Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed Whole Genome Sequencing Study.

Autor:	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.; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA., Li X; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA., Li Z; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.; Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, IN, USA.; Center for Computational Biology & Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA., Holdcraft JA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA., Arnett DK; 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., Bis JC; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA., Blangero J; Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA., Boerwinkle E; 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., Bowden DW; Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA., Cade BE; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.; Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA., Carlson JC; 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., Carson AP; Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA., Chen YI; 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., Curran JE; Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA., de Vries PS; 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., Dutcher SK; The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA., Ellinor PT; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.; Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA., Floyd JS; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.; Department of Epidemiology, University of Washington, Seattle, WA, USA., Fornage M; Center for Human Genetics, University of Texas Health at Houston, Houston, TX, USA., Freedman BI; Department of Internal Medicine, Nephrology, Wake Forest University School of Medicine, Winston-Salem, NC, USA., Gabriel S; Broad Institute of Harvard and MIT, Cambridge, MA, USA., Germer S; New York Genome Center, New York, NY, USA., Gibbs RA; Baylor College of Medicine Human Genome Sequencing Center, Houston, TX, USA., Guo X; 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., He J; 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., Heard-Costa N; Framingham Heart Study, Framingham, MA, USA.; Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA., Hildalgo B; Department of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham, AL, USA., Hou L; Department of Preventive Medicine, Northwestern University, Chicago, IL, USA., Irvin MR; Department of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham, AL, USA., Joehanes R; Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA., Kaplan RC; 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., Kardia SL; Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA., Kelly TN; Department of Medicine, Division of Nephrology, University of Illinois Chicago, Chicago, IL, USA., Kim R; Psomagen, Inc. (formerly Macrogen USA), Rockville, MD, USA., Kooperberg C; Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA., Kral BG; GeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Levy D; 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., Li C; 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., Liu C; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.; Framingham Heart Study, Framingham, MA, USA., Lloyd-Jone D; Department of Preventive Medicine, Northwestern University, Chicago, IL, USA., Loos RJ; 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., Mahaney MC; Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA., Martin LW; George Washington University School of Medicine and Health Sciences, Washington, DC, USA., Mathias RA; GeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Minster RL; Department of Human Genetics and Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA., Mitchell BD; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA., Montasser ME; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA., Morrison AC; 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., Murabito JM; Framingham Heart Study, Framingham, MA, USA.; Department of Medicine, Boston Medical Center, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA., Naseri T; Ministry of Health, Apia, Samoa., O'Connell JR; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA., Palmer ND; Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA., Preuss MH; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Psaty BM; 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., Raffield LM; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Rao DC; Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA., Redline S; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Reiner AP; Department of Epidemiology, University of Washington, Seattle, WA, USA., Rich SS; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA., Ruepena MS; Lutia i Puava ae Mapu i Fagalele, Apia, Samoa., Sheu WH; National Health Research Institute (NHRI), Taiwan., Smith JA; Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA., Smith A; Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA., Tiwari HK; Department of Biostatistics, University of Alabama, Birmingham, AL, USA., Tsai MY; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA., Viaud-Martinez KA; Illumina Laboratory Services, Illumina Inc., San Diego, CA, USA., Wang Z; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Yanek LR; GeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Zhao W; Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA., Rotter JI; 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., Lin X; 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., Natarajan P; 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., Peloso GM; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Jazyk:	angličtina
Zdroj:	MedRxiv : the preprint server for health sciences [medRxiv] 2023 Jun 29. Date of Electronic Publication: 2023 Jun 29.
DOI:	10.1101/2023.06.28.23291966
Abstrakt:	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. Competing Interests: Declaration of interests P.N. reports investigator-initiated grant support from Amgen, Apple, AstraZeneca, and Boston Scientific, personal fees from Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Genentech, TenSixteen Bio, and Novartis, scientific advisory board membership of geneXwell and TenSixteen Bio, and spousal employment at Vertex, all unrelated to the present work. B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. L.M.R is a consultant for the TOPMed Administrative Coordinating Center (through Westat). M.E.M. receives funding from Regeneron Pharmaceutical Inc. unrelated to this work. X. Lin is a consultant of AbbVie Pharmaceuticals and Verily Life Sciences. The remaining authors declare no competing interests.
Databáze:	MEDLINE
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