Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease

Jonas B. Nielsen; Oren Rom; Ida Surakka; Sarah E. Graham; Wei Zhou; Tanmoy Roychowdhury; Lars G. Fritsche; Sarah A. Gagliano Taliun; Carlo Sidore; Yuhao Liu; Maiken E. Gabrielsen; Anne Heidi Skogholt; Brooke Wolford; William Overton; Ying Zhao; Jin Chen; He Zhang; Whitney E. Hornsby; Akua Acheampong; Austen Grooms; Amanda Schaefer; Gregory J.M. Zajac; Luis Villacorta; Jifeng Zhang; Ben Brumpton; Mari Løset; Vivek Rai; Pia R. Lundegaard; Morten S. Olesen; Kent D. Taylor; Nicholette D. Palmer; Yii Der Chen; Seung H. Choi; Steven A. Lubitz; Patrick T. Ellinor; Kathleen C. Barnes; Michelle Daya; Nicholas Rafaels; Scott T. Weiss; Jessica Lasky-Su; Russell P. Tracy; Ramachandran S. Vasan; L. Adrienne Cupples; Rasika A. Mathias; Lisa R. Yanek; Lewis C. Becker; Patricia A. Peyser; Lawrence F. Bielak; Jennifer A. Smith; Stella Aslibekyan; Bertha A. Hidalgo; Donna K. Arnett; Marguerite R. Irvin; James G. Wilson; Solomon K. Musani; Adolfo Correa; Stephen S. Rich; Xiuqing Guo; Jerome I. Rotter; Barbara A. Konkle; Jill M. Johnsen; Allison E. Ashley-Koch; Marilyn J. Telen; Vivien A. Sheehan; John Blangero; Joanne E. Curran; Juan M. Peralta; Courtney Montgomery; Wayne H.H. Sheu; Ren Hua Chung; Karen Schwander; Seyed M. Nouraie; Victor R. Gordeuk; Yingze Zhang; Charles Kooperberg; Alexander P. Reiner; Rebecca D. Jackson; Eugene R. Bleecker; Deborah A. Meyers; Xingnan Li; Sayantan Das; Ketian Yu; Jonathon LeFaive; Albert Smith; Tom Blackwell; Daniel Taliun; Sebastian Zollner; Lukas Forer; Sebastian Schoenherr; Christian Fuchsberger; Anita Pandit; Matthew Zawistowski; Sachin Kheterpal; Chad M. Brummett; Pradeep Natarajan; David Schlessinger; Seunggeun Lee; Hyun Min Kang; Francesco Cucca; Oddgeir L. Holmen; Bjørn O. Åsvold; Michael Boehnke; Sekar Kathiresan; Goncalo R. Abecasis; Y. Eugene Chen; Cristen J. Willer; Kristian Hveem

doi:10.1038/s41467-020-20086-3

Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease

Jonas B. Nielsen, Oren Rom, Ida Surakka, Sarah E. Graham, Wei Zhou, Tanmoy Roychowdhury, Lars G. Fritsche, Sarah A. Gagliano Taliun, Carlo Sidore, Yuhao Liu, Maiken E. Gabrielsen, Anne Heidi Skogholt, Brooke Wolford, William Overton, Ying Zhao, Jin Chen, He Zhang, Whitney E. Hornsby, Akua Acheampong, Austen GroomsAmanda Schaefer, Gregory J.M. Zajac, Luis Villacorta, Jifeng Zhang, Ben Brumpton, Mari Løset, Vivek Rai, Pia R. Lundegaard, Morten S. Olesen, Kent D. Taylor, Nicholette D. Palmer, Yii Der Chen, Seung H. Choi, Steven A. Lubitz, Patrick T. Ellinor, Kathleen C. Barnes, Michelle Daya, Nicholas Rafaels, Scott T. Weiss, Jessica Lasky-Su, Russell P. Tracy, Ramachandran S. Vasan, L. Adrienne Cupples, Rasika A. Mathias, Lisa R. Yanek, Lewis C. Becker, Patricia A. Peyser, Lawrence F. Bielak, Jennifer A. Smith, Stella Aslibekyan, Bertha A. Hidalgo, Donna K. Arnett, Marguerite R. Irvin, James G. Wilson, Solomon K. Musani, Adolfo Correa, Stephen S. Rich, Xiuqing Guo, Jerome I. Rotter, Barbara A. Konkle, Jill M. Johnsen, Allison E. Ashley-Koch, Marilyn J. Telen, Vivien A. Sheehan, John Blangero, Joanne E. Curran, Juan M. Peralta, Courtney Montgomery, Wayne H.H. Sheu, Ren Hua Chung, Karen Schwander, Seyed M. Nouraie, Victor R. Gordeuk, Yingze Zhang, Charles Kooperberg, Alexander P. Reiner, Rebecca D. Jackson, Eugene R. Bleecker, Deborah A. Meyers, Xingnan Li, Sayantan Das, Ketian Yu, Jonathon LeFaive, Albert Smith, Tom Blackwell, Daniel Taliun, Sebastian Zollner, Lukas Forer, Sebastian Schoenherr, Christian Fuchsberger, Anita Pandit, Matthew Zawistowski, Sachin Kheterpal, Chad M. Brummett, Pradeep Natarajan, David Schlessinger, Seunggeun Lee, Hyun Min Kang, Francesco Cucca, Oddgeir L. Holmen, Bjørn O. Åsvold, Michael Boehnke, Sekar Kathiresan, Goncalo R. Abecasis, Y. Eugene Chen, Cristen J. Willer, Kristian Hveem

