Distribution and clinical impact of functional variants in 50,726 whole-exome sequences from the DiscovEHR study
Top Cited Papers
- 23 December 2016
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 354 (6319)
- https://doi.org/10.1126/science.aaf6814
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.Keywords
Funding Information
- Regeneron Pharmaceuticals
This publication has 78 references indexed in Scilit:
- An integrated map of genetic variation from 1,092 human genomesNature, 2012
- An informatics approach to analyzing the incidentalomeGenetics in Medicine, 2012
- A rare variant in MYH6 is associated with high risk of sick sinus syndromeNature Genetics, 2011
- GCTA: A Tool for Genome-wide Complex Trait AnalysisAmerican Journal of Human Genetics, 2011
- A map of human genome variation from population-scale sequencingNature, 2010
- Population structure and genome-wide patterns of variation in Ireland and BritainEuropean Journal of Human Genetics, 2010
- DNA sequencing of a cytogenetically normal acute myeloid leukaemia genomeNature, 2008
- Methods for Detecting Associations with Rare Variants for Common Diseases: Application to Analysis of Sequence DataAmerican Journal of Human Genetics, 2008
- Natural Selection on Genes that Underlie Human Disease SusceptibilityCurrent Biology, 2008
- Sequence Variations inPCSK9,Low LDL, and Protection against Coronary Heart DiseaseThe New England Journal of Medicine, 2006