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Integrative analysi...
Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits
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- Glicksberg, Benjamin S. (författare)
- Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Inst Next Generat Healthcare, One Gustave L Levy Pl, New York, NY 10029 USA;Univ Calif San Francisco, Bakar Computat Hlth Sci Inst, San Francisco, CA 94158 USA
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- Amadori, Letizia (författare)
- Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Cardiovasc Res Ctr, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Cardiovasc Inst, One Gustave L Levy Pl, New York, NY 10029 USA
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- Akers, Nicholas K. (författare)
- Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA
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visa fler...
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- Sukhavasi, Katyayani (författare)
- Univ Tartu, Inst Biomed & Translat Med, Dept Pathophysiol, Ravila 19, EE-50411 Tartu, Estonia
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- Franzen, Oscar (författare)
- Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Clin Gene Networks AB, Jungfrugatan 10, S-11444 Stockholm, Sweden;Karolinska Inst, Integrated Cardio Metab Ctr, Dept Med, S-14157 Huddinge, Sweden
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- Li, Li (författare)
- Karolinska Institutet,Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Inst Next Generat Healthcare, One Gustave L Levy Pl, New York, NY 10029 USA,Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Sema4, Stamford, CT 06902 USA,Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Univ Tartu, Inst Biomed & Translat Med, Dept Pathophysiol, Ravila 19, EE-50411 Tartu, Estonia;Clin Gene Networks AB, Jungfrugatan 10, S-11444 Stockholm, Sweden;Karolinska Univ Sjukhuset Huddinge, Integrated Cardio Metab Ctr, Karolinska Inst, Dept Med, S-14186 Stockholm, Sweden
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- Belbin, Gillian M. (författare)
- Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, One Gustave L Levy Pl, New York, NY 10029 USA
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- Akers, Kristin L. (författare)
- Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Sema4, Stamford, CT 06902 USA
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- Shameer, Khader (författare)
- Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Inst Next Generat Healthcare, One Gustave L Levy Pl, New York, NY 10029 USA
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- Badgeley, Marcus A. (författare)
- Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Inst Next Generat Healthcare, One Gustave L Levy Pl, New York, NY 10029 USA
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- Johnson, Kipp W. (författare)
- Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Inst Next Generat Healthcare, One Gustave L Levy Pl, New York, NY 10029 USA
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- Readhead, Ben (författare)
- Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Inst Next Generat Healthcare, One Gustave L Levy Pl, New York, NY 10029 USA
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- Darrow, Bruce J. (författare)
- Icahn Sch Med Mt Sinai, Cardiovasc Res Ctr, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Cardiovasc Inst, One Gustave L Levy Pl, New York, NY 10029 USA
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- Kenny, Eimear E. (författare)
- Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Dept Prevent Med, One Gustave L Levy Pl, New York, NY 10029 USA
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- Betsholtz, Christer (författare)
- Uppsala universitet,Vaskulärbiologi
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- Ermel, Raili (författare)
- Tartu Univ Hosp, Dept Cardiac Surg, 1a Ludwig Puusepa St, EE-50406 Tartu, Estonia
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- Skogsberg, Josefin (författare)
- Karolinska Univ Sjukhuset Huddinge, Integrated Cardio Metab Ctr, Karolinska Inst, Dept Med, S-14186 Stockholm, Sweden
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- Ruusalepp, Arno (författare)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi,Clin Gene Networks AB, Jungfrugatan 10, S-11444 Stockholm, Sweden
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- Schadt, Eric E. (författare)
- Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Inst Next Generat Healthcare, One Gustave L Levy Pl, New York, NY 10029 USA;Clin Gene Networks AB, Jungfrugatan 10, S-11444 Stockholm, Sweden;Sema4, Stamford, CT 06902 USA
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- Dudleyt, Joel T. (författare)
- Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Inst Next Generat Healthcare, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Dept Hlth Policy & Res, One Gustave L Levy Pl, New York, NY 10029 USA
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- Ren, Hongxia (författare)
- Indiana Univ, Herman B Wells Ctr Pediat Res, Ctr Diabet & Metab Dis, Dept Pediat,Stark Neurosci Res Inst, 635 Barnhill Dr,MS2049, Indianapolis, IN 46202 USA
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- Kovacic, Jason C. (författare)
- Icahn Sch Med Mt Sinai, Cardiovasc Res Ctr, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Cardiovasc Inst, One Gustave L Levy Pl, New York, NY 10029 USA
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- Giannarelli, Chiara (författare)
- Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Cardiovasc Res Ctr, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Cardiovasc Inst, One Gustave L Levy Pl, New York, NY 10029 USA
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- Liu, Shuyu D. (författare)
- Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Sema4, Stamford, CT 06902 USA
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- Bjorkegren, Johan L. M. (författare)
- Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Univ Tartu, Inst Biomed & Translat Med, Dept Pathophysiol, Ravila 19, EE-50411 Tartu, Estonia;Clin Gene Networks AB, Jungfrugatan 10, S-11444 Stockholm, Sweden;Karolinska Univ Sjukhuset Huddinge, Integrated Cardio Metab Ctr, Karolinska Inst, Dept Med, S-14186 Stockholm, Sweden
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- Chen, Rong (författare)
- Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Sema4, Stamford, CT 06902 USA
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(creator_code:org_t)
- 2019-07-25
- 2019
- Engelska.
