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

Frederick E. Dewey, Michael F. Murray, John D. Overton, Lukas Habegger, Joseph B. Leader, Samantha N. Fetterolf, Colm O'Dushlaine, Cristopher V. Van Hout, Jeffrey Staples, Claudia Gonzaga-Jauregui, Raghu Metpally, Sarah A. Pendergrass, Monica A. Giovanni, H. Lester Kirchner, Suganthi Balasubramanian, Noura S. Abul-Husn, Dustin N. Hartzel, Daniel R. Lavage, Korey A. Kost, Jonathan S. PackerAlexander E. Lopez, John Penn, Semanti Mukherjee, Nehal Gosalia, Manoj Kanagaraj, Alexander H. Li, Lyndon J. Mitnaul, Lance J. Adams, Thomas N. Person, Kavita Praveen, Anthony Marcketta, Matthew S. Lebo, Christina A. Austin-Tse, Heather M. Mason-Suares, Shannon Bruse, Scott Mellis, Robert Phillips, Neil Stahl, Andrew Murphy, Aris Economides, Kimberly A. Skelding, Christopher D. Still, James R. Elmore, Ingrid B. Borecki, George D. Yancopoulos, F. Daniel Davis, William A. Faucett, Omri Gottesman, Marylyn D. Ritchie, Alan R. Shuldiner, Jeffrey G. Reid, David H. Ledbetter, Aris Baras, David J. Carey

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish (US)
Article numberaaf6814
JournalScience
Volume354
Issue number6319
DOIs
StatePublished - Dec 23 2016

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Hospital Distribution Systems
Exome
Electronic Health Records
Integrated Delivery of Health Care
Genes
Lipids
Precision Medicine
Genomics
Nucleotides
Alleles
Phenotype
Health
Therapeutics
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • General

Cite this

Dewey, F. E., Murray, M. F., Overton, J. D., Habegger, L., Leader, J. B., Fetterolf, S. N., ... Carey, D. J. (2016). Distribution and clinical impact of functional variants in 50,726 whole-exome sequences from the DiscovEHR study. Science, 354(6319), [aaf6814]. https://doi.org/10.1126/science.aaf6814
Dewey, Frederick E. ; Murray, Michael F. ; Overton, John D. ; Habegger, Lukas ; Leader, Joseph B. ; Fetterolf, Samantha N. ; O'Dushlaine, Colm ; Van Hout, Cristopher V. ; Staples, Jeffrey ; Gonzaga-Jauregui, Claudia ; Metpally, Raghu ; Pendergrass, Sarah A. ; Giovanni, Monica A. ; Kirchner, H. Lester ; Balasubramanian, Suganthi ; Abul-Husn, Noura S. ; Hartzel, Dustin N. ; Lavage, Daniel R. ; Kost, Korey A. ; Packer, Jonathan S. ; Lopez, Alexander E. ; Penn, John ; Mukherjee, Semanti ; Gosalia, Nehal ; Kanagaraj, Manoj ; Li, Alexander H. ; Mitnaul, Lyndon J. ; Adams, Lance J. ; Person, Thomas N. ; Praveen, Kavita ; Marcketta, Anthony ; Lebo, Matthew S. ; Austin-Tse, Christina A. ; Mason-Suares, Heather M. ; Bruse, Shannon ; Mellis, Scott ; Phillips, Robert ; Stahl, Neil ; Murphy, Andrew ; Economides, Aris ; Skelding, Kimberly A. ; Still, Christopher D. ; Elmore, James R. ; Borecki, Ingrid B. ; Yancopoulos, George D. ; Davis, F. Daniel ; Faucett, William A. ; Gottesman, Omri ; Ritchie, Marylyn D. ; Shuldiner, Alan R. ; Reid, Jeffrey G. ; Ledbetter, David H. ; Baras, Aris ; Carey, David J. / Distribution and clinical impact of functional variants in 50,726 whole-exome sequences from the DiscovEHR study. In: Science. 2016 ; Vol. 354, No. 6319.
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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 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.",
author = "Dewey, {Frederick E.} and Murray, {Michael F.} and Overton, {John D.} and Lukas Habegger and Leader, {Joseph B.} and Fetterolf, {Samantha N.} and Colm O'Dushlaine and {Van Hout}, {Cristopher V.} and Jeffrey Staples and Claudia Gonzaga-Jauregui and Raghu Metpally and Pendergrass, {Sarah A.} and Giovanni, {Monica A.} and Kirchner, {H. Lester} and Suganthi Balasubramanian and Abul-Husn, {Noura S.} and Hartzel, {Dustin N.} and Lavage, {Daniel R.} and Kost, {Korey A.} and Packer, {Jonathan S.} and Lopez, {Alexander E.} and John Penn and Semanti Mukherjee and Nehal Gosalia and Manoj Kanagaraj and Li, {Alexander H.} and Mitnaul, {Lyndon J.} and Adams, {Lance J.} and Person, {Thomas N.} and Kavita Praveen and Anthony Marcketta and Lebo, {Matthew S.} and Austin-Tse, {Christina A.} and Mason-Suares, {Heather M.} and Shannon Bruse and Scott Mellis and Robert Phillips and Neil Stahl and Andrew Murphy and Aris Economides and Skelding, {Kimberly A.} and Still, {Christopher D.} and Elmore, {James R.} and Borecki, {Ingrid B.} and Yancopoulos, {George D.} and Davis, {F. Daniel} and Faucett, {William A.} and Omri Gottesman and Ritchie, {Marylyn D.} and Shuldiner, {Alan R.} and Reid, {Jeffrey G.} and Ledbetter, {David H.} and Aris Baras and Carey, {David J.}",
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Dewey, FE, Murray, MF, Overton, JD, Habegger, L, Leader, JB, Fetterolf, SN, O'Dushlaine, C, Van Hout, CV, Staples, J, Gonzaga-Jauregui, C, Metpally, R, Pendergrass, SA, Giovanni, MA, Kirchner, HL, Balasubramanian, S, Abul-Husn, NS, Hartzel, DN, Lavage, DR, Kost, KA, Packer, JS, Lopez, AE, Penn, J, Mukherjee, S, Gosalia, N, Kanagaraj, M, Li, AH, Mitnaul, LJ, Adams, LJ, Person, TN, Praveen, K, Marcketta, A, Lebo, MS, Austin-Tse, CA, Mason-Suares, HM, Bruse, S, Mellis, S, Phillips, R, Stahl, N, Murphy, A, Economides, A, Skelding, KA, Still, CD, Elmore, JR, Borecki, IB, Yancopoulos, GD, Davis, FD, Faucett, WA, Gottesman, O, Ritchie, MD, Shuldiner, AR, Reid, JG, Ledbetter, DH, Baras, A & Carey, DJ 2016, 'Distribution and clinical impact of functional variants in 50,726 whole-exome sequences from the DiscovEHR study', Science, vol. 354, no. 6319, aaf6814. https://doi.org/10.1126/science.aaf6814

