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 journalArticlepeer-review

27 Scopus citations


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 languageEnglish
Article number6417
JournalNature Communications
Issue number1
StatePublished - 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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