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Ingår i: BMC Medical Genomics. - : BMC. - 1755-8794. ; 12
- Relaterad länk:
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://bmcmedgenomi...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- BackgroundGenetic loss-of-function variants (LoFs) associated with disease traits are increasingly recognized as critical evidence for the selection of therapeutic targets. We integrated the analysis of genetic and clinical data from 10,511 individuals in the Mount Sinai BioMe Biobank to identify genes with loss-of-function variants (LoFs) significantly associated with cardiovascular disease (CVD) traits, and used RNA-sequence data of seven metabolic and vascular tissues isolated from 600 CVD patients in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study for validation. We also carried out in vitro functional studies of several candidate genes, and in vivo studies of one gene.ResultsWe identified LoFs in 433 genes significantly associated with at least one of 10 major CVD traits. Next, we used RNA-sequence data from the STARNET study to validate 115 of the 433 LoF harboring-genes in that their expression levels were concordantly associated with corresponding CVD traits. Together with the documented hepatic lipid-lowering gene, APOC3, the expression levels of six additional liver LoF-genes were positively associated with levels of plasma lipids in STARNET. Candidate LoF-genes were subjected to gene silencing in HepG2 cells with marked overall effects on cellular LDLR, levels of triglycerides and on secreted APOB100 and PCSK9. In addition, we identified novel LoFs in DGAT2 associated with lower plasma cholesterol and glucose levels in BioMe that were also confirmed in STARNET, and showed a selective DGAT2-inhibitor in C57BL/6 mice not only significantly lowered fasting glucose levels but also affected body weight.ConclusionIn sum, by integrating genetic and electronic medical record data, and leveraging one of the world's largest human RNA-sequence datasets (STARNET), we identified known and novel CVD-trait related genes that may serve as targets for CVD therapeutics and as such merit further investigation.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
Nyckelord
- Loss-of-function variant
- Cardiovascular traits
- Genetic association
- Integrative data analysis
- Target identification and validation
- Electronic Medical Records
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- ref (ämneskategori)
- art (ämneskategori)
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Glicksberg, Benj ...
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Amadori, Letizia
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Akers, Nicholas ...
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Sukhavasi, Katya ...
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Franzen, Oscar
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Li, Li
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visa fler...
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Belbin, Gillian ...
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Akers, Kristin L ...
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Shameer, Khader
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Badgeley, Marcus ...
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Johnson, Kipp W.
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Readhead, Ben
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Darrow, Bruce J.
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Kenny, Eimear E.
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Betsholtz, Chris ...
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Ermel, Raili
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Skogsberg, Josef ...
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Ruusalepp, Arno
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Schadt, Eric E.
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Dudleyt, Joel T.
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Ren, Hongxia
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Kovacic, Jason C ...
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Giannarelli, Chi ...
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Liu, Shuyu D.
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Bjorkegren, Joha ...
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Chen, Rong
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MEDICIN OCH HÄLS ...
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BMC Medical Geno ...
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Uppsala universitet
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Karolinska Institutet