Nature Communications (May 2024)
Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes
- Rebecca Keener,
- Surya B. Chhetri,
- Carla J. Connelly,
- Margaret A. Taub,
- Matthew P. Conomos,
- Joshua Weinstock,
- Bohan Ni,
- Benjamin Strober,
- Stella Aslibekyan,
- Paul L. Auer,
- Lucas Barwick,
- Lewis C. Becker,
- John Blangero,
- Eugene R. Bleecker,
- Jennifer A. Brody,
- Brian E. Cade,
- Juan C. Celedon,
- Yi-Cheng Chang,
- L. Adrienne Cupples,
- Brian Custer,
- Barry I. Freedman,
- Mark T. Gladwin,
- Susan R. Heckbert,
- Lifang Hou,
- Marguerite R. Irvin,
- Carmen R. Isasi,
- Jill M. Johnsen,
- Eimear E. Kenny,
- Charles Kooperberg,
- Ryan L. Minster,
- Take Naseri,
- Satupa’itea Viali,
- Sergei Nekhai,
- Nathan Pankratz,
- Patricia A. Peyser,
- Kent D. Taylor,
- Marilyn J. Telen,
- Baojun Wu,
- Lisa R. Yanek,
- Ivana V. Yang,
- Christine Albert,
- Donna K. Arnett,
- Allison E. Ashley-Koch,
- Kathleen C. Barnes,
- Joshua C. Bis,
- Thomas W. Blackwell,
- Eric Boerwinkle,
- Esteban G. Burchard,
- April P. Carson,
- Zhanghua Chen,
- Yii-Der Ida Chen,
- Dawood Darbar,
- Mariza de Andrade,
- Patrick T. Ellinor,
- Myriam Fornage,
- Bruce D. Gelb,
- Frank D. Gilliland,
- Jiang He,
- Talat Islam,
- Stefan Kaab,
- Sharon L. R. Kardia,
- Shannon Kelly,
- Barbara A. Konkle,
- Rajesh Kumar,
- Ruth J. F. Loos,
- Fernando D. Martinez,
- Stephen T. McGarvey,
- Deborah A. Meyers,
- Braxton D. Mitchell,
- Courtney G. Montgomery,
- Kari E. North,
- Nicholette D. Palmer,
- Juan M. Peralta,
- Benjamin A. Raby,
- Susan Redline,
- Stephen S. Rich,
- Dan Roden,
- Jerome I. Rotter,
- Ingo Ruczinski,
- David Schwartz,
- Frank Sciurba,
- M. Benjamin Shoemaker,
- Edwin K. Silverman,
- Moritz F. Sinner,
- Nicholas L. Smith,
- Albert V. Smith,
- Hemant K. Tiwari,
- Ramachandran S. Vasan,
- Scott T. Weiss,
- L. Keoki Williams,
- Yingze Zhang,
- Elad Ziv,
- Laura M. Raffield,
- Alexander P. Reiner,
- NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium,
- TOPMed Hematology and Hemostasis Working Group,
- TOPMed Structural Variation Working Group,
- Marios Arvanitis,
- Carol W. Greider,
- Rasika A. Mathias,
- Alexis Battle
Affiliations
- Rebecca Keener
- Department of Biomedical Engineering, Johns Hopkins University
- Surya B. Chhetri
- Department of Biomedical Engineering, Johns Hopkins University
- Carla J. Connelly
- Department of Molecular Biology and Genetics, Johns Hopkins University
- Margaret A. Taub
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health
- Matthew P. Conomos
- Department of Biostatistics, School of Public Health, University of Washington
- Joshua Weinstock
- Department of Biomedical Engineering, Johns Hopkins University
- Bohan Ni
- Department of Computer Science, Johns Hopkins University
- Benjamin Strober
- Department of Epidemiology, Harvard School of Public Health
- Stella Aslibekyan
- University of Alabama at Birmingham
- Paul L. Auer
- Division of Biostatistics, Institute for Health & Equity, and Cancer Center, Medical College of Wisconsin
- Lucas Barwick
- LTRC Data Coordinating Center, The Emmes Company, LLC
- Lewis C. Becker
- GeneSTAR Research Program, Department of Medicine, Johns Hopkins School of Medicine
- John Blangero
- Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine
- Eugene R. Bleecker
- Department of Medicine, Division of Genetics, Genomics and Precision Medicine, University of Arizona
- Jennifer A. Brody
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington
- Brian E. Cade
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital
- Juan C. Celedon
- Division of Pediatric Pulmonary Medicine, University of Pittsburgh
- Yi-Cheng Chang
- Department of Internal Medicine, National Taiwan University
- L. Adrienne Cupples
- Department of Biostatistics, Boston University School of Public Health
- Brian Custer
- Vitalant Research Institute
- Barry I. Freedman
- Internal Medicine - Nephrology, Wake Forest University School of Medicine
- Mark T. Gladwin
- School of Medicine, University of Maryland
- Susan R. Heckbert
- Department of Epidemiology, University of Washington
- Lifang Hou
- Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University
- Marguerite R. Irvin
- Department of Epidemiology, University of Alabama Birmingham
- Carmen R. Isasi
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine
- Jill M. Johnsen
- Department of Medicine and Institute for Stem Cell & Regenerative Medicine, University of Washington
- Eimear E. Kenny
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai
- Charles Kooperberg
- Division of Public Health Sciences, Fred Hutchinson Cancer Center
- Ryan L. Minster
- Department of Human Genetics, University of Pittsburgh Graduate School of Public Health
- Take Naseri
- Naseri & Associates Public Health Consultancy Firm and Family Health Clinic
- Satupa’itea Viali
- Oceania University of Medicine
- Sergei Nekhai
- Center for Sickle Cell Disease and Department of Medicine, College of Medicine, Howard University
- Nathan Pankratz
- Department of Laboratory Medicine and Pathology, University of Minnesota
- Patricia A. Peyser
- Department of Epidemiology, School of Public Health, University of Michigan
- Kent D. Taylor
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
- Marilyn J. Telen
- Department of Medicine, Duke University Medical Center
- Baojun Wu
- Center for Individualized and Genomic Medicine Research (CIGMA), Department of Internal Medicine, Henry Ford Health System
- Lisa R. Yanek
- Department of Medicine, Johns Hopkins University School of Medicine
- Ivana V. Yang
