ArticlemedRxiv : the preprint server for health sciences2023
Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed Whole Genome Sequencing Study.
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75 authors at 20 institutions in 4 countries.
Yuxuan WangDepartment of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Margaret Sunitha SelvarajCardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Xihao LiDepartment of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Zilin LiDepartment of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Jacob A HoldcraftDepartment of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Donna K ArnettProvost Office, University of South Carolina, Columbia, SC, USA.
Joshua C BisCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
John BlangeroDepartment of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
Eric BoerwinkleHuman 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 BowdenDepartment of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Brian E CadeDepartment of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Jenna C CarlsonDepartment of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
April P CarsonDepartment of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
Yii-Der Ida ChenThe 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 CurranDepartment 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 VriesHuman 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 DutcherThe McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA.
Patrick T EllinorCardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
James S FloydCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
Myriam FornageCenter for Human Genetics, University of Texas Health at Houston, Houston, TX, USA.
Barry I FreedmanDepartment of Internal Medicine, Nephrology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Stacey GabrielBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Soren GermerNew York Genome Center, New York, NY, USA.
Richard A GibbsBaylor College of Medicine Human Genome Sequencing Center, Houston, TX, USA.
Xiuqing GuoThe 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 HeDepartment of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA.
Nancy Heard-CostaFramingham Heart Study, Framingham, MA, USA.
Bertha HildalgoDepartment of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham, AL, USA.
Lifang HouDepartment of Preventive Medicine, Northwestern University, Chicago, IL, USA.
Marguerite R IrvinDepartment of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham, AL, USA.
Roby JoehanesPopulation Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Robert C KaplanDepartment of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
Sharon Lr KardiaDepartment of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
Tanika N KellyDepartment of Medicine, Division of Nephrology, University of Illinois Chicago, Chicago, IL, USA.
Ryan KimPsomagen, Inc. (formerly Macrogen USA), Rockville, MD, USA.
Charles KooperbergDivision of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Brian G KralGeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Daniel LevyFramingham Heart Study, Framingham, MA, USA.
Changwei LiTulane University Translational Science Institute, New Orleans, LA, USA.
Chunyu LiuDepartment of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Don Lloyd-JoneDepartment of Preventive Medicine, Northwestern University, Chicago, IL, USA.
Ruth Jf LoosThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Michael C MahaneyDepartment of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
Lisa W MartinGeorge Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Rasika A MathiasGeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Ryan L MinsterDepartment of Human Genetics and Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA.
Braxton D MitchellDepartment of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
May E MontasserDepartment of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
Alanna C MorrisonHuman 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.
Joanne M MurabitoFramingham Heart Study, Framingham, MA, USA.
Take NaseriMinistry of Health, Apia, Samoa.
Jeffrey R O'ConnellDepartment of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
Nicholette D PalmerDepartment of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Michael H PreussThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Bruce M PsatyCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
Laura M RaffieldDepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Dabeeru C RaoDivision of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA.
Susan RedlineDepartment of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Alexander P ReinerDepartment of Epidemiology, University of Washington, Seattle, WA, USA.
Stephen S RichCenter for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
Muagututi'a Sefuiva RuepenaLutia i Puava ae Mapu i Fagalele, Apia, Samoa.
Wayne H-H SheuNational Health Research Institute (NHRI), Taiwan.
Jennifer A SmithDepartment of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
Albert SmithDepartment of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
Hemant K TiwariDepartment of Biostatistics, University of Alabama, Birmingham, AL, USA.
Michael Y TsaiDepartment of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
Karine A Viaud-MartinezIllumina Laboratory Services, Illumina Inc., San Diego, CA, USA.
