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

doi:10.1038/s41467-024-48394-y

Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes

Nat Commun. 2024 May 24;15(1):4417. doi: 10.1038/s41467-024-48394-y.

Authors

Rebecca Keener¹, Surya B Chhetri¹, Carla J Connelly², Margaret A Taub³, Matthew P Conomos⁴, Joshua Weinstock¹, Bohan Ni⁵, Benjamin Strober⁶, Stella Aslibekyan⁷, Paul L Auer⁸, Lucas Barwick⁹, Lewis C Becker¹⁰, John Blangero¹¹, Eugene R Bleecker^{12

13}, Jennifer A Brody¹⁴, Brian E Cade^{15

16}, Juan C Celedon¹⁷, Yi-Cheng Chang^{18

19

20}, L Adrienne Cupples^{21

22}, Brian Custer^{23

24}, Barry I Freedman²⁵, Mark T Gladwin²⁶, Susan R Heckbert²⁷, Lifang Hou²⁸, Marguerite R Irvin²⁹, Carmen R Isasi³⁰, Jill M Johnsen³¹, Eimear E Kenny^{32

33}, Charles Kooperberg³⁴, Ryan L Minster³⁵, Take Naseri^{36

37}, Satupa'itea Viali^{38

39

40}, Sergei Nekhai⁴¹, Nathan Pankratz⁴², Patricia A Peyser⁴³, Kent D Taylor⁴⁴, Marilyn J Telen⁴⁵, Baojun Wu⁴⁶, Lisa R Yanek⁴⁷, Ivana V Yang⁴⁸, Christine Albert^{49

50}, Donna K Arnett⁵¹, Allison E Ashley-Koch⁴⁵, Kathleen C Barnes⁵², Joshua C Bis¹⁴, Thomas W Blackwell^{53

54}, Eric Boerwinkle⁵⁵, Esteban G Burchard^{56

57}, April P Carson⁵⁸, Zhanghua Chen⁵⁹, Yii-Der Ida Chen⁴⁴, Dawood Darbar⁶⁰, Mariza de Andrade⁶¹, Patrick T Ellinor⁶², Myriam Fornage⁶³, Bruce D Gelb⁶⁴, Frank D Gilliland⁵⁹, Jiang He⁶⁵, Talat Islam⁵⁹, Stefan Kaab⁶⁶, Sharon L R Kardia⁶⁷, Shannon Kelly^{23

68}, Barbara A Konkle⁶⁹, Rajesh Kumar^{70

71}, Ruth J F Loos³², Fernando D Martinez⁷², Stephen T McGarvey⁷³, Deborah A Meyers^{12

13}, Braxton D Mitchell⁷⁴, Courtney G Montgomery⁷⁵, Kari E North⁷⁶, Nicholette D Palmer⁷⁷, Juan M Peralta¹¹, Benjamin A Raby^{78

79}, Susan Redline^{15

16}, Stephen S Rich⁸⁰, Dan Roden⁸¹, Jerome I Rotter⁴⁴, Ingo Ruczinski³, David Schwartz⁸², Frank Sciurba⁸³, M Benjamin Shoemaker⁸⁴, Edwin K Silverman¹⁵, Moritz F Sinner⁶⁶, Nicholas L Smith⁶⁵, Albert V Smith⁸⁵, Hemant K Tiwari⁸⁶, Ramachandran S Vasan⁸⁷, Scott T Weiss^{15

49}, L Keoki Williams⁴⁶, Yingze Zhang⁸⁸, Elad Ziv⁵⁶, Laura M Raffield⁸⁹, Alexander P Reiner³⁴; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; TOPMed Hematology and Hemostasis Working Group; TOPMed Structural Variation Working Group; Marios Arvanitis⁹⁰, Carol W Greider^{91