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

Abstract

Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10⁻⁸) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD.

Original language	English
Article number	6417
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-20086-3
State	Published - Dec 2020

Bibliographical note

Funding Information:
G.R.A. works for Regeneron Pharmaceuticals. P.N. reports grant support from Amgen, Apple, and Boston Scientific, and is a scientific advisor to Apple. S.A.L. receives sponsored research support from Bristol Myers Squibb / Pfizer, Bayer HealthCare, and Boehringer Ingelheim, and has consulted for Bristol Myers Squibb / Pfizer. P.T.E. has consulted for Novartis, Quest Diagnostics and Bayer AG. S.T.W. has received royalties from UpToDate. S.A. holds equity in 23andMe, Inc. All other authors declare no competing interests. The spouse of C.J.W. works for Regeneron Pharmaceuticals.

Funding Information:
The Trøndelag Health (HUNT) Study is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology), Trøndelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public Health. WGS for NHLBI TOPMed studies (Freeze 5: AACAC, AFGen, Amish, ARIC+VTE, Asthma_Afr, Asthma_CR, CHS, COPDGene, Framingham, GeneStar, GENOA, GenSalt, GOLDN, HyperGen, Jackson, MESA, MLOF/Hemophilia, OMG-SCD, PharmHU, REDS-III-SCD, SAFHS, Sarcoidosis, SARP, THRV, walk-PhaSST, WHI) was performed at Baylor Human Genome Sequencing Center, Broad Institute of MIT and Harvard, Illumina Genomic Services, Macrogen Corp, New York Genome Center, University of Washington Northwest Genomics Center). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1). Phenotype harmonization, data management, sample-identity QC, and general study coordination, were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. This research has been conducted using the UK Biobank Resource under application number 24460. The K.G. Jebesen Center for Genetic Epidemiology is financed by Stiftelsen Kristian Gerhard Jebsen; Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology (NTNU) and Central Norway Regional Health Authority. Whole-genome sequencing for the HUNT Study was funded by HL109946. Whole-genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). J.B.N. is supported by grants from the Danish Heart Foundation (16-R107-A6779) and the Lundbeck Foundation (R220-2016-1434). O.R. is supported by the National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health (NIH) grant K99HL150233, American Heart Association Postdoctoral Fellowship 19POST34380224, and the Michigan-Israel Partnership Research Grant. S.A.L. is supported by NIH grant 1R01HL139731 and American Heart Asso- ciation 18SFRN34250007. I.S. is supported by a Precision Health Scholars Award from the University of Michigan Medical School. L.V. is supported by NIH grant R01-HL123333. P.N. is supported by NIH grant K08-HL140203. J.Z. is supported by NIH grant R01-HL138139. Y.E.C is supported by NIH grants R01-HL068878 and R01-HL137214. C.J.W. is supported by NIH grants R35-HL135824, R01-HL127564, R01-HL117626-02-S1, and R01-HL130705. The SardiNIA research is supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health (NIH) (contracts N01-AG-1-2109 and HHSN271201100005C). This work is also supported by the National Institutes of Health (NHLBI grant HL117626).

