2016
DOI: 10.1126/science.aaf6814
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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 … Show more

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Cited by 497 publications
(511 citation statements)
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References 80 publications
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“…1e)), it is expected that the much more genetically diverse human population would have an even larger degree of variation in this parameter. Indeed, natural or engineered loss of Tnni3k promotes higher MNDCM content in mice (as shown here), and the ExAC 36 and DiscovEHR 37 collections indicate that many heterozygous TNNI3K loss-of-function alleles exist in the human population, with some individuals identified to carry homozygous loss-of-function alleles. Additionally, while regeneration cannot be studied directly in humans, patients with initially similar degrees of infarction are known to have substantially different extents of ventricular remodeling and long-term outcomes 38,39 , and some of this divergence might be explained by genetic variation.…”
Section: Discussionsupporting
confidence: 56%
“…1e)), it is expected that the much more genetically diverse human population would have an even larger degree of variation in this parameter. Indeed, natural or engineered loss of Tnni3k promotes higher MNDCM content in mice (as shown here), and the ExAC 36 and DiscovEHR 37 collections indicate that many heterozygous TNNI3K loss-of-function alleles exist in the human population, with some individuals identified to carry homozygous loss-of-function alleles. Additionally, while regeneration cannot be studied directly in humans, patients with initially similar degrees of infarction are known to have substantially different extents of ventricular remodeling and long-term outcomes 38,39 , and some of this divergence might be explained by genetic variation.…”
Section: Discussionsupporting
confidence: 56%
“…For example, the power of human genetics in therapeutic target validation has been underscored by a retrospective analysis that selecting targets with supportive human genetics evidence doubled the success rate in clinical development 2 . A recent report on the clinical impact of loss-of-function (LoF) genetic variants in 50,726 exomes confirmed previously known associations between genes such as PCSK9 and cardiovascular disease-related phenotypic traits, and identified novel associations with therapeutic implications 3 . Genomics and genetics also play an increasingly important role in other areas in drug discovery such as biomarker identification for drug efficacy 4 and safety 5 , understanding drug mechanisms of action 6 , and selecting disease relevant experimental models 7 .…”
Section: Introductionmentioning
confidence: 70%
“…Mammals have much higher base substitution rates than yeast [11], and even the human germline, in spite of its much lower mutation rate than the soma, contains an average of 21 rare and several hundred common loss-of-function mutations (LOFs), i.e. genetic variants predicted to seriously disrupt the function of protein-coding genes [59]. This information was obtained by sequencing exomes of over 50,000 unrelated individuals.…”
Section: Functional Impact Of Somatic Mutationsmentioning
confidence: 99%