Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes.
- Resource Type
- Academic Journal
- Authors
- Keener R; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.; Chhetri SB; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.; Connelly CJ; Department of Molecular Biology and Genetics, Johns Hopkins University, Baltimore, MD, USA.; Taub MA; Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.; Conomos MP; Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA, USA.; Weinstock J; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.; Ni B; Department of Computer Science, Johns Hopkins University, Baltimore, MD, USA.; Strober B; Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.; Aslibekyan S; University of Alabama at Birmingham, Birmingham, AL, USA.; Auer PL; Division of Biostatistics, Institute for Health & Equity, and Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.; Barwick L; LTRC Data Coordinating Center, The Emmes Company, LLC, Rockville, MD, USA.; Becker LC; GeneSTAR Research Program, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, 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.; Bleecker ER; Department of Medicine, Division of Genetics, Genomics and Precision Medicine, University of Arizona, Tucson, AZ, USA.; Division of Pharmacogenomics, University of Arizona, Tucson, AZ, USA.; Brody JA; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.; Cade BE; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.; Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.; Celedon JC; Division of Pediatric Pulmonary Medicine, University of Pittsburgh, Pittsburgh, PA, USA.; Chang YC; Department of Internal Medicine, National Taiwan University, Taipei, Taiwan.; Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei, Taiwan.; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.; Cupples LA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.; The National Heart, Lung, and Blood Institute, Boston University's Framingham Heart Study, Framingham, MA, USA.; Custer B; Vitalant Research Institute, San Francisco, CA, USA.; Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA.; Freedman BI; Internal Medicine - Nephrology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.; Gladwin MT; School of Medicine, University of Maryland, Baltimore, MD, USA.; Heckbert SR; Department of Epidemiology, University of Washington, Seattle, WA, USA.; Hou L; Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Evanston, IL, USA.; Irvin MR; Department of Epidemiology, University of Alabama Birmingham, Birmingham, AL, USA.; Isasi CR; Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.; Johnsen JM; Department of Medicine and Institute for Stem Cell & Regenerative Medicine, University of Washington, Seattle, WA, USA.; Kenny EE; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Center for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Kooperberg C; Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.; Minster RL; Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.; Naseri T; Naseri & Associates Public Health Consultancy Firm and Family Health Clinic, Apia, Samoa.; International Health Institute, School of Public Health, Brown University, Providence, RI, USA.; Viali S; Oceania University of Medicine, Apia, Samoa.; School of Medicine, National University of Samoa, Apia, Samoa.; Department of Chronic Disease Epidemiology, Yale University School of Public Health, New Haven, CT, USA.; Nekhai S; Center for Sickle Cell Disease and Department of Medicine, College of Medicine, Howard University, Washington DC, USA.; Pankratz N; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.; Peyser PA; Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.; Taylor KD; 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.; Telen MJ; Department of Medicine, Duke University Medical Center, Durham, NC, USA.; Wu B; Center for Individualized and Genomic Medicine Research (CIGMA), Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA.; Yanek LR; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Yang IV; Departments of Biomedical Informatics, Medicine, and Epidemiology, University of Colorado, Boulder, CO, USA.; Albert C; Harvard Medical School, Boston, MA, USA.; Division of Cardiovascular, Brigham and Women's Hospital, Boston, MA, USA.; Arnett DK; Department of Epidemiology and Biostatistics, University of South Carolina, Columbia, SC, USA.; Ashley-Koch AE; Department of Medicine, Duke University Medical Center, Durham, NC, USA.; Barnes KC; Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.; Bis JC; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.; Blackwell TW; Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.; Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA.; Boerwinkle E; Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA.; Burchard EG; Department of Medicine, University of California San Francisco, San Francisco, CA, USA.; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.; Carson AP; Department of Medicine, University of Mississippi Medical Center, Jackson, MI, USA.; Chen Z; Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, 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.; Darbar D; Division of Cardiology, University of Illinois at Chicago, Chicago, IL, USA.; de Andrade M; Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA.; Ellinor PT; Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Fornage M; Institute of Molecular Medicine, McGovern Medical School, the University of Texas Health Science Center at Houston, Houston, TX, USA.; Gelb BD; Mindich Child Health and Development Institute and Departments of Pediatrics and Genetics and Genomic Sciences, Icahn School of Medicine, New York, NY, USA.; Gilliland FD; Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA.; He J; Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA.; Islam T; Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA.; Kaab S; Department of Cardiology, University Hospital, LMU Munich, Munich, Germany.; Kardia SLR; Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA.; Kelly S; Vitalant Research Institute, San Francisco, CA, USA.; University of California San Francisco Benioff Children's Hospital, Oakland, CA, USA.; Konkle BA; Department of Medicine, University of Washington, Seattle, WA, USA.; Kumar R; Northwestern University Feinberg School of Medicine, Chicago, IL, USA.; The Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.; Loos RJF; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Martinez FD; Asthma & Airway Disease Research Center, University of Arizona, Tucson, AZ, USA.; McGarvey ST; Department of Epidemiology & International Health Institute, Brown University School of Public Health, Providence, RI, USA.; Meyers DA; Department of Medicine, Division of Genetics, Genomics and Precision Medicine, University of Arizona, Tucson, AZ, USA.; Division of Pharmacogenomics, University of Arizona, Tucson, AZ, USA.; Mitchell BD; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.; Montgomery CG; Genes and Human Disease, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.; North KE; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Palmer ND; Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA.; Peralta JM; Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.; Raby BA; Division of Pulmonary and Critical Care, Brigham and Women's Hospital, Boston, MA, USA.; Division of Pulmonary Medicine, Boston Children's Hospital, Boston, MA, USA.; Redline S; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.; Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.; Rich SS; Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.; Roden D; Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, 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.; Ruczinski I; Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.; Schwartz D; Departments of Medicine and Immunology, University of Colorado, Boulder, CO, USA.; Sciurba F; Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA.; Shoemaker MB; Departments of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.; Silverman EK; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.; Sinner MF; Department of Cardiology, University Hospital, LMU Munich, Munich, Germany.; Smith NL; Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA.; Smith AV; Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.; Tiwari HK; Department of Biostatistics, University of Alabama Birmingham, Birmingham, AL, USA.; Vasan RS; Department of Medicine, Boston University School of Medicine, Boston, MA, USA.; Weiss ST; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA.; Williams LK; Center for Individualized and Genomic Medicine Research (CIGMA), Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA.; Zhang Y; Division of Pulmonary Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA.; Ziv E; Department of Medicine, University of California San Francisco, San Francisco, CA, USA.; Raffield LM; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Reiner AP; Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.; Arvanitis M; Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD, USA.; Greider CW; Department of Molecular Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA, USA.; University Professor Johns Hopkins University, Baltimore, MD, USA.; Mathias RA; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. rmathias@jhmi.edu.; Battle A; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA. ajbattle@jhu.edu.; Department of Computer Science, Johns Hopkins University, Baltimore, MD, USA. ajbattle@jhu.edu.; Department of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA. ajbattle@jhu.edu.; Malone Center for Engineering in Healthcare, Johns Hopkins University, Baltimore, MD, USA. ajbattle@jhu.edu.; Data Science and AI Institute, Johns Hopkins University, Baltimore, MD, USA. ajbattle@jhu.edu.
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- Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
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- Language
- English
Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation.
(© 2024. The Author(s).)