1. Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes
- Author
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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, and Alexis Battle
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Science - 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.
- Published
- 2024
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