Loss-of-function genomic variants with impact on liver-related blood traits highlight potential therapeutic targets for cardiovascular disease
Authors: Nielsen Jonas B. , Rom Oren , Surakka Ida , Graham Sarah E. , Zhou Wei , Fritsche Lars G. , Gagliano Taliun Sarah A. , Sidore Carlo , Liu Yuhao , Gabrielsen Maiken E. , Skogholt Anne Heidi , Wolford Brooke , Overton William , Hornsby Whitney E. , Acheampong Akua , Grooms Austen , Roychowdhury Tanmoy , Schaefer Amanda , Zajac Gregory JM , Villacorta Luis , Zhang Jifeng , Brumpton Ben , Løset Mari , Rai Vivek , Taylor Kent D. , Palmer Nicholette D. , Chen Yii-Der , Choi Seung Hoan , Lubitz Steven A. , Ellinor Patrick T. , Barnes Kathleen C. , Daya Michelle , Rafaels Nicholas , Weiss Scott T. , Lasky-Su Jessica , Tracy Russell P. , Vasan Ramachandran S. , Cupples L. Adrienne , Mathias Rasika A. , Yanek Lisa R. , Becker Lewis C. , Peyser Patricia A. , Bielak Lawrence F. , Smith Jennifer A. , Aslibekyan Stella , Hildalgo Bertha A. , Arnett Donna K. , Irvin Marguerite R. , Wilson James G. , Musani Solomon K. , Correa Adolfo , Rich Stephen S. , Guo Xiuqing , Rotter Jerome I. , Konkle Barbara A. , Johnsen Jill M. , Ashley-Koch Allison E. , Telen Marilyn J. , Sheehan Vivien A. , Blangero John , Curran Joanne E. , Peralta Juan M. , Montgomery Courtney , Sheu Wayne H-H , Chung Ren-Hua , Schwander Karen , Nouraie Seyed M. , Gordeuk Victor R. , Zhang Yingze , Kooperberg Charles , Reiner Alexander P. , Jackson Rebecca D. , Bleecker Eugene R. , Meyers Deborah A. , Li Xingnan , Das Sayantan , Yu Ketian , LeFaive Jonathon , Smith Albert , Blackwell Tom , Taliun Daniel , Zollner Sebastian , Forer Lukas , Schoenherr Sebastian , Fuchsberger Christian , Pandit Anita , Zawistowski Matthew , Kheterpal Sachin , Brummett Chad M. , Natarajan Pradeep , Schlessinger David , Lee Seunggeun , Kang Hyun Min , Cucca Francesco , Holmen Oddgeir L. , Åsvold Bjørn O. , Boehnke Michael , Kathiresan Sekar , Abecasis Goncalo , Chen Y. Eugene , Willer Cristen J. , Hveem Kristian 
Published: April 2019

Cardiovascular diseases (CVD), and in particular cerebrovascular and ischemic heart diseases, are leading causes of death globally.1Lowering circulating lipids is an important treatment strategy to reduce risk.2,3However, some pharmaceutical mechanisms of reducing CVD may increase risk of fatty liver disease or other metabolic disorders.4,5,6To 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 (5×) whole-genome sequencing and targeted genotyping, deep genotype imputation based on the TOPMed reference panel7, 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=1.3×10−8) but demonstrated no association with liver enzymes or non-fasting blood glucose levels. Silencing ofZNF529in human hepatocytes resulted in upregulation of LDL receptor (LDLR) and increased LDL-C uptake in the cells, suggesting that inhibition ofZNF529or 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.