skelding
authors.affiliation: Geisinger Health System, Danville, PA 17822, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Still
authors.affiliation: Geisinger Health System, Danville, PA 17822, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Elmore
authors.affiliation: Regeneron Genetics Center, Tarrytown, NY 10591, USA.
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Borecki
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA.
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
authors.affiliation: Geisinger Health System, Danville, PA 17822, USA.
authors.forename: F Daniel
authors.initials: FD
authors.lastname: Davis
authors.affiliation: Geisinger Health System, Danville, PA 17822, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Faucett
authors.affiliation: Regeneron Genetics Center, Tarrytown, NY 10591, USA.
authors.forename: Omri
authors.initials: O
authors.lastname: Gottesman
authors.affiliation: Geisinger Health System, Danville, PA 17822, USA.
authors.forename: Marylyn D
authors.initials: MD
authors.lastname: Ritchie
authors.affiliation: Regeneron Genetics Center, Tarrytown, NY 10591, USA.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Shuldiner
authors.affiliation: Regeneron Genetics Center, Tarrytown, NY 10591, USA.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Reid
authors.affiliation: Geisinger Health System, Danville, PA 17822, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Ledbetter
authors.affiliation: Regeneron Genetics Center, Tarrytown, NY 10591, USA.
authors.forename: Aris
authors.initials: A
authors.lastname: Baras
authors.affiliation: Geisinger Health System, Danville, PA 17822, USA. djcarey@geisinger.edu frederick.dewey@regeneron.com.
authors.forename: David J
authors.initials: DJ
authors.lastname: Carey
mesh_terms: D000328:Adult; D019033:Delivery of Health Care, Integrated; D004194:Disease / Q000235:genetics*; D015195:Drug Design; D057286:Electronic Health Records; D059472:Exome / Q000235:genetics*; D005787:Gene Frequency; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D054643:INDEL Mutation; D008055:Lipids / Q000097:blood; D058990:Molecular Targeted Therapy; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA
chemical_list: D000960:Hypolipidemic Agents; D008055:Lipids