TY - JOUR T1 - Loss-of-function genomic variants with impact on liver-related blood traits highlight potential therapeutic targets for cardiovascular disease JF - bioRxiv DO - 10.1101/597377 SP - 597377 AU - Jonas B. Nielsen AU - Oren Rom AU - Ida Surakka AU - Sarah E. Graham AU - Wei Zhou AU - Lars G. Fritsche AU - Sarah A. Gagliano Taliun AU - Carlo Sidore AU - Yuhao Liu AU - Maiken E. Gabrielsen AU - Anne Heidi Skogholt AU - Brooke Wolford AU - William Overton AU - Whitney E. Hornsby AU - Akua Acheampong AU - Austen Grooms AU - Tanmoy Roychowdhury AU - Amanda Schaefer AU - Gregory JM Zajac AU - Luis Villacorta AU - Jifeng Zhang AU - Ben Brumpton AU - Mari Løset AU - Vivek Rai AU - Kent D. Taylor AU - Nicholette D. Palmer AU - Yii-Der Chen AU - Seung Hoan Choi AU - Steven A. Lubitz AU - Patrick T. Ellinor AU - Kathleen C. Barnes AU - Michelle Daya AU - Nicholas Rafaels AU - Scott T. Weiss AU - Jessica Lasky-Su AU - Russell P. Tracy AU - Ramachandran S. Vasan AU - L. Adrienne Cupples AU - Rasika A. Mathias AU - Lisa R. Yanek AU - Lewis C. Becker AU - Patricia A. Peyser AU - Lawrence F. Bielak AU - Jennifer A. Smith AU - Stella Aslibekyan AU - Bertha A. Hildalgo AU - Donna K. Arnett AU - Marguerite R. Irvin AU - James G. Wilson AU - Solomon K. Musani AU - Adolfo Correa AU - Stephen S. Rich AU - Xiuqing Guo AU - Jerome I. Rotter AU - Barbara A. Konkle AU - Jill M. Johnsen AU - Allison E. Ashley-Koch AU - Marilyn J. Telen AU - Vivien A. Sheehan AU - John Blangero AU - Joanne E. Curran AU - Juan M. Peralta AU - Courtney Montgomery AU - Wayne H-H Sheu AU - Ren-Hua Chung AU - Karen Schwander AU - Seyed M. Nouraie AU - Victor R. Gordeuk AU - Yingze Zhang AU - Charles Kooperberg AU - Alexander P. Reiner AU - Rebecca D. Jackson AU - Eugene R. Bleecker AU - Deborah A. Meyers AU - Xingnan Li AU - Sayantan Das AU - Ketian Yu AU - Jonathon LeFaive AU - Albert Smith AU - Tom Blackwell AU - Daniel Taliun AU - Sebastian Zollner AU - Lukas Forer AU - Sebastian Schoenherr AU - Christian Fuchsberger AU - Anita Pandit AU - Matthew Zawistowski AU - Sachin Kheterpal AU - Chad M. Brummett AU - Pradeep Natarajan AU - David Schlessinger AU - Seunggeun Lee AU - Hyun Min Kang AU - Francesco Cucca AU - Oddgeir L. Holmen AU - Bjørn O. Åsvold AU - Michael Boehnke AU - Sekar Kathiresan AU - Goncalo Abecasis AU - Y. Eugene Chen AU - Cristen J. Willer AU - Kristian Hveem Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/04/02/597377.abstract N2 - Cardiovascular diseases (CVD), and in particular cerebrovascular and ischemic heart diseases, are leading causes of death globally.1 Lowering circulating lipids is an important treatment strategy to reduce risk.2,3 However, some pharmaceutical mechanisms of reducing CVD may increase risk of fatty liver disease or other metabolic disorders.4,5,6 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 (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 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. ER -