Publisher Copyright:
© 2020, The Author(s).

ASJC Scopus subject areas

Physics and Astronomy (all)
Chemistry (all)
Biochemistry, Genetics and Molecular Biology (all)

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10.1038/s41467-020-20086-3

Cite this

Nielsen, J. B., Rom, O., Surakka, I., Graham, S. E., Zhou, W., Roychowdhury, T., Fritsche, L. G., Gagliano Taliun, S. A., Sidore, C., Liu, Y., Gabrielsen, M. E., Skogholt, A. H., Wolford, B., Overton, W., Zhao, Y., Chen, J., Zhang, H., Hornsby, W. E., Acheampong, A., ... Hveem, K. (2020). Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease. Nature Communications, 11(1), Article 6417. https://doi.org/10.1038/s41467-020-20086-3

@article{d4d37fbe080f47bc848137a7f420e6f4,

title = "Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease",

abstract = "Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10−8) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD.",

author = "Nielsen, {Jonas B.} and Oren Rom and Ida Surakka and Graham, {Sarah E.} and Wei Zhou and Tanmoy Roychowdhury and Fritsche, {Lars G.} and {Gagliano Taliun}, {Sarah A.} and Carlo Sidore and Yuhao Liu and Gabrielsen, {Maiken E.} and Skogholt, {Anne Heidi} and Brooke Wolford and William Overton and Ying Zhao and Jin Chen and He Zhang and Hornsby, {Whitney E.} and Akua Acheampong and Austen Grooms and Amanda Schaefer and Zajac, {Gregory J.M.} and Luis Villacorta and Jifeng Zhang and Ben Brumpton and Mari L{\o}set and Vivek Rai and Lundegaard, {Pia R.} and Olesen, {Morten S.} and Taylor, {Kent D.} and Palmer, {Nicholette D.} and Chen, {Yii Der} and Choi, {Seung H.} and Lubitz, {Steven A.} and Ellinor, {Patrick T.} and Barnes, {Kathleen C.} and Michelle Daya and Nicholas Rafaels and Weiss, {Scott T.} and Jessica Lasky-Su and Tracy, {Russell P.} and Vasan, {Ramachandran S.} and Cupples, {L. Adrienne} and Mathias, {Rasika A.} and Yanek, {Lisa R.} and Becker, {Lewis C.} and Peyser, {Patricia A.} and Bielak, {Lawrence F.} and Smith, {Jennifer A.} and Stella Aslibekyan and Hidalgo, {Bertha A.} and Arnett, {Donna K.} and Irvin, {Marguerite R.} and Wilson, {James G.} and Musani, {Solomon K.} and Adolfo Correa and Rich, {Stephen S.} and Xiuqing Guo and Rotter, {Jerome I.} and Konkle, {Barbara A.} and Johnsen, {Jill M.} and Ashley-Koch, {Allison E.} and Telen, {Marilyn J.} and Sheehan, {Vivien A.} and John Blangero and Curran, {Joanne E.} and Peralta, {Juan M.} and Courtney Montgomery and Sheu, {Wayne H.H.} and Chung, {Ren Hua} and Karen Schwander and Nouraie, {Seyed M.} and Gordeuk, {Victor R.} and Yingze Zhang and Charles Kooperberg and Reiner, {Alexander P.} and Jackson, {Rebecca D.} and Bleecker, {Eugene R.} and Meyers, {Deborah A.} and Xingnan Li and Sayantan Das and Ketian Yu and Jonathon LeFaive and Albert Smith and Tom Blackwell and Daniel Taliun and Sebastian Zollner and Lukas Forer and Sebastian Schoenherr and Christian Fuchsberger and Anita Pandit and Matthew Zawistowski and Sachin Kheterpal and Brummett, {Chad M.} and Pradeep Natarajan and David Schlessinger and Seunggeun Lee and Kang, {Hyun Min} and Francesco Cucca and Holmen, {Oddgeir L.} and {\AA}svold, {Bj{\o}rn O.} and Michael Boehnke and Sekar Kathiresan and Abecasis, {Goncalo R.} and Chen, {Y. Eugene} and Willer, {Cristen J.} and Kristian Hveem",