Zhe WangThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Lisa R YanekGeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Wei ZhaoDepartment of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Jerome I RotterThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Xihong LinProgram in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Pradeep NatarajanCardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Gina M PelosoDepartment of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Boston University · USBroad Institute · USUniversity of Michigan · USUniversity of Washington · USJohns Hopkins University · USThe University of Texas Health Science Center at Houston · USThe University of Texas Rio Grande Valley · USUCLA Medical Center · USUniversity of Alabama at Birmingham · USUniversity of Maryland, Baltimore · USWake Forest University · USBrigham and Women's Hospital · USHarvard University · USIcahn School of Medicine at Mount Sinai · USNational Institutes of Health · USNorthwestern University · USTulane University · USUniversity of Pittsburgh · USAlbert Einstein College of Medicine · USBaylor College of Medicine · US
Funding
PEDIGREE ANALYSIS OF LIPOPROTEIN PHENOTYPESP01HL045522 · NHLBI · TEXAS BIOMEDICAL RESEARCH INSTITUTE · PI BLANGERO, JOHN · 1991 to 2012
$27.6MTranslating Molecular and Clinical Data to Population Lung Cancer Risk AssessmentU19CA203654 · NCI · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · PI Christopher I. Amos, Rayjean J. Hung · 2017 to 2026
$23.7MPolygenic Risk Scores for Diverse Populations - Bridging Research and Clinical CareR01HL151152 · NHLBI · FRED HUTCHINSON CANCER RESEARCH CENTER · PI Christy Leigh Avery, Jennifer Below · 2020 to 2026
$12.3MGenome-wide Search for CVD Gene-Environment InteractionsU01HL072515 · NHLBI · UNIVERSITY OF MARYLAND BALTIMORE · PI SHULDINER, ALAN R. · 2002 to 2008
$11.2MStatistical Methods for Analysis of Massive Genetic and Genomic Data in Cancer ResearchR35CA197449 · NCI · HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH · PI XIHONG LIN · 2015 to 2026
$10.9MCHARGE Consortium: Omics Discovery for CVD and Aging PhenotypesR01HL105756 · NHLBI · UNIVERSITY OF WASHINGTON · PI Bruce M Psaty, NICHOLAS L SMITH · 2011 to 2026
$9.5MWhole Genome Sequencing to Identify Causal Genetic Variants Influencing CVD RiskR01HL113323 · NHLBI · UNIVERSITY OF TEXAS RIO GRANDE VALLEY · PI BLANGERO, JOHN, CURRAN, JOANNE E. · 2012 to 2016
$8.2MIntegrated cellular, mouse and human research on a novel missense variant influencing adiposity in SamoansR01HL093093 · NHLBI · BROWN UNIVERSITY · PI MCGARVEY, STEPHEN T. · 2009 to 2019
$8.2MGenetic Epidemiology of Blood Pressure InterventionU01HL072507 · NHLBI · TULANE UNIVERSITY OF LOUISIANA · PI HE, JIANG · 2002 to 2008
$7.6MUsing genetic variation to study biology of blood lipids & coronary heart diseaseR01HL127564 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Pradeep Natarajan, Gina Marie Peloso · 2015 to 2026
$7.3MPhenotypic and Molecular Signatures for Sleep Apnea and Related MorbiditiesR35HL135818 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI REDLINE, SUSAN S. · 2017 to 2023
$7.2MClonal hematopoiesis in the Womens Health Initiative Memory StudyR01HL148565 · NHLBI · FRED HUTCHINSON CANCER RESEARCH CENTER · PI ALEXANDER P REINER, Eric A. Whitsel · 2019 to 2026
$5.9MNCI NIH HHS R35 CA197449NCI NIH HHS U19 CA203654NHGRI NIH HHS U01 HG009088NHLBI NIH HHS K01 HL135405NHLBI NIH HHS P01 HL045522NHLBI NIH HHS R01 HL046380NHLBI NIH HHS R01 HL087263NHLBI NIH HHS R01 HL090682NHLBI NIH HHS R01 HL093093NHLBI NIH HHS R01 HL105756NHLBI NIH HHS R01 HL113323NHLBI NIH HHS R01 HL113338NHLBI NIH HHS R01 HL121007NHLBI NIH HHS R01 HL127564NHLBI NIH HHS R01 HL135242NHLBI NIH HHS R01 HL140570NHLBI NIH HHS R01 HL142711NHLBI NIH HHS R01 HL148050NHLBI NIH HHS R01 HL148565NHLBI NIH HHS R01 HL151152NHLBI NIH HHS R01 HL151283NHLBI NIH HHS R01 HL153805NHLBI NIH HHS R01 HL163560NHLBI NIH HHS R03 HL154284NHLBI NIH HHS R35 HL135818NHLBI NIH HHS U01 HL072507NHLBI NIH HHS U01 HL072515NIA NIH HHS R01 AG018728NIDDK NIH HHS U01 DK085524NIMH NIH HHS R01 MH078111NIMH NIH HHS R01 MH078143NIMH NIH HHS R01 MH083824
Abstract
Long non-coding RNAs (lncRNAs) are known to perform important regulatory functions. Large-scale whole genome sequencing (WGS) studies and new statistical methods for variant set tests now provide an opportunity to assess the 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 blood lipid levels (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 variations and rare protein coding variations 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 lncRNA, implicating new therapeutic opportunities.
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