Loss-of-function genomic variants with impact on liver-related blood traits highlight potential therapeutic targets for cardiovascular disease
By
Jonas B Nielsen,
Oren Rom,
Ida Surakka,
Sarah E Graham,
Wei Zhou,
Lars G. Fritsche,
Sarah A Gagliano Taliun,
Carlo Sidore,
Yuhao Liu,
Maiken E Gabrielsen,
Anne Heidi Skogholt,
Brooke Wolford,
William Overton,
Whitney E. Hornsby,
Akua Acheampong,
Austen Grooms,
Tanmoy Roychowdhury,
Amanda Schaefer,
Gregory JM Zajac,
Luis Villacorta,
Jifeng Zhang,
Ben M Brumpton,
Mari Løset,
Vivek Rai,
Kent D Taylor,
Nicholette D Palmer,
Yii-Der Chen,
Seung Hoan 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 Hildalgo,
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,
Gonçalo R. Abecasis,
Y Eugene Chen,
Cristen J. Willer,
Kristian Hveem
Posted 02 Apr 2019
bioRxiv DOI: 10.1101/597377
Cardiovascular diseases (CVD), and in particular cerebrovascular and ischemic heart diseases, are leading causes of death globally. Lowering circulating lipids is an important treatment strategy to reduce risk. However, some pharmaceutical mechanisms of reducing CVD may increase risk of fatty liver disease or other metabolic disorders. To identify potential novel therapeutic targets, which may reduce risk of CVD without increasing risk of metabolic disease, we focused on the simultaneous evaluation of quantitative traits related to liver function and CVD. Using a combination of low-coverage (5x) whole-genome sequencing and targeted genotyping, deep genotype imputation based on the TOPMed reference pane, and genome-wide association study (GWAS) meta-analysis, we analyzed 12 liver-related blood traits (including liver enzymes, blood lipids, and markers of iron metabolism) in up to 203,476 people from three population-based cohorts of different ancestries. We identified 88 likely causal protein-altering variants that were associated with one or more liver-related blood traits. We identified several loss-of-function (LoF) variants reducing low-density lipoprotein cholesterol (LDL-C) or risk of CVD without increased risk of liver disease or diabetes, including variants in known lipid genes (e.g. APOB, LPL). A novel LoF variant, ZNF529:p.K405X, was associated with decreased levels of LDL-C (P=1.3x10-8) but demonstrated no association with liver enzymes or non-fasting blood glucose levels. Silencing of ZNF529 in human hepatocytes resulted in upregulation of LDL receptor (LDLR) and increased LDL-C uptake in the cells, suggesting that inhibition of ZNF529 or its gene product could be used for treating hypercholesterolemia and hence reduce the risk of CVD. Taken together, we demonstrate that simultaneous consideration of multiple phenotypes and a focus on rare protein-altering variants may identify promising therapeutic targets.
Download data
- Downloaded 739 times
- Download rankings, all-time:
- Site-wide: 30,115
- In genomics: 2,750
- Year to date:
- Site-wide: 50,366
- Since beginning of last month:
- Site-wide: 62,508
Altmetric data
Downloads over time
Distribution of downloads per paper, site-wide
PanLingua
News
- 27 Nov 2020: The website and API now include results pulled from medRxiv as well as bioRxiv.
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!