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

被引：401

作者：

Dewey, Frederick E. ^{[1
]}

Murray, Michael F. ^{[2
]}

Overton, John D. ^{[1
]}

Habegger, Lukas ^{[1
]}

Leader, Joseph B. ^{[2
]}

Fetterolf, Samantha N. ^{[2
]}

O'Dushlaine, Colm ^{[1
]}

Van Hout, Cristopher V. ^{[1
]}

Staples, Jeffrey ^{[1
]}

Gonzaga-Jauregui, Claudia ^{[1
]}

Metpally, Raghu ^{[2
]}

Pendergrass, Sarah A. ^{[2
]}

Giovanni, Monica A. ^{[2
]}

Kirchner, H. Lester ^{[2
]}

Balasubramanian, Suganthi ^{[1
]}

Abul-Husn, Noura S. ^{[1
]}

Hartzel, Dustin N. ^{[2
]}

Lavage, Daniel R. ^{[2
]}

Kost, Korey A. ^{[2
]}

Packer, Jonathan S. ^{[1
]}

Lopez, Alexander E. ^{[1
]}

Penn, John ^{[1
]}

Mukherjee, Semanti ^{[1
]}

Gosalia, Nehal ^{[1
]}

Kanagaraj, Manoj ^{[1
]}

Li, Alexander H. ^{[1
]}

Mitnaul, Lyndon J. ^{[1
]}

Adams, Lance J. ^{[2
]}

Person, Thomas N. ^{[2
]}

Praveen, Kavita ^{[1
]}

Marcketta, Anthony ^{[1
]}

Lebo, Matthew S. ^{[3
]}

Austin-Tse, Christina A. ^{[3
]}

Mason-Suares, Heather M. ^{[3
]}

Bruse, Shannon ^{[1
]}

Mellis, Scott ^{[4
]}

Phillips, Robert ^{[4
]}

Stahl, Neil ^{[4
]}

Murphy, Andrew ^{[4
]}

Economides, Aris ^{[1
]}

Skelding, Kimberly A. ^{[2
]}

Still, Christopher D. ^{[2
]}

Elmore, James R. ^{[2
]}

Borecki, Ingrid B. ^{[1
]}

Yancopoulos, George D. ^{[4
]}

Davis, F. Daniel ^{[2
]}

Faucett, William A. ^{[2
]}

Gottesman, Omri ^{[1
]}

Ritchie, Marylyn D. ^{[2
]}

Shuldiner, Alan R. ^{[1
]}

机构：

[1] Regeneron Genet Ctr, Tarrytown, NY 10591 USA

[2] Geisinger Hlth Syst, Danville, PA 17822 USA

[3] Mol Med Lab, Cambridge, MA 02139 USA

[4] Regeneron Pharmaceut, Tarrytown, NY 10591 USA

来源：

SCIENCE | 2016年 / 354卷 / 6319期

关键词：

OF-FUNCTION VARIANTS; B SYNTHESIS INHIBITOR; IDENTIFIES RARE; DENSITY-LIPOPROTEIN; HEART-DISEASE; LOW-FREQUENCY; RISK; GENOME; ASSOCIATION; PCSK9;

D O I：

10.1126/science.aaf6814

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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 similar to 4.2 million rare single-nucleotide variants and insertion/deletion events, of which similar to 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.

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