note = "Funding Information: G.R.A. works for Regeneron Pharmaceuticals. P.N. reports grant support from Amgen, Apple, and Boston Scientific, and is a scientific advisor to Apple. S.A.L. receives sponsored research support from Bristol Myers Squibb / Pfizer, Bayer HealthCare, and Boehringer Ingelheim, and has consulted for Bristol Myers Squibb / Pfizer. P.T.E. has consulted for Novartis, Quest Diagnostics and Bayer AG. S.T.W. has received royalties from UpToDate. S.A. holds equity in 23andMe, Inc. All other authors declare no competing interests. The spouse of C.J.W. works for Regeneron Pharmaceuticals. Funding Information: The Tr{\o}ndelag Health (HUNT) Study is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology), Tr{\o}ndelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public Health. WGS for NHLBI TOPMed studies (Freeze 5: AACAC, AFGen, Amish, ARIC+VTE, Asthma_Afr, Asthma_CR, CHS, COPDGene, Framingham, GeneStar, GENOA, GenSalt, GOLDN, HyperGen, Jackson, MESA, MLOF/Hemophilia, OMG-SCD, PharmHU, REDS-III-SCD, SAFHS, Sarcoidosis, SARP, THRV, walk-PhaSST, WHI) was performed at Baylor Human Genome Sequencing Center, Broad Institute of MIT and Harvard, Illumina Genomic Services, Macrogen Corp, New York Genome Center, University of Washington Northwest Genomics Center). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1). Phenotype harmonization, data management, sample-identity QC, and general study coordination, were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. This research has been conducted using the UK Biobank Resource under application number 24460. The K.G. Jebesen Center for Genetic Epidemiology is financed by Stiftelsen Kristian Gerhard Jebsen; Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology (NTNU) and Central Norway Regional Health Authority. Whole-genome sequencing for the HUNT Study was funded by HL109946. Whole-genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). J.B.N. is supported by grants from the Danish Heart Foundation (16-R107-A6779) and the Lundbeck Foundation (R220-2016-1434). O.R. is supported by the National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health (NIH) grant K99HL150233, American Heart Association Postdoctoral Fellowship 19POST34380224, and the Michigan-Israel Partnership Research Grant. S.A.L. is supported by NIH grant 1R01HL139731 and American Heart Asso- ciation 18SFRN34250007. I.S. is supported by a Precision Health Scholars Award from the University of Michigan Medical School. L.V. is supported by NIH grant R01-HL123333. P.N. is supported by NIH grant K08-HL140203. J.Z. is supported by NIH grant R01-HL138139. Y.E.C is supported by NIH grants R01-HL068878 and R01-HL137214. C.J.W. is supported by NIH grants R35-HL135824, R01-HL127564, R01-HL117626-02-S1, and R01-HL130705. The SardiNIA research is supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health (NIH) (contracts N01-AG-1-2109 and HHSN271201100005C). This work is also supported by the National Institutes of Health (NHLBI grant HL117626). Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

