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Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes.
Keener, Rebecca; Chhetri, Surya B; Connelly, Carla J; Taub, Margaret A; Conomos, Matthew P; Weinstock, Joshua; Ni, Bohan; Strober, Benjamin; Aslibekyan, Stella; Auer, Paul L; Barwick, Lucas; Becker, Lewis C; Blangero, John; Bleecker, Eugene R; Brody, Jennifer A; Cade, Brian E; Celedon, Juan C; Chang, Yi-Cheng; Cupples, L Adrienne; Custer, Brian; Freedman, Barry I; Gladwin, Mark T; Heckbert, Susan R; Hou, Lifang; Irvin, Marguerite R; Isasi, Carmen R; Johnsen, Jill M; Kenny, Eimear E; Kooperberg, Charles; Minster, Ryan L; Naseri, Take; Viali, Satupa'itea; Nekhai, Sergei; Pankratz, Nathan; Peyser, Patricia A; Taylor, Kent D; Telen, Marilyn J; Wu, Baojun; Yanek, Lisa R; Yang, Ivana V; Albert, Christine; Arnett, Donna K; Ashley-Koch, Allison E; Barnes, Kathleen C; Bis, Joshua C; Blackwell, Thomas W; Boerwinkle, Eric; Burchard, Esteban G; Carson, April P; Chen, Zhanghua.
Afiliação
  • 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.
  • Brody JA; Division of Pharmacogenomics, University of Arizona, Tucson, AZ, USA.
  • Cade BE; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
  • Celedon JC; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
  • Chang YC; Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.
  • Cupples LA; Division of Pediatric Pulmonary Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
  • Custer B; Department of Internal Medicine, National Taiwan University, Taipei, Taiwan.
  • Freedman BI; Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei, Taiwan.
  • Gladwin MT; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
  • Heckbert SR; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
  • Hou L; The National Heart, Lung, and Blood Institute, Boston University's Framingham Heart Study, Framingham, MA, USA.
  • Irvin MR; Vitalant Research Institute, San Francisco, CA, USA.
  • Isasi CR; Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA.
  • Johnsen JM; Internal Medicine - Nephrology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
  • Kenny EE; School of Medicine, University of Maryland, Baltimore, MD, USA.
  • Kooperberg C; Department of Epidemiology, University of Washington, Seattle, WA, USA.
  • Minster RL; Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Evanston, IL, USA.
  • Naseri T; Department of Epidemiology, University of Alabama Birmingham, Birmingham, AL, USA.
  • Viali S; Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Nekhai S; Department of Medicine and Institute for Stem Cell & Regenerative Medicine, University of Washington, Seattle, WA, USA.
  • Pankratz N; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Peyser PA; Center for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Taylor KD; Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
  • Telen MJ; Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.
  • Wu B; Naseri & Associates Public Health Consultancy Firm and Family Health Clinic, Apia, Samoa.
  • Yanek LR; International Health Institute, School of Public Health, Brown University, Providence, RI, USA.
  • Yang IV; Oceania University of Medicine, Apia, Samoa.
  • Albert C; School of Medicine, National University of Samoa, Apia, Samoa.
  • Arnett DK; Department of Chronic Disease Epidemiology, Yale University School of Public Health, New Haven, CT, USA.
  • Ashley-Koch AE; Center for Sickle Cell Disease and Department of Medicine, College of Medicine, Howard University, Washington DC, USA.
  • Barnes KC; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
  • Bis JC; Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
  • Blackwell TW; 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.
  • Boerwinkle E; Department of Medicine, Duke University Medical Center, Durham, NC, USA.
  • Burchard EG; Center for Individualized and Genomic Medicine Research (CIGMA), Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA.
  • Carson AP; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Chen Z; Departments of Biomedical Informatics, Medicine, and Epidemiology, University of Colorado, Boulder, CO, USA.
Nat Commun ; 15(1): 4417, 2024 May 24.
Article em En | MEDLINE | ID: mdl-38789417
ABSTRACT
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Telômero / Estudo de Associação Genômica Ampla / Homeostase do Telômero Limite: Humans Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Telômero / Estudo de Associação Genômica Ampla / Homeostase do Telômero Limite: Humans Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos