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

Yuxuan Wang; Margaret Sunitha Selvaraj; Xihao Li; Zilin Li; Jacob A Holdcraft; Donna K Arnett; Joshua C Bis; John Blangero; Eric Boerwinkle; Donald W Bowden; Brian E Cade; Jenna C Carlson; April P Carson; Yii-Der Ida Chen; Joanne E Curran; Paul S de Vries; Susan K Dutcher; Patrick T Ellinor; James S Floyd; Myriam Fornage; Barry I Freedman; Stacey Gabriel; Soren Germer; Richard A Gibbs; Xiuqing Guo; Jiang He; Nancy Heard-Costa; Bertha Hildalgo; Lifang Hou; Marguerite R Irvin; Roby Joehanes; Robert C Kaplan; Sharon Lr Kardia; Tanika N Kelly; Ryan Kim; Charles Kooperberg; Brian G Kral; Daniel Levy; Changwei Li; Chunyu Liu; Don Lloyd-Jone; Ruth Jf Loos; Michael C Mahaney; Lisa W Martin; Rasika A Mathias; Ryan L Minster; Braxton D Mitchell; May E Montasser; Alanna C Morrison; Joanne M Murabito; Take Naseri; Jeffrey R O'Connell; Nicholette D Palmer; Michael H Preuss; Bruce M Psaty; Laura M Raffield; Dabeeru C Rao; Susan Redline; Alexander P Reiner; Stephen S Rich; Muagututi'a Sefuiva Ruepena; Wayne H-H Sheu; Jennifer A Smith; Albert Smith; Hemant K Tiwari; Michael Y Tsai; Karine A Viaud-Martinez; Zhe Wang; Lisa R Yanek; Wei Zhao; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; Jerome I Rotter; Xihong Lin; Pradeep Natarajan; Gina M Peloso

doi:10.1016/j.ajhg.2023.09.003

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

Am J Hum Genet. 2023 Oct 5;110(10):1704-1717. doi: 10.1016/j.ajhg.2023.09.003.

Authors

Yuxuan Wang¹, Margaret Sunitha Selvaraj², Xihao Li³, Zilin Li⁴, Jacob A Holdcraft¹, Donna K Arnett⁵, Joshua C Bis⁶, John Blangero⁷, Eric Boerwinkle⁸, Donald W Bowden⁹, Brian E Cade¹⁰, Jenna C Carlson¹¹, April P Carson¹², Yii-Der Ida Chen¹³, Joanne E Curran⁷, Paul S de Vries⁸, Susan K Dutcher¹⁴, Patrick T Ellinor¹⁵, James S Floyd¹⁶, Myriam Fornage¹⁷, Barry I Freedman¹⁸, Stacey Gabriel¹⁹, Soren Germer²⁰, Richard A Gibbs²¹, Xiuqing Guo¹³, Jiang He²², Nancy Heard-Costa²³, Bertha Hildalgo²⁴, Lifang Hou²⁵, Marguerite R Irvin²⁴, Roby Joehanes²⁶, Robert C Kaplan²⁷, Sharon Lr Kardia²⁸, Tanika N Kelly²⁹, Ryan Kim³⁰, Charles Kooperberg³¹, Brian G Kral³², Daniel Levy³³, Changwei Li³⁴, Chunyu Liu³⁵, Don Lloyd-Jone²⁵, Ruth Jf Loos³⁶, Michael C Mahaney⁷, Lisa W Martin³⁷, Rasika A Mathias³², Ryan L Minster³⁸, Braxton D Mitchell³⁹, May E Montasser³⁹, Alanna C Morrison⁸, Joanne M Murabito⁴⁰, Take Naseri⁴¹, Jeffrey R O'Connell³⁹, Nicholette D Palmer⁹, Michael H Preuss⁴², Bruce M Psaty⁴³, Laura M Raffield⁴⁴, Dabeeru C Rao⁴⁵, Susan Redline⁴⁶, Alexander P Reiner⁴⁷, Stephen S Rich⁴⁸, Muagututi'a Sefuiva Ruepena⁴⁹, Wayne H-H Sheu⁵⁰, Jennifer A Smith²⁸, Albert Smith⁵¹, Hemant K Tiwari⁵², Michael Y Tsai⁵³, Karine A Viaud-Martinez⁵⁴, Zhe Wang⁴², Lisa R Yanek³², Wei Zhao²⁸; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; Jerome I Rotter¹³, Xihong Lin⁵⁵, Pradeep Natarajan², Gina M Peloso⁵⁶

Affiliations

¹ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
² 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.
³ 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.
⁴ 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.
⁵ 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.
⁶ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
⁷ Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
⁸ 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.
⁹ Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
¹⁰ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.
¹¹ 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.
¹² Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
¹³ 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.
¹⁴ The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA.
¹⁵ Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA; Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁶ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA.
¹⁷ Center for Human Genetics, University of Texas Health at Houston, Houston, TX, USA.
¹⁸ Department of Internal Medicine, Nephrology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
¹⁹ Broad Institute of Harvard and MIT, Cambridge, MA, USA.
²⁰ New York Genome Center, New York, NY, USA.
²¹ Baylor College of Medicine Human Genome Sequencing Center, Houston, TX, USA.
²² 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.
²³ Framingham Heart Study, Framingham, MA, USA; Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
²⁴ Department of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham, AL, USA.
²⁵ Department of Preventive Medicine, Northwestern University, Chicago, IL, USA.
²⁶ Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
²⁷ 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.
²⁸ Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
²⁹ Department of Medicine, Division of Nephrology, University of Illinois Chicago, Chicago, IL, USA.
³⁰ Psomagen, Inc. (formerly Macrogen USA), Rockville, MD, USA.
³¹ Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
³² GeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³³ Framingham Heart Study, Framingham, MA, USA; Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
³⁴ Tulane University Translational Science Institute, New Orleans, LA, USA; Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA.
³⁵ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA; Framingham Heart Study, Framingham, MA, USA.
³⁶ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; NNF Center for Basic Metabolic Research, University of Copenhagen, Cophenhagen, Denmark.
³⁷ George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
³⁸ Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
³⁹ Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
⁴⁰ Framingham Heart Study, Framingham, MA, USA; Department of Medicine, Boston Medical Center, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA.
⁴¹ Naseri & Associates Public Health Consultancy Firm and Family Health Clinic, Apia, Samoa; International Health Institute, School of Public Health, Brown University, Providence, RI, USA.
⁴² The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴³ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA; Department of Health Systems and Population Health, University of Washington, Seattle, WA, USA.
⁴⁴ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴⁵ Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA.
⁴⁶ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁴⁷ Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁴⁸ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
⁴⁹ Lutia i Puava ae Mapu i Fagalele, Apia, Samoa.
⁵⁰ Institute of Molecular and Genomic Medicine, National Health Research Institute (NHRI), Miaoli County, Taiwan.
⁵¹ Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
⁵² Department of Biostatistics, University of Alabama, Birmingham, AL, USA.
⁵³ Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
⁵⁴ Illumina Laboratory Services, Illumina Inc., San Diego, CA, USA.
⁵⁵ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Statistics, Harvard University, Cambridge, MA, USA.
⁵⁶ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA. Electronic address: gpeloso@bu.edu.

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.

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

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Genome-Wide Association Study
Humans
Lipids / genetics
Polymorphism, Single Nucleotide / genetics
Precision Medicine
RNA, Long Noncoding* / genetics
Whole Genome Sequencing / methods

Substances

RNA, Long Noncoding
Lipids

Abstract

Publication types

MeSH terms

Substances

Grants and funding