Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed whole-genome sequencing study

Yuxuan Wang, Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Margaret Sunitha Selvaraj, Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
Xihao Li, Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Zilin Li, School of Mathematics and Statistics, Northeast Normal University, Changchun, Jilin, China; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Jacob A. Holdcraft, Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Donna K. Arnett, Provost Office, University of South Carolina, Columbia, SC, USA; Department of Epidemiology and Biostatistics, University of South Carolina Arnold School of Public Health, Columbia, SC, USA.
Joshua C. Bis, Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
John Blangero, Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
Eric Boerwinkle, Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Donald W. Bowden, Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Brian E. Cade, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.
Jenna C. Carlson, Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Biostatistics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
April P. Carson, Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
Yii-Der Ida Chen, The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Joanne E. Curran, Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
Paul S. de Vries, Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Susan K. Dutcher, The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA.
Patrick T. Ellinor, Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA; Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
James S. Floyd, Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA.
Myriam Fornage, Center for Human Genetics, University of Texas Health at Houston, Houston, TX, USA.
Barry I. Freedman, Department of Internal Medicine, Nephrology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Stacey Gabriel, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Soren Germer, New York Genome Center, New York, NY, USA.
Richard A. Gibbs, Baylor College of Medicine Human Genome Sequencing Center, Houston, TX, USA.
Xiuqing Guo, The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Jiang He, Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA; Tulane University Translational Science Institute, New Orleans, LA, USA.
Nancy Heard-Costa, Framingham Heart Study, Framingham, MA, USA; Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
Bertha Hildalgo, Department of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham, AL, USA.
Lifang Hou, Department of Preventive Medicine, Northwestern University, Chicago, IL, USA.
Marguerite R. Irvin, Department of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham, AL, USA.
Roby Joehanes, Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Robert C. Kaplan, Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA; Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.

Document Type

Journal Article

Publication Date

10-5-2023

Journal

American journal of human genetics

Volume

110

Issue

10

DOI

10.1016/j.ajhg.2023.09.003

Keywords

association; blood lipid; cholesterol; lncRNA; rare variants; whole-genome sequencing

Abstract

Long non-coding RNAs (lncRNAs) are known to perform important regulatory functions in lipid metabolism. Large-scale whole-genome sequencing (WGS) studies and new statistical methods for variant set tests now provide an opportunity to assess more associations between rare variants in lncRNA genes and complex traits across the genome. In this study, we used high-coverage WGS from 66,329 participants of diverse ancestries with measurement of blood lipids and lipoproteins (LDL-C, HDL-C, TC, and TG) in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program to investigate the role of lncRNAs in lipid variability. We aggregated rare variants for 165,375 lncRNA genes based on their genomic locations and conducted rare-variant aggregate association tests using the STAAR (variant-set test for association using annotation information) framework. We performed STAAR conditional analysis adjusting for common variants in known lipid GWAS loci and rare-coding variants in nearby protein-coding genes. Our analyses revealed 83 rare lncRNA variant sets significantly associated with blood lipid levels, all of which were located in known lipid GWAS loci (in a ±500-kb window of a Global Lipids Genetics Consortium index variant). Notably, 61 out of 83 signals (73%) were conditionally independent of common regulatory variation and rare protein-coding variation at the same loci. We replicated 34 out of 61 (56%) conditionally independent associations using the independent UK Biobank WGS data. Our results expand the genetic architecture of blood lipids to rare variants in lncRNAs.

Department

Medicine

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