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.

Here the authors conduct a multi-ancestry meta-analysis of telomere length, used diverse approaches to identify genes underlying association signals, and experimentally validated POP5 and KBTBD6 as regulators of telomere length in human cells.

Details

Title
Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes
Author
Keener, Rebecca 1   VIAFID ORCID Logo  ; Chhetri, Surya B. 1 ; Connelly, Carla J. 2 ; Taub, Margaret A. 3 ; Conomos, Matthew P. 4   VIAFID ORCID Logo  ; Weinstock, Joshua 1   VIAFID ORCID Logo  ; Ni, Bohan 5 ; Strober, Benjamin 6   VIAFID ORCID Logo  ; Aslibekyan, Stella 7 ; Auer, Paul L. 8   VIAFID ORCID Logo  ; Barwick, Lucas 9 ; Becker, Lewis C. 10 ; Blangero, John 11   VIAFID ORCID Logo  ; Bleecker, Eugene R. 12 ; Brody, Jennifer A. 13   VIAFID ORCID Logo  ; Cade, Brian E. 14   VIAFID ORCID Logo  ; Celedon, Juan C. 15   VIAFID ORCID Logo  ; Chang, Yi-Cheng 16 ; Cupples, L. Adrienne 17   VIAFID ORCID Logo  ; Custer, Brian 18   VIAFID ORCID Logo  ; Freedman, Barry I. 19   VIAFID ORCID Logo  ; Gladwin, Mark T. 20   VIAFID ORCID Logo  ; Heckbert, Susan R. 21   VIAFID ORCID Logo  ; Hou, Lifang 22 ; Irvin, Marguerite R. 23 ; Isasi, Carmen R. 24 ; Johnsen, Jill M. 25   VIAFID ORCID Logo  ; Kenny, Eimear E. 26 ; Kooperberg, Charles 27   VIAFID ORCID Logo  ; Minster, Ryan L. 28   VIAFID ORCID Logo  ; Naseri, Take 29 ; Viali, Satupa’itea 30 ; Nekhai, Sergei 31   VIAFID ORCID Logo  ; Pankratz, Nathan 32   VIAFID ORCID Logo  ; Peyser, Patricia A. 33   VIAFID ORCID Logo  ; Taylor, Kent D. 34 ; Telen, Marilyn J. 35   VIAFID ORCID Logo  ; Wu, Baojun 36 ; Yanek, Lisa R. 37   VIAFID ORCID Logo  ; Yang, Ivana V. 38 ; Albert, Christine 39 ; Arnett, Donna K. 40 ; Ashley-Koch, Allison E. 35   VIAFID ORCID Logo  ; Barnes, Kathleen C. 41 ; Bis, Joshua C. 13   VIAFID ORCID Logo  ; Blackwell, Thomas W. 42 ; Boerwinkle, Eric 43 ; Burchard, Esteban G. 44   VIAFID ORCID Logo  ; Carson, April P. 45   VIAFID ORCID Logo  ; Chen, Zhanghua 46 ; Chen, Yii-Der Ida 34   VIAFID ORCID Logo  ; Darbar, Dawood 47   VIAFID ORCID Logo  ; de Andrade, Mariza 48 ; Ellinor, Patrick T. 49   VIAFID ORCID Logo  ; Fornage, Myriam 50   VIAFID ORCID Logo  ; Gelb, Bruce D. 51   VIAFID ORCID Logo  ; Gilliland, Frank D. 46   VIAFID ORCID Logo  ; He, Jiang 52 ; Islam, Talat 46 ; Kaab, Stefan 53   VIAFID ORCID Logo  ; Kardia, Sharon L. R. 54 ; Kelly, Shannon 55 ; Konkle, Barbara A. 56 ; Kumar, Rajesh 57 ; Loos, Ruth J. F. 58   VIAFID ORCID Logo  ; Martinez, Fernando D. 59 ; McGarvey, Stephen T. 60   VIAFID ORCID Logo  ; Meyers, Deborah A. 12 ; Mitchell, Braxton D. 61   VIAFID ORCID Logo  ; Montgomery, Courtney G. 62   VIAFID ORCID Logo  ; North, Kari E. 63   VIAFID ORCID Logo  ; Palmer, Nicholette D. 64   VIAFID ORCID Logo  ; Peralta, Juan M. 11   VIAFID ORCID Logo  ; Raby, Benjamin A. 65 ; Redline, Susan 14   VIAFID ORCID Logo  ; Rich, Stephen S. 66   VIAFID ORCID Logo  ; Roden, Dan 67   VIAFID ORCID Logo  ; Rotter, Jerome I. 34   VIAFID ORCID Logo  ; Ruczinski, Ingo 3 ; Schwartz, David 68 ; Sciurba, Frank 69 ; Shoemaker, M. Benjamin 70 ; Silverman, Edwin K. 71 ; Sinner, Moritz F. 53   VIAFID ORCID Logo  ; Smith, Nicholas L. 52   VIAFID ORCID Logo  ; Smith, Albert V. 72   VIAFID ORCID Logo  ; Tiwari, Hemant K. 73 ; Vasan, Ramachandran S. 74   VIAFID ORCID Logo  ; Weiss, Scott T. 75   VIAFID ORCID Logo  ; Williams, L. Keoki 36 ; Zhang, Yingze 76   VIAFID ORCID Logo  ; Ziv, Elad 77   VIAFID ORCID Logo  ; Raffield, Laura M. 78   VIAFID ORCID Logo  ; Reiner, Alexander P. 27   VIAFID ORCID Logo  ; Arvanitis, Marios 79 ; Greider, Carol W. 80   VIAFID ORCID Logo  ; Mathias, Rasika A. 37   VIAFID ORCID Logo  ; Battle, Alexis 81   VIAFID ORCID Logo 

 Johns Hopkins University, Department of Biomedical Engineering, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
 Johns Hopkins University, Department of Molecular Biology and Genetics, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
 Johns Hopkins Bloomberg School of Public Health, Department of Biostatistics, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
 University of Washington, Department of Biostatistics, School of Public Health, Seattle, USA (GRID:grid.34477.33) (ISNI:0000 0001 2298 6657) 
 Johns Hopkins University, Department of Computer Science, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
 Harvard School of Public Health, Department of Epidemiology, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
 University of Alabama at Birmingham, Birmingham, USA (GRID:grid.265892.2) (ISNI:0000 0001 0634 4187) 
 Medical College of Wisconsin, Division of Biostatistics, Institute for Health & Equity, and Cancer Center, Milwaukee, USA (GRID:grid.30760.32) (ISNI:0000 0001 2111 8460) 
 LLC, LTRC Data Coordinating Center, The Emmes Company, Rockville, USA (GRID:grid.280434.9) (ISNI:0000 0004 0459 5494) 
10  Johns Hopkins School of Medicine, GeneSTAR Research Program, Department of Medicine, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
11  University of Texas Rio Grande Valley School of Medicine, Department of Human Genetics and South Texas Diabetes and Obesity Institute, Brownsville, USA (GRID:grid.449717.8) (ISNI:0000 0004 5374 269X) 
12  University of Arizona, Department of Medicine, Division of Genetics, Genomics and Precision Medicine, Tucson, USA (GRID:grid.134563.6) (ISNI:0000 0001 2168 186X); University of Arizona, Division of Pharmacogenomics, Tucson, USA (GRID:grid.134563.6) (ISNI:0000 0001 2168 186X) 
13  University of Washington, Cardiovascular Health Research Unit, Department of Medicine, Seattle, USA (GRID:grid.34477.33) (ISNI:0000 0001 2298 6657) 
14  Brigham and Women’s Hospital, Channing Division of Network Medicine, Department of Medicine, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294); Harvard Medical School, Division of Sleep Medicine, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
15  University of Pittsburgh, Division of Pediatric Pulmonary Medicine, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000) 
16  National Taiwan University, Department of Internal Medicine, Taipei, Taiwan (GRID:grid.19188.39) (ISNI:0000 0004 0546 0241); National Taiwan University, Graduate Institute of Medical Genomics and Proteomics, Taipei, Taiwan (GRID:grid.19188.39) (ISNI:0000 0004 0546 0241); Academia Sinica, Institute of Biomedical Sciences, Taipei, Taiwan (GRID:grid.28665.3f) (ISNI:0000 0001 2287 1366) 
17  Boston University School of Public Health, Department of Biostatistics, Boston, USA (GRID:grid.189504.1) (ISNI:0000 0004 1936 7558); Boston University’s Framingham Heart Study, The National Heart, Lung, and Blood Institute, Framingham, USA (GRID:grid.510954.c) (ISNI:0000 0004 0444 3861) 
18  Vitalant Research Institute, San Francisco, USA (GRID:grid.418404.d) (ISNI:0000 0004 0395 5996); University of California San Francisco, Department of Laboratory Medicine, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
19  Wake Forest University School of Medicine, Internal Medicine - Nephrology, Winston-Salem, USA (GRID:grid.241167.7) (ISNI:0000 0001 2185 3318) 
20  University of Maryland, School of Medicine, Baltimore, USA (GRID:grid.411024.2) (ISNI:0000 0001 2175 4264) 
21  University of Washington, Department of Epidemiology, Seattle, USA (GRID:grid.34477.33) (ISNI:0000 0001 2298 6657) 
22  Northwestern University, Department of Preventive Medicine, Feinberg School of Medicine, Evanston, USA (GRID:grid.16753.36) (ISNI:0000 0001 2299 3507) 
23  University of Alabama Birmingham, Department of Epidemiology, Birmingham, USA (GRID:grid.265892.2) (ISNI:0000 0001 0634 4187) 
24  Albert Einstein College of Medicine, Department of Epidemiology and Population Health, Bronx, USA (GRID:grid.251993.5) (ISNI:0000 0001 2179 1997) 
25  University of Washington, Department of Medicine and Institute for Stem Cell & Regenerative Medicine, Seattle, USA (GRID:grid.34477.33) (ISNI:0000000122986657) 
26  Icahn School of Medicine at Mount Sinai, The Charles Bronfman Institute for Personalized Medicine, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351); Icahn School of Medicine at Mount Sinai, Center for Genomic Health, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
27  Fred Hutchinson Cancer Center, Division of Public Health Sciences, Seattle, USA (GRID:grid.270240.3) (ISNI:0000 0001 2180 1622) 
28  University of Pittsburgh Graduate School of Public Health, Department of Human Genetics, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000) 
29  Naseri & Associates Public Health Consultancy Firm and Family Health Clinic, Apia, Samoa (GRID:grid.21925.3d); Brown University, International Health Institute, School of Public Health, Providence, USA (GRID:grid.40263.33) (ISNI:0000 0004 1936 9094) 
30  Oceania University of Medicine, Apia, Samoa (GRID:grid.40263.33); National University of Samoa, School of Medicine, Apia, Samoa (GRID:grid.449380.2) (ISNI:0000 0001 0823 7860); Yale University School of Public Health, Department of Chronic Disease Epidemiology, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710) 
31  Howard University, Center for Sickle Cell Disease and Department of Medicine, College of Medicine, Washington DC, USA (GRID:grid.257127.4) (ISNI:0000 0001 0547 4545) 
32  University of Minnesota, Department of Laboratory Medicine and Pathology, Minneapolis, USA (GRID:grid.17635.36) (ISNI:0000 0004 1936 8657) 
33  University of Michigan, Department of Epidemiology, School of Public Health, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000 0004 1936 7347) 
34  The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Torrance, USA (GRID:grid.279946.7) (ISNI:0000 0004 0521 0744) 
35  Duke University Medical Center, Department of Medicine, Durham, USA (GRID:grid.189509.c) (ISNI:0000 0001 0024 1216) 
36  Henry Ford Health System, Center for Individualized and Genomic Medicine Research (CIGMA), Department of Internal Medicine, Detroit, USA (GRID:grid.239864.2) (ISNI:0000 0000 8523 7701) 
37  Johns Hopkins University School of Medicine, Department of Medicine, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
38  University of Colorado, Departments of Biomedical Informatics, Medicine, and Epidemiology, Boulder, USA (GRID:grid.266190.a) (ISNI:0000 0000 9621 4564) 
39  Harvard Medical School, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Brigham and Women’s Hospital, Division of Cardiovascular, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294) 
40  University of South Carolina, Department of Epidemiology and Biostatistics, Columbia, USA (GRID:grid.254567.7) (ISNI:0000 0000 9075 106X) 
41  Anschutz Medical Campus, Department of Medicine, University of Colorado Denver, Aurora, USA (GRID:grid.430503.1) (ISNI:0000 0001 0703 675X) 
