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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

Author

Listed:
  • 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
    University of Arizona)

  • Jennifer A. Brody

    (University of Washington)

  • Brian E. Cade

    (Brigham and Women’s Hospital
    Harvard Medical School)

  • Juan C. Celedon

    (University of Pittsburgh)

  • Yi-Cheng Chang

    (National Taiwan University
    National Taiwan University
    Academia Sinica)

  • L. Adrienne Cupples

    (Boston University School of Public Health
    Boston University’s Framingham Heart Study)

  • Brian Custer

    (Vitalant Research Institute
    University of California San Francisco)

  • 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
    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
    Brown University)

  • Satupa’itea Viali

    (Oceania University of Medicine
    National University of Samoa
    Yale University School of Public Health)

  • 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
    Brigham and Women’s Hospital)

  • 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
    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
    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
    University of California San Francisco Benioff Children’s Hospital)

  • Barbara A. Konkle

    (University of Washington)

  • Rajesh Kumar

    (Northwestern University Feinberg School of Medicine
    The Ann and Robert H. Lurie Children’s Hospital of Chicago)

  • 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
    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
    Boston Children’s Hospital)

  • Susan Redline

    (Brigham and Women’s Hospital
    Harvard Medical School)

  • 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
    Harvard Medical School)

  • 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
    University Professor Johns Hopkins University)

  • Rasika A. Mathias

    (Johns Hopkins University School of Medicine)

  • Alexis Battle

    (Johns Hopkins University
    Johns Hopkins University
    Johns Hopkins University
    Johns Hopkins University)

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.

Suggested Citation

  • 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 & Lewi, 2024. "Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48394-y
    DOI: 10.1038/s41467-024-48394-y
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    References listed on IDEAS

    as
    1. Claudia Giambartolomei & Damjan Vukcevic & Eric E Schadt & Lude Franke & Aroon D Hingorani & Chris Wallace & Vincent Plagnol, 2014. "Bayesian Test for Colocalisation between Pairs of Genetic Association Studies Using Summary Statistics," PLOS Genetics, Public Library of Science, vol. 10(5), pages 1-15, May.
    2. Joshua S. Weinstock & Jayakrishnan Gopakumar & Bala Bharathi Burugula & Md Mesbah Uddin & Nikolaus Jahn & Julia A. Belk & Hind Bouzid & Bence Daniel & Zhuang Miao & Nghi Ly & Taralynn M. Mack & Sofia , 2023. "Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis," Nature, Nature, vol. 616(7958), pages 755-763, April.
    3. Rajkumar Dorajoo & Xuling Chang & Resham Lal Gurung & Zheng Li & Ling Wang & Renwei Wang & Kenneth B. Beckman & Jennifer Adams-Haduch & Yiamunaa M & Sylvia Liu & Wee Yang Meah & Kar Seng Sim & Su Chi , 2019. "Loci for human leukocyte telomere length in the Singaporean Chinese population and trans-ethnic genetic studies," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    4. Daniel J. Weiner & Ajay Nadig & Karthik A. Jagadeesh & Kushal K. Dey & Benjamin M. Neale & Elise B. Robinson & Konrad J. Karczewski & Luke J. O’Connor, 2023. "Polygenic architecture of rare coding variation across 394,783 exomes," Nature, Nature, vol. 614(7948), pages 492-499, February.
    5. Bas van Steensel & Titia de Lange, 1997. "Control of telomere length by the human telomeric protein TRF1," Nature, Nature, vol. 385(6618), pages 740-743, February.
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