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

TLDR

The DiscovEHR collaboration links high‑throughput exome sequencing with longitudinal electronic health records to study genetic variation in a large population. The study sequenced exomes of 50,726 adults, identifying ~4.2 million rare variants, including ~176,000 predicted loss‑of‑function mutations. Linking these variants to EHR phenotypes revealed therapeutic‑target associations, novel rare alleles affecting lipid and blood traits, that 3.5 % of participants carry deleterious variants in 76 actionable genes, and positioned the dataset as a blueprint for precision medicine.

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.