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Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed Whole Genome Sequencing Study.
Wang, Yuxuan; Selvaraj, Margaret Sunitha; Li, Xihao; Li, Zilin; Holdcraft, Jacob A; Arnett, Donna K; Bis, Joshua C; Blangero, John; Boerwinkle, Eric; Bowden, Donald W; Cade, Brian E; Carlson, Jenna C; Carson, April P; Chen, Yii-Der Ida; Curran, Joanne E; de Vries, Paul S; Dutcher, Susan K; Ellinor, Patrick T; Floyd, James S; Fornage, Myriam; Freedman, Barry I; Gabriel, Stacey; Germer, Soren; Gibbs, Richard A; Guo, Xiuqing; He, Jiang; Heard-Costa, Nancy; Hildalgo, Bertha; Hou, Lifang; Irvin, Marguerite R; Joehanes, Roby; Kaplan, Robert C; Kardia, Sharon Lr; Kelly, Tanika N; Kim, Ryan; Kooperberg, Charles; Kral, Brian G; Levy, Daniel; Li, Changwei; Liu, Chunyu; Lloyd-Jone, Don; Loos, Ruth Jf; Mahaney, Michael C; Martin, Lisa W; Mathias, Rasika A; Minster, Ryan L; Mitchell, Braxton D; Montasser, May E; Morrison, Alanna C; Murabito, Joanne M.
Afiliação
  • Wang Y; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
  • Selvaraj MS; Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Li X; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Li Z; Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • Holdcraft JA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • Arnett DK; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • Bis JC; Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, IN, USA.
  • Blangero J; Center for Computational Biology & Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
  • Boerwinkle E; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
  • Bowden DW; Provost Office, University of South Carolina, Columbia, SC, USA.
  • Cade BE; Department of Epidemiology and Biostatistics, University of South Carolina Arnold School of Public Health, Columbia, SC, USA.
  • Carlson JC; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
  • Carson AP; Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
  • Chen YI; 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.
  • Curran JE; Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
  • de Vries PS; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
  • Dutcher SK; Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.
  • Ellinor PT; Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
  • Floyd JS; Department of Biostatistics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
  • Fornage M; Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
  • Freedman BI; 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.
  • Gabriel S; Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
  • Germer S; 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.
  • Gibbs RA; The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA.
  • Guo X; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
  • He J; Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Heard-Costa N; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
  • Hildalgo B; Department of Epidemiology, University of Washington, Seattle, WA, USA.
  • Hou L; Center for Human Genetics, University of Texas Health at Houston, Houston, TX, USA.
  • Irvin MR; Department of Internal Medicine, Nephrology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
  • Joehanes R; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Kaplan RC; New York Genome Center, New York, NY, USA.
  • Kardia SL; Baylor College of Medicine Human Genome Sequencing Center, Houston, TX, USA.
  • Kelly TN; 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.
  • Kim R; Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA.
  • Kooperberg C; Tulane University Translational Science Institute, New Orleans, LA, USA.
  • Kral BG; Framingham Heart Study, Framingham, MA, USA.
  • Levy D; Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
  • Li C; Department of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham, AL, USA.
  • Liu C; Department of Preventive Medicine, Northwestern University, Chicago, IL, USA.
  • Lloyd-Jone D; Department of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham, AL, USA.
  • Loos RJ; Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • Mahaney MC; Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Martin LW; Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
  • Mathias RA; Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
  • Minster RL; Department of Medicine, Division of Nephrology, University of Illinois Chicago, Chicago, IL, USA.
  • Mitchell BD; Psomagen, Inc. (formerly Macrogen USA), Rockville, MD, USA.
  • Montasser ME; Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
  • Morrison AC; GeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Murabito JM; Framingham Heart Study, Framingham, MA, USA.
medRxiv ; 2023 Jun 29.
Article em En | MEDLINE | ID: mdl-37425772
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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Texto completo: 1 Base de dados: MEDLINE Tipo de estudo: Risk_factors_studies Idioma: En Ano de publicação: 2023 Tipo de documento: Article
Texto completo
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XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Tipo de estudo: Risk_factors_studies Idioma: En Ano de publicação: 2023 Tipo de documento: Article