doi = "10.1038/s41467-020-20086-3",

language = "English",

volume = "11",

number = "1",

}

Nielsen, JB, Rom, O, Surakka, I, Graham, SE, Zhou, W, Roychowdhury, T, Fritsche, LG, Gagliano Taliun, SA, Sidore, C, Liu, Y, Gabrielsen, ME, Skogholt, AH, Wolford, B, Overton, W, Zhao, Y, Chen, J, Zhang, H, Hornsby, WE, Acheampong, A, Grooms, A, Schaefer, A, Zajac, GJM, Villacorta, L, Zhang, J, Brumpton, B, Løset, M, Rai, V, Lundegaard, PR, Olesen, MS, Taylor, KD, Palmer, ND, Chen, YD, Choi, SH, Lubitz, SA, Ellinor, PT, Barnes, KC, Daya, M, Rafaels, N, Weiss, ST, Lasky-Su, J, Tracy, RP, Vasan, RS, Cupples, LA, Mathias, RA, Yanek, LR, Becker, LC, Peyser, PA, Bielak, LF, Smith, JA, Aslibekyan, S, Hidalgo, BA, Arnett, DK, Irvin, MR, Wilson, JG, Musani, SK, Correa, A, Rich, SS, Guo, X, Rotter, JI, Konkle, BA, Johnsen, JM, Ashley-Koch, AE, Telen, MJ, Sheehan, VA, Blangero, J, Curran, JE, Peralta, JM, Montgomery, C, Sheu, WHH, Chung, RH, Schwander, K, Nouraie, SM, Gordeuk, VR, Zhang, Y, Kooperberg, C, Reiner, AP, Jackson, RD, Bleecker, ER, Meyers, DA, Li, X, Das, S, Yu, K, LeFaive, J, Smith, A, Blackwell, T, Taliun, D, Zollner, S, Forer, L, Schoenherr, S, Fuchsberger, C, Pandit, A, Zawistowski, M, Kheterpal, S, Brummett, CM, Natarajan, P, Schlessinger, D, Lee, S, Kang, HM, Cucca, F, Holmen, OL, Åsvold, BO, Boehnke, M, Kathiresan, S, Abecasis, GR, Chen, YE, Willer, CJ & Hveem, K 2020, 'Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease', Nature Communications, vol. 11, no. 1, 6417. https://doi.org/10.1038/s41467-020-20086-3

TY - JOUR

T1 - Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease

AU - Nielsen, Jonas B.

AU - Rom, Oren

AU - Surakka, Ida

AU - Graham, Sarah E.

AU - Zhou, Wei

AU - Roychowdhury, Tanmoy

AU - Fritsche, Lars G.

AU - Gagliano Taliun, Sarah A.

AU - Sidore, Carlo

AU - Liu, Yuhao

AU - Gabrielsen, Maiken E.

AU - Skogholt, Anne Heidi

AU - Wolford, Brooke

AU - Overton, William

AU - Zhao, Ying

AU - Chen, Jin

AU - Zhang, He

AU - Hornsby, Whitney E.

AU - Acheampong, Akua

AU - Grooms, Austen

AU - Schaefer, Amanda

AU - Zajac, Gregory J.M.

AU - Villacorta, Luis

AU - Zhang, Jifeng

AU - Brumpton, Ben

AU - Løset, Mari

AU - Rai, Vivek

AU - Lundegaard, Pia R.

AU - Olesen, Morten S.

AU - Taylor, Kent D.

AU - Palmer, Nicholette D.

AU - Chen, Yii Der

AU - Choi, Seung H.

AU - Lubitz, Steven A.

AU - Ellinor, Patrick T.

AU - Barnes, Kathleen C.

AU - Daya, Michelle

AU - Rafaels, Nicholas

AU - Weiss, Scott T.

AU - Lasky-Su, Jessica

AU - Tracy, Russell P.

AU - Vasan, Ramachandran S.

AU - Cupples, L. Adrienne

AU - Mathias, Rasika A.

AU - Yanek, Lisa R.

AU - Becker, Lewis C.

AU - Peyser, Patricia A.

AU - Bielak, Lawrence F.

AU - Smith, Jennifer A.

AU - Aslibekyan, Stella

AU - Hidalgo, Bertha A.

AU - Arnett, Donna K.

AU - Irvin, Marguerite R.

AU - Wilson, James G.

AU - Musani, Solomon K.

AU - Correa, Adolfo

AU - Rich, Stephen S.

AU - Guo, Xiuqing

AU - Rotter, Jerome I.

AU - Konkle, Barbara A.

AU - Johnsen, Jill M.

AU - Ashley-Koch, Allison E.

AU - Telen, Marilyn J.

AU - Sheehan, Vivien A.

AU - Blangero, John

AU - Curran, Joanne E.

AU - Peralta, Juan M.

AU - Montgomery, Courtney

AU - Sheu, Wayne H.H.

AU - Chung, Ren Hua

AU - Schwander, Karen

AU - Nouraie, Seyed M.

AU - Gordeuk, Victor R.

AU - Zhang, Yingze

AU - Kooperberg, Charles

AU - Reiner, Alexander P.

AU - Jackson, Rebecca D.

AU - Bleecker, Eugene R.

AU - Meyers, Deborah A.

