Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes.
Journal
Nature communications
Series/Report No.
Nature Communications
Journal Volume
15
Journal Issue
1
ISSN
2041-1723
Date Issued
2024-05-24
Author(s)
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
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
Chen, Yii-Der Ida
Darbar, Dawood
de 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
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.
SDGs
Publisher
Springer Science and Business Media LLC
Type
journal article