- Departments of Biomedical Informatics, Medicine, and Epidemiology, University of Colorado
- Christine Albert
- Harvard Medical School
- Donna K. Arnett
- Department of Epidemiology and Biostatistics, University of South Carolina
- Allison E. Ashley-Koch
- Department of Medicine, Duke University Medical Center
- Kathleen C. Barnes
- Department of Medicine, University of Colorado Denver, Anschutz Medical Campus
- Joshua C. Bis
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington
- Thomas W. Blackwell
- Department of Biostatistics, University of Michigan School of Public Health
- Eric Boerwinkle
- Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston
- Esteban G. Burchard
- Department of Medicine, University of California San Francisco
- April P. Carson
- Department of Medicine, University of Mississippi Medical Center
- Zhanghua Chen
- Department of Population and Public Health Sciences, University of Southern California
- Yii-Der Ida Chen
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
- Dawood Darbar
- Division of Cardiology, University of Illinois at Chicago
- Mariza de Andrade
- Division of Biomedical Statistics and Informatics, Mayo Clinic
- Patrick T. Ellinor
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard
- Myriam Fornage
- Institute of Molecular Medicine, McGovern Medical School, the University of Texas Health Science Center at Houston
- Bruce D. Gelb
- Mindich Child Health and Development Institute and Departments of Pediatrics and Genetics and Genomic Sciences, Icahn School of Medicine
- Frank D. Gilliland
- Department of Population and Public Health Sciences, University of Southern California
- Jiang He
- Department of Medicine, Tulane University School of Medicine
- Talat Islam
- Department of Population and Public Health Sciences, University of Southern California
- Stefan Kaab
- Department of Cardiology, University Hospital, LMU Munich
- Sharon L. R. Kardia
- Department of Epidemiology, University of Michigan School of Public Health
- Shannon Kelly
- Vitalant Research Institute
- Barbara A. Konkle
- Department of Medicine, University of Washington
- Rajesh Kumar
- Northwestern University Feinberg School of Medicine
- Ruth J. F. Loos
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai
- Fernando D. Martinez
- Asthma & Airway Disease Research Center, University of Arizona
- Stephen T. McGarvey
- Department of Epidemiology & International Health Institute, Brown University School of Public Health
- Deborah A. Meyers
- Department of Medicine, Division of Genetics, Genomics and Precision Medicine, University of Arizona
- Braxton D. Mitchell
- Department of Medicine, University of Maryland School of Medicine
- Courtney G. Montgomery
- Genes and Human Disease, Oklahoma Medical Research Foundation
- Kari E. North
- Department of Epidemiology, University of North Carolina at Chapel Hill
- Nicholette D. Palmer
- Department of Biochemistry, Wake Forest University School of Medicine
- Juan M. Peralta
- Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine
- Benjamin A. Raby
- Division of Pulmonary and Critical Care, Brigham and Women’s Hospital
- Susan Redline
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital
- Stephen S. Rich
- Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia
- Dan Roden
- Department of Medicine, Vanderbilt University School of Medicine
- Jerome I. Rotter
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
- Ingo Ruczinski
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health
- David Schwartz
- Departments of Medicine and Immunology, University of Colorado
- Frank Sciurba
- Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh
- M. Benjamin Shoemaker
- Departments of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University Medical Center
- Edwin K. Silverman
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital
- Moritz F. Sinner
- Department of Cardiology, University Hospital, LMU Munich
- Nicholas L. Smith
- Department of Medicine, Tulane University School of Medicine
- Albert V. Smith
- Department of Biostatistics, University of Michigan
- Hemant K. Tiwari
- Department of Biostatistics, University of Alabama Birmingham
- Ramachandran S. Vasan
- Department of Medicine, Boston University School of Medicine
- Scott T. Weiss
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital
- L. Keoki Williams
- Center for Individualized and Genomic Medicine Research (CIGMA), Department of Internal Medicine, Henry Ford Health System
- Yingze Zhang
- Division of Pulmonary Allergy and Critical Care Medicine, University of Pittsburgh
- Elad Ziv
- Department of Medicine, University of California San Francisco
- Laura M. Raffield
- Department of Genetics, University of North Carolina at Chapel Hill
- Alexander P. Reiner
- Division of Public Health Sciences, Fred Hutchinson Cancer Center
- NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
- TOPMed Hematology and Hemostasis Working Group
- TOPMed Structural Variation Working Group
- Marios Arvanitis
- Department of Medicine, Division of Cardiology, Johns Hopkins University
- Carol W. Greider
- Department of Molecular Cell and Developmental Biology, University of California Santa Cruz
- Rasika A. Mathias
- Department of Medicine, Johns Hopkins University School of Medicine
- Alexis Battle
- Department of Biomedical Engineering, Johns Hopkins University
- DOI
- https://doi.org/10.1038/s41467-024-48394-y
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 1 – 21
Abstract
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.