92}, Rasika A Mathias⁹³, Alexis Battle^{94

95

96

97

98}

Affiliations

¹ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
² Department of Molecular Biology and Genetics, Johns Hopkins University, Baltimore, MD, USA.
³ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁴ Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA, USA.
⁵ Department of Computer Science, Johns Hopkins University, Baltimore, MD, USA.
⁶ Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
⁷ University of Alabama at Birmingham, Birmingham, AL, USA.
⁸ Division of Biostatistics, Institute for Health & Equity, and Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.
⁹ LTRC Data Coordinating Center, The Emmes Company, LLC, Rockville, MD, USA.
¹⁰ GeneSTAR Research Program, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
¹¹ Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
¹² Department of Medicine, Division of Genetics, Genomics and Precision Medicine, University of Arizona, Tucson, AZ, USA.
¹³ Division of Pharmacogenomics, University of Arizona, Tucson, AZ, USA.
¹⁴ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
¹⁵ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
¹⁶ Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.
¹⁷ Division of Pediatric Pulmonary Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
¹⁸ Department of Internal Medicine, National Taiwan University, Taipei, Taiwan.
¹⁹ Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei, Taiwan.
²⁰ Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
²¹ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
²² The National Heart, Lung, and Blood Institute, Boston University's Framingham Heart Study, Framingham, MA, USA.
²³ Vitalant Research Institute, San Francisco, CA, USA.
²⁴ Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA.
²⁵ Internal Medicine - Nephrology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
²⁶ School of Medicine, University of Maryland, Baltimore, MD, USA.
²⁷ Department of Epidemiology, University of Washington, Seattle, WA, USA.
²⁸ Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Evanston, IL, USA.
²⁹ Department of Epidemiology, University of Alabama Birmingham, Birmingham, AL, USA.
³⁰ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
³¹ Department of Medicine and Institute for Stem Cell & Regenerative Medicine, University of Washington, Seattle, WA, USA.
³² The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³³ Center for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³⁴ Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
³⁵ Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.
³⁶ Naseri & Associates Public Health Consultancy Firm and Family Health Clinic, Apia, Samoa.
³⁷ International Health Institute, School of Public Health, Brown University, Providence, RI, USA.
³⁸ Oceania University of Medicine, Apia, Samoa.
³⁹ School of Medicine, National University of Samoa, Apia, Samoa.
⁴⁰ Department of Chronic Disease Epidemiology, Yale University School of Public Health, New Haven, CT, USA.
⁴¹ Center for Sickle Cell Disease and Department of Medicine, College of Medicine, Howard University, Washington DC, USA.
⁴² Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
⁴³ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
⁴⁴ 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.
⁴⁵ Department of Medicine, Duke University Medical Center, Durham, NC, USA.
⁴⁶ Center for Individualized and Genomic Medicine Research (CIGMA), Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA.
⁴⁷ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴⁸ Departments of Biomedical Informatics, Medicine, and Epidemiology, University of Colorado, Boulder, CO, USA.
⁴⁹ Harvard Medical School, Boston, MA, USA.
⁵⁰ Division of Cardiovascular, Brigham and Women's Hospital, Boston, MA, USA.
⁵¹ Department of Epidemiology and Biostatistics, University of South Carolina, Columbia, SC, USA.
⁵² Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
⁵³ Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
⁵⁴ Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
⁵⁵ 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.
⁵⁶ Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
⁵⁷ Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
⁵⁸ Department of Medicine, University of Mississippi Medical Center, Jackson, MI, USA.
⁵⁹ Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA.
⁶⁰ Division of Cardiology, University of Illinois at Chicago, Chicago, IL, USA.
⁶¹ Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA.
⁶² Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁶³ Institute of Molecular Medicine, McGovern Medical School, the University of Texas Health Science Center at Houston, Houston, TX, USA.
⁶⁴ Mindich Child Health and Development Institute and Departments of Pediatrics and Genetics and Genomic Sciences, Icahn School of Medicine, New York, NY, USA.
⁶⁵ Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
⁶⁶ Department of Cardiology, University Hospital, LMU Munich, Munich, Germany.
⁶⁷ Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA.
⁶⁸ University of California San Francisco Benioff Children's Hospital, Oakland, CA, USA.
⁶⁹ Department of Medicine, University of Washington, Seattle, WA, USA.
⁷⁰ Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁷¹ The Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.
⁷² Asthma & Airway Disease Research Center, University of Arizona, Tucson, AZ, USA.
⁷³ Department of Epidemiology & International Health Institute, Brown University School of Public Health, Providence, RI, USA.
⁷⁴ Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
⁷⁵ Genes and Human Disease, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
⁷⁶ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁷⁷ Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
⁷⁸ Division of Pulmonary and Critical Care, Brigham and Women's Hospital, Boston, MA, USA.
⁷⁹ Division of Pulmonary Medicine, Boston Children's Hospital, Boston, MA, USA.
⁸⁰ Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
⁸¹ Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
⁸² Departments of Medicine and Immunology, University of Colorado, Boulder, CO, USA.
⁸³ Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
⁸⁴ Departments of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
⁸⁵ Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
⁸⁶ Department of Biostatistics, University of Alabama Birmingham, Birmingham, AL, USA.
⁸⁷ Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
⁸⁸ Division of Pulmonary Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
⁸⁹ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁹⁰ Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD, USA.
⁹¹ Department of Molecular Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA, USA.
⁹² University Professor Johns Hopkins University, Baltimore, MD, USA.
⁹³ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. rmathias@jhmi.edu.
⁹⁴ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA. ajbattle@jhu.edu.
⁹⁵ Department of Computer Science, Johns Hopkins University, Baltimore, MD, USA. ajbattle@jhu.edu.
⁹⁶ Department of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA. ajbattle@jhu.edu.
⁹⁷ Malone Center for Engineering in Healthcare, Johns Hopkins University, Baltimore, MD, USA. ajbattle@jhu.edu.
⁹⁸ Data Science and AI Institute, Johns Hopkins University, Baltimore, MD, USA. ajbattle@jhu.edu.

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.

Publication types

Meta-Analysis

MeSH terms

CRISPR-Cas Systems
Gene Expression Regulation
Genome-Wide Association Study*
Humans
K562 Cells
Polymorphism, Single Nucleotide
Telomere Homeostasis* / genetics
Telomere* / genetics
Telomere* / metabolism

Abstract

Publication types

MeSH terms

Grants and funding