Journal Article

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

Dewey, Frederick E.

2016

Overview

Precision medicine promises the ability to identify risks and treat patients on the basis of pathogenic genetic variation. Two studies combined exome sequencing results for over 50,000 people with their electronic health records. Dewey et al. found that ∼3.5% of individuals in their cohort had clinically actionable genetic variants. Many of these variants affected blood lipid levels that could influence cardiovascular health. Abul-Husn et al. extended these findings to investigate the genetics and treatment of familial hypercholesterolemia, a risk factor for cardiovascular disease, within their patient pool. Genetic screening helped identify at-risk patients who could benefit from increased treatment. Science , this issue p. 10.1126/science.aaf6814 , p. 10.1126/science.aaf7000 More than 50,000 exomes, coupled with electronic health records, inform on medically relevant genetic variants. 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.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: Adult / Blood / Cardiovascular diseases / Delivery of Health Care, Integrated / Disease - genetics / Drug Design / Electronic Health Records / Exome - genetics / Gene Frequency / Genes / Genetic Disorders / Genetic diversity / Genetic screening / Genetic variance / Genetics / Genomics / Health / Health care / Health promotion / Health Services / High-Throughput Nucleotide Sequencing / Humans / Hypolipidemic Agents - pharmacology / INDEL Mutation / Laboratory tests / Lipids / Lipids - blood / Medicine / Molecular Targeted Therapy / Patients / Polymorphism, Single Nucleotide / Precision medicine / Records (Forms) / RESEARCH ARTICLE SUMMARY / Risk factors / Sequence Analysis, DNA