AU - Li, Xingnan

AU - Das, Sayantan

AU - Yu, Ketian

AU - LeFaive, Jonathon

AU - Smith, Albert

AU - Blackwell, Tom

AU - Taliun, Daniel

AU - Zollner, Sebastian

AU - Forer, Lukas

AU - Schoenherr, Sebastian

AU - Fuchsberger, Christian

AU - Pandit, Anita

AU - Zawistowski, Matthew

AU - Kheterpal, Sachin

AU - Brummett, Chad M.

AU - Natarajan, Pradeep

AU - Schlessinger, David

AU - Lee, Seunggeun

AU - Kang, Hyun Min

AU - Cucca, Francesco

AU - Holmen, Oddgeir L.

AU - Åsvold, Bjørn O.

AU - Boehnke, Michael

AU - Kathiresan, Sekar

AU - Abecasis, Goncalo R.

AU - Chen, Y. Eugene

AU - Willer, Cristen J.

AU - Hveem, Kristian

N1 - Funding Information: G.R.A. works for Regeneron Pharmaceuticals. P.N. reports grant support from Amgen, Apple, and Boston Scientific, and is a scientific advisor to Apple. S.A.L. receives sponsored research support from Bristol Myers Squibb / Pfizer, Bayer HealthCare, and Boehringer Ingelheim, and has consulted for Bristol Myers Squibb / Pfizer. P.T.E. has consulted for Novartis, Quest Diagnostics and Bayer AG. S.T.W. has received royalties from UpToDate. S.A. holds equity in 23andMe, Inc. All other authors declare no competing interests. The spouse of C.J.W. works for Regeneron Pharmaceuticals. Funding Information: The Trøndelag Health (HUNT) Study is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology), Trøndelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public Health. WGS for NHLBI TOPMed studies (Freeze 5: AACAC, AFGen, Amish, ARIC+VTE, Asthma_Afr, Asthma_CR, CHS, COPDGene, Framingham, GeneStar, GENOA, GenSalt, GOLDN, HyperGen, Jackson, MESA, MLOF/Hemophilia, OMG-SCD, PharmHU, REDS-III-SCD, SAFHS, Sarcoidosis, SARP, THRV, walk-PhaSST, WHI) was performed at Baylor Human Genome Sequencing Center, Broad Institute of MIT and Harvard, Illumina Genomic Services, Macrogen Corp, New York Genome Center, University of Washington Northwest Genomics Center). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1). Phenotype harmonization, data management, sample-identity QC, and general study coordination, were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. This research has been conducted using the UK Biobank Resource under application number 24460. The K.G. Jebesen Center for Genetic Epidemiology is financed by Stiftelsen Kristian Gerhard Jebsen; Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology (NTNU) and Central Norway Regional Health Authority. Whole-genome sequencing for the HUNT Study was funded by HL109946. Whole-genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). J.B.N. is supported by grants from the Danish Heart Foundation (16-R107-A6779) and the Lundbeck Foundation (R220-2016-1434). O.R. is supported by the National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health (NIH) grant K99HL150233, American Heart Association Postdoctoral Fellowship 19POST34380224, and the Michigan-Israel Partnership Research Grant. S.A.L. is supported by NIH grant 1R01HL139731 and American Heart Asso- ciation 18SFRN34250007. I.S. is supported by a Precision Health Scholars Award from the University of Michigan Medical School. L.V. is supported by NIH grant R01-HL123333. P.N. is supported by NIH grant K08-HL140203. J.Z. is supported by NIH grant R01-HL138139. Y.E.C is supported by NIH grants R01-HL068878 and R01-HL137214. C.J.W. is supported by NIH grants R35-HL135824, R01-HL127564, R01-HL117626-02-S1, and R01-HL130705. The SardiNIA research is supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health (NIH) (contracts N01-AG-1-2109 and HHSN271201100005C). This work is also supported by the National Institutes of Health (NHLBI grant HL117626). Publisher Copyright: © 2020, The Author(s).

PY - 2020/12

Y1 - 2020/12

N2 - Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10−8) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD.

AB - Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10−8) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD.

UR - http://www.scopus.com/inward/record.url?scp=85097789750&partnerID=8YFLogxK

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U2 - 10.1038/s41467-020-20086-3

DO - 10.1038/s41467-020-20086-3

M3 - Article

C2 - 33339817

AN - SCOPUS:85097789750

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 6417

ER -

Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease

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UN SDGs

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