42  University of Michigan School of Public Health, Department of Biostatistics, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000 0004 1936 7347); University of Michigan School of Public Health, Center for Statistical Genetics, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000 0004 1936 7347) 
43  University of Texas Health Science Center at Houston, Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, Houston, USA (GRID:grid.267308.8) (ISNI:0000 0000 9206 2401) 
44  University of California San Francisco, Department of Medicine, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California San Francisco, Department of Bioengineering and Therapeutic Sciences, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
45  University of Mississippi Medical Center, Department of Medicine, Jackson, USA (GRID:grid.410721.1) (ISNI:0000 0004 1937 0407) 
46  University of Southern California, Department of Population and Public Health Sciences, Los Angeles, USA (GRID:grid.42505.36) (ISNI:0000 0001 2156 6853) 
47  University of Illinois at Chicago, Division of Cardiology, Chicago, USA (GRID:grid.185648.6) (ISNI:0000 0001 2175 0319) 
48  Mayo Clinic, Division of Biomedical Statistics and Informatics, Rochester, USA (GRID:grid.66875.3a) (ISNI:0000 0004 0459 167X) 
49  The Broad Institute of MIT and Harvard, Cardiovascular Disease Initiative, Cambridge, USA (GRID:grid.66859.34) (ISNI:0000 0004 0546 1623) 
50  the University of Texas Health Science Center at Houston, Institute of Molecular Medicine, McGovern Medical School, Houston, USA (GRID:grid.267308.8) (ISNI:0000 0000 9206 2401) 
51  Icahn School of Medicine, Mindich Child Health and Development Institute and Departments of Pediatrics and Genetics and Genomic Sciences, New York, USA (GRID:grid.511829.6) 
52  Tulane University School of Medicine, Department of Medicine, New Orleans, USA (GRID:grid.265219.b) (ISNI:0000 0001 2217 8588) 
53  LMU Munich, Department of Cardiology, University Hospital, Munich, Germany (GRID:grid.5252.0) (ISNI:0000 0004 1936 973X) 
54  University of Michigan School of Public Health, Department of Epidemiology, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000 0004 1936 7347) 
55  Vitalant Research Institute, San Francisco, USA (GRID:grid.418404.d) (ISNI:0000 0004 0395 5996); University of California San Francisco Benioff Children’s Hospital, Oakland, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
56  University of Washington, Department of Medicine, Seattle, USA (GRID:grid.34477.33) (ISNI:0000 0001 2298 6657) 
57  Northwestern University Feinberg School of Medicine, Chicago, USA (GRID:grid.16753.36) (ISNI:0000 0001 2299 3507); The Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, USA (GRID:grid.413808.6) (ISNI:0000 0004 0388 2248) 
58  Icahn School of Medicine at Mount Sinai, The Charles Bronfman Institute for Personalized Medicine, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
59  University of Arizona, Asthma & Airway Disease Research Center, Tucson, USA (GRID:grid.134563.6) (ISNI:0000 0001 2168 186X) 
60  Brown University School of Public Health, Department of Epidemiology & International Health Institute, Providence, USA (GRID:grid.40263.33) (ISNI:0000 0004 1936 9094) 
61  University of Maryland School of Medicine, Department of Medicine, Baltimore, USA (GRID:grid.411024.2) (ISNI:0000 0001 2175 4264) 
62  Oklahoma Medical Research Foundation, Genes and Human Disease, Oklahoma City, USA (GRID:grid.274264.1) (ISNI:0000 0000 8527 6890) 
63  University of North Carolina at Chapel Hill, Department of Epidemiology, Chapel Hill, USA (GRID:grid.10698.36) (ISNI:0000 0001 2248 3208) 