Distribution and clinical impact of functional variants in 50,726 whole-exome sequences from the DiscovEHR study. / Dewey, Frederick E.; Murray, Michael F.; Overton, John D.; Habegger, Lukas; Leader, Joseph B.; Fetterolf, Samantha N.; O'Dushlaine, Colm; Van Hout, Cristopher V.; Staples, Jeffrey; Gonzaga-Jauregui, Claudia; Metpally, Raghu; Pendergrass, Sarah A.; Giovanni, Monica A.; Kirchner, H. Lester; Balasubramanian, Suganthi; Abul-Husn, Noura S.; Hartzel, Dustin N.; Lavage, Daniel R.; Kost, Korey A.; Packer, Jonathan S.; Lopez, Alexander E.; Penn, John; Mukherjee, Semanti; Gosalia, Nehal; Kanagaraj, Manoj; Li, Alexander H.; Mitnaul, Lyndon J.; Adams, Lance J.; Person, Thomas N.; Praveen, Kavita; Marcketta, Anthony; Lebo, Matthew S.; Austin-Tse, Christina A.; Mason-Suares, Heather M.; Bruse, Shannon; Mellis, Scott; Phillips, Robert; Stahl, Neil; Murphy, Andrew; Economides, Aris; Skelding, Kimberly A.; Still, Christopher D.; Elmore, James R.; Borecki, Ingrid B.; Yancopoulos, George D.; Davis, F. Daniel; Faucett, William A.; Gottesman, Omri; Ritchie, Marylyn D.; Shuldiner, Alan R.; Reid, Jeffrey G.; Ledbetter, David H.; Baras, Aris; Carey, David J.

In: Science, Vol. 354, No. 6319, aaf6814, 23.12.2016.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Distribution and clinical impact of functional variants in 50,726 whole-exome sequences from the DiscovEHR study

AU - Dewey, Frederick E.

AU - Murray, Michael F.

AU - Overton, John D.

AU - Habegger, Lukas

AU - Leader, Joseph B.

AU - Fetterolf, Samantha N.

AU - O'Dushlaine, Colm

AU - Van Hout, Cristopher V.

AU - Staples, Jeffrey

AU - Gonzaga-Jauregui, Claudia

AU - Metpally, Raghu

AU - Pendergrass, Sarah A.

AU - Giovanni, Monica A.

AU - Kirchner, H. Lester

AU - Balasubramanian, Suganthi

AU - Abul-Husn, Noura S.

AU - Hartzel, Dustin N.

AU - Lavage, Daniel R.

AU - Kost, Korey A.

AU - Packer, Jonathan S.

AU - Lopez, Alexander E.

AU - Penn, John

AU - Mukherjee, Semanti

AU - Gosalia, Nehal

AU - Kanagaraj, Manoj

AU - Li, Alexander H.

AU - Mitnaul, Lyndon J.

AU - Adams, Lance J.

AU - Person, Thomas N.

AU - Praveen, Kavita

AU - Marcketta, Anthony

AU - Lebo, Matthew S.

AU - Austin-Tse, Christina A.

AU - Mason-Suares, Heather M.

AU - Bruse, Shannon

AU - Mellis, Scott

AU - Phillips, Robert

AU - Stahl, Neil

AU - Murphy, Andrew

AU - Economides, Aris

AU - Skelding, Kimberly A.

AU - Still, Christopher D.

AU - Elmore, James R.

AU - Borecki, Ingrid B.

AU - Yancopoulos, George D.

AU - Davis, F. Daniel

AU - Faucett, William A.

AU - Gottesman, Omri

AU - Ritchie, Marylyn D.

AU - Shuldiner, Alan R.

AU - Reid, Jeffrey G.

AU - Ledbetter, David H.

AU - Baras, Aris

AU - Carey, David J.

PY - 2016/12/23

Y1 - 2016/12/23

N2 - 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.

AB - 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.

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Dewey FE, Murray MF, Overton JD, Habegger L, Leader JB, Fetterolf SN et al. Distribution and clinical impact of functional variants in 50,726 whole-exome sequences from the DiscovEHR study. Science. 2016 Dec 23;354(6319). aaf6814. https://doi.org/10.1126/science.aaf6814