Large-scale genetic studies of integrated health care populations, with phenotypic data captured natively in the documentation of clinical care, have the potential to unveil genetic associations that point the way to new biology and therapeutic targets. This setting also represents an ideal test bed for the implementation of genomics in routine clinical care in service of precision medicine.

The DiscovEHR collaboration between the Regeneron Genetics Center and Geisinger Health System aims to catalyze genomic discovery and precision medicine by coupling high-throughput exome sequencing to longitudinal electronic health records (EHRs) of participants in Geisinger’s MyCode Community Health Initiative. Here, we describe initial insights from whole-exome sequencing of 50,726 adult participants of predominantly European ancestry using clinical phenotypes derived from EHRs.

The median duration of EHR data associated with sequenced participants was 14 years, with a median of 87 clinical encounters, 687 laboratory tests, and seven procedures per participant. Forty-eight percent of sequenced individuals had one or more first- or second-degree relatives in the sample, and genome-wide autozygosity was similar to other outbred European populations. We found ~4.2 million single-nucleotide variants and insertion/deletion events, of which ~176,000 are predicted to result in loss of gene function (LoF). The overwhelming majority of these genetic variants occurred at a minor allele frequency of ≤1%, and more than half were singletons. Each participant harbored a median of 21 rare predicted LoFs. At this sample size, ~92% of sequenced genes, including genes that encode existing drug targets or confer risk for highly penetrant genetic diseases, harbor rare heterozygous predicted LoF variants. About 7% of sequenced genes contained rare homozygous predicted LoF variants in at least one individual. Linking these data to EHR-derived laboratory phenotypes revealed consequences of partial or complete LoF in humans. Among these were previously unidentified associations between predicted LoFs in CSF2RB and basophil and eosinophil counts, and EGLN1-associated erythrocytosis segregating in genetically identified family networks. Using predicted LoFs as a model for drug target antagonism, we found associations supporting the majority of therapeutic targets for lipid lowering. To highlight the opportunity for genotype-phenotype association discovery, we performed exome-wide association analyses of EHR-derived lipid values, newly implicating rare predicted LoFs, and deleterious missense variants in G6PC in association with triglyceride levels. In a survey of 76 clinically actionable disease-associated genes, we estimated that 3.5% of individuals harbor pathogenic or likely pathogenic variants that meet criteria for clinical action. Review of the EHR uncovered findings associated with the monogenic condition in ~65% of pathogenic variant carriers’ medical records.

The findings reported here demonstrate the value of large-scale sequencing in an integrated health system population, add to the knowledge base regarding the phenotypic consequences of human genetic variation, and illustrate the challenges and promise of genomic medicine implementation. DiscovEHR provides a blueprint for large-scale precision medicine initiatives and genomics-guided therapeutic target discovery.

(A) Associations between predicted LoF variants in lipid drug target genes and lipid levels. Boxes correspond to effect size, given as the …