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; Der Ida Chen, Yii-; Darbar, Dawood; Andrade, Mariza; Ellinor, Patrick T.; Fornage, Myriam; Gelb, Bruce D.; Gilliland, Frank D.; He, Jiang; Islam, Talat; Kaab, Stefan; Kardia, Sharon L. R.; Kelly, Shannon; Konkle, Barbara A.; Kumar, Rajesh; Loos, Ruth J. F.; Martinez, Fernando D.; McGarvey, Stephen T.; Meyers, Deborah A.; Mitchell, Braxton D.; Montgomery, Courtney G.; North, Kari E.; Palmer, Nicholette D.; Peralta, Juan M.; Raby, Benjamin A.; Redline, Susan; Rich, Stephen S.; Roden, Dan; Rotter, Jerome I.; Ruczinski, Ingo; Schwartz, David; Sciurba, Frank; Shoemaker, M. Benjamin; Silverman, Edwin K.; Sinner, Moritz F.; Smith, Nicholas L.; Smith, Albert V.; Tiwari, Hemant K.; Vasan, Ramachandran S.; Weiss, Scott T.; Williams, L. Keoki; Zhang, Yingze; Ziv, Elad; Raffield, Laura M.; Reiner, Alexander P.; Arvanitis, Marios; Greider, Carol W.; Mathias, Rasika A.; Battle, Alexis

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 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, Marios Arvanitis, Carol W. Greider, Rasika A. Mathias () and Alexis Battle ()
Additional contact information
Rebecca Keener: Johns Hopkins University
Surya B. Chhetri: Johns Hopkins University
Carla J. Connelly: Johns Hopkins University
Margaret A. Taub: Johns Hopkins Bloomberg School of Public Health
Matthew P. Conomos: University of Washington
Joshua Weinstock: Johns Hopkins University
Bohan Ni: Johns Hopkins University
Benjamin Strober: Harvard School of Public Health
Stella Aslibekyan: University of Alabama at Birmingham
Paul L. Auer: Medical College of Wisconsin
Lucas Barwick: LLC
Lewis C. Becker: Johns Hopkins School of Medicine
John Blangero: University of Texas Rio Grande Valley School of Medicine
Eugene R. Bleecker: University of Arizona
Jennifer A. Brody: University of Washington
Brian E. Cade: Brigham and Women’s Hospital
Juan C. Celedon: University of Pittsburgh
Yi-Cheng Chang: National Taiwan University
L. Adrienne Cupples: Boston University School of Public Health
Brian Custer: Vitalant Research Institute
Barry I. Freedman: Wake Forest University School of Medicine
Mark T. Gladwin: University of Maryland
Susan R. Heckbert: University of Washington
Lifang Hou: Northwestern University
Marguerite R. Irvin: University of Alabama Birmingham
Carmen R. Isasi: Albert Einstein College of Medicine
Jill M. Johnsen: University of Washington
Eimear E. Kenny: Icahn School of Medicine at Mount Sinai
Charles Kooperberg: Fred Hutchinson Cancer Center
Ryan L. Minster: 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: Howard University
Nathan Pankratz: University of Minnesota
Patricia A. Peyser: University of Michigan
Kent D. Taylor: The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Marilyn J. Telen: Duke University Medical Center
Baojun Wu: Henry Ford Health System
Lisa R. Yanek: Johns Hopkins University School of Medicine
Ivana V. Yang: University of Colorado
Christine Albert: Harvard Medical School
Donna K. Arnett: University of South Carolina
Allison E. Ashley-Koch: Duke University Medical Center
Kathleen C. Barnes: Anschutz Medical Campus
Joshua C. Bis: University of Washington
Thomas W. Blackwell: University of Michigan School of Public Health
Eric Boerwinkle: University of Texas Health Science Center at Houston
Esteban G. Burchard: University of California San Francisco
April P. Carson: University of Mississippi Medical Center
Zhanghua Chen: University of Southern California
Yii- Der Ida Chen: The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Dawood Darbar: University of Illinois at Chicago
Mariza Andrade: Mayo Clinic
Patrick T. Ellinor: The Broad Institute of MIT and Harvard
Myriam Fornage: the University of Texas Health Science Center at Houston
Bruce D. Gelb: Icahn School of Medicine
Frank D. Gilliland: University of Southern California
Jiang He: Tulane University School of Medicine
Talat Islam: University of Southern California
Stefan Kaab: LMU Munich
Sharon L. R. Kardia: University of Michigan School of Public Health
Shannon Kelly: Vitalant Research Institute
Barbara A. Konkle: University of Washington
Rajesh Kumar: Northwestern University Feinberg School of Medicine
Ruth J. F. Loos: Icahn School of Medicine at Mount Sinai
Fernando D. Martinez: University of Arizona
Stephen T. McGarvey: Brown University School of Public Health
Deborah A. Meyers: University of Arizona
Braxton D. Mitchell: University of Maryland School of Medicine
Courtney G. Montgomery: Oklahoma Medical Research Foundation
Kari E. North: University of North Carolina at Chapel Hill
Nicholette D. Palmer: Wake Forest University School of Medicine
Juan M. Peralta: University of Texas Rio Grande Valley School of Medicine
Benjamin A. Raby: Brigham and Women’s Hospital
Susan Redline: Brigham and Women’s Hospital
Stephen S. Rich: University of Virginia
Dan Roden: Vanderbilt University School of Medicine
Jerome I. Rotter: The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Ingo Ruczinski: Johns Hopkins Bloomberg School of Public Health
David Schwartz: University of Colorado
Frank Sciurba: University of Pittsburgh
M. Benjamin Shoemaker: Vanderbilt University Medical Center
Edwin K. Silverman: Brigham and Women’s Hospital
Moritz F. Sinner: LMU Munich
Nicholas L. Smith: Tulane University School of Medicine
Albert V. Smith: University of Michigan
Hemant K. Tiwari: University of Alabama Birmingham
Ramachandran S. Vasan: Boston University School of Medicine
Scott T. Weiss: Brigham and Women’s Hospital
L. Keoki Williams: Henry Ford Health System
Yingze Zhang: University of Pittsburgh
Elad Ziv: University of California San Francisco
Laura M. Raffield: University of North Carolina at Chapel Hill
Alexander P. Reiner: Fred Hutchinson Cancer Center
Marios Arvanitis: Johns Hopkins University
Carol W. Greider: University of California Santa Cruz
Rasika A. Mathias: Johns Hopkins University School of Medicine
Alexis Battle: Johns Hopkins University

Nature Communications, 2024, vol. 15, issue 1, 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.

Date: 2024
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DOI: 10.1038/s41467-024-48394-y

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