64  Wake Forest University School of Medicine, Department of Biochemistry, Winston-Salem, USA (GRID:grid.241167.7) (ISNI:0000 0001 2185 3318) 
65  Brigham and Women’s Hospital, Division of Pulmonary and Critical Care, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294); Boston Children’s Hospital, Division of Pulmonary Medicine, Boston, USA (GRID:grid.2515.3) (ISNI:0000 0004 0378 8438) 
66  University of Virginia, Center for Public Health Genomics, Department of Public Health Sciences, Charlottesville, USA (GRID:grid.27755.32) (ISNI:0000 0000 9136 933X) 
67  Vanderbilt University School of Medicine, Department of Medicine, Nashville, USA (GRID:grid.152326.1) (ISNI:0000 0001 2264 7217) 
68  University of Colorado, Departments of Medicine and Immunology, Boulder, USA (GRID:grid.266190.a) (ISNI:0000 0000 9621 4564) 
69  University of Pittsburgh, Division of Pulmonary, Allergy and Critical Care Medicine, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000) 
70  Vanderbilt University Medical Center, Departments of Medicine, Pharmacology, and Biomedical Informatics, Nashville, USA (GRID:grid.412807.8) (ISNI:0000 0004 1936 9916) 
71  Brigham and Women’s Hospital, Channing Division of Network Medicine, Department of Medicine, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294) 
72  University of Michigan, Department of Biostatistics, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000 0004 1936 7347) 
73  University of Alabama Birmingham, Department of Biostatistics, Birmingham, USA (GRID:grid.265892.2) (ISNI:0000 0001 0634 4187) 
74  Boston University School of Medicine, Department of Medicine, Boston, USA (GRID:grid.189504.1) (ISNI:0000 0004 1936 7558) 
75  Brigham and Women’s Hospital, Channing Division of Network Medicine, Department of Medicine, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294); Harvard Medical School, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
76  University of Pittsburgh, Division of Pulmonary Allergy and Critical Care Medicine, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000) 
77  University of California San Francisco, Department of Medicine, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
78  University of North Carolina at Chapel Hill, Department of Genetics, Chapel Hill, USA (GRID:grid.10698.36) (ISNI:0000 0001 2248 3208) 
79  Johns Hopkins University, Department of Medicine, Division of Cardiology, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
80  University of California Santa Cruz, Department of Molecular Cell and Developmental Biology, Santa Cruz, USA (GRID:grid.205975.c) (ISNI:0000 0001 0740 6917); University Professor Johns Hopkins University, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
81  Johns Hopkins University, Department of Biomedical Engineering, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311); Johns Hopkins University, Department of Computer Science, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311); Johns Hopkins University, Department of Genetic Medicine, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311); Johns Hopkins University, Malone Center for Engineering in Healthcare, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311); Johns Hopkins University, Data Science and AI Institute, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
Pages
4417
Publication year
2024
Publication date
2024
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3059661459
Copyright
© The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.