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

Dewey FE1, Murray MF2, Overton JD3, Habegger L3, Leader JB2, Fetterolf SN2, O'Dushlaine C3, Van Hout CV3, Staples J3, Gonzaga-Jauregui C3, Metpally R2, Pendergrass SA2, Giovanni MA2, Kirchner HL2, Balasubramanian S3, Abul-Husn NS3, Hartzel DN2, Lavage DR2, Kost KA2, Packer JS3, Lopez AE3, Penn J3, Mukherjee S3, Gosalia N3, Kanagaraj M3, Li AH3, Mitnaul LJ3, Adams LJ2, Person TN2, Praveen K3, Marcketta A3, Lebo MS4, Austin-Tse CA4, Mason-Suares HM4, Bruse S3, Mellis S5, Phillips R5, Stahl N5, Murphy A5, Economides A3, Skelding KA2, Still CD2, Elmore JR2, Borecki IB3, Yancopoulos GD5, Davis FD2, Faucett WA2, Gottesman O3, Ritchie MD2, Shuldiner AR3, Reid JG3, Ledbetter DH2, Baras A3, Carey DJ6.

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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.