Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes
Creators: name: Gelb, Bruce D.
name: Minster, Ryan L.
name: Martinez, Fernando D.
name: Darbar, Dawood
name: Peralta, Juan M.
name: Konkle, Barbara A.
name: Carson, April P.
name: Bis, Joshua C.
name: Boerwinkle, Eric
name: Loos, Ruth J. F.
name: Arvanitis, Marios
name: Schwartz, David
name: Kelly, Shannon
name: Sinner, Moritz F.
name: Irvin, Marguerite R.
name: Blackwell, Thomas W.
name: Kumar, Rajesh
name: Zhang, Yingze
name: Kardia, Sharon L. R.
name: Isasi, Carmen R.
name: Chen, Zhanghua
name: McGarvey, Stephen T.
name: Kaab, Stefan
name: Mathias, Rasika A.
name: Smith, Nicholas L.
name: Meyers, Deborah A.
name: Battle, Alexis
name: de Andrade, Mariza
name: Kenny, Eimear E.
name: Chang, Yi-Cheng
name: Gladwin, Mark T.
name: Blangero, John
name: Smith, Albert V.
name: Wu, Baojun
name: Taylor, Kent D.
name: Raffield, Laura M.
name: Raby, Benjamin A.
name: Celedon, Juan C.
name: Mitchell, Braxton D.
name: Arnett, Donna K.
name: Ellinor, Patrick T.
name: Barnes, Kathleen C.
name: Sciurba, Frank
name: Peyser, Patricia A.
name: Ziv, Elad
name: Brody, Jennifer A.
name: Yanek, Lisa R.
name: Ashley-Koch, Allison E.
name: Taub, Margaret A.
name: Pankratz, Nathan
name: Williams, L. Keoki
name: Redline, Susan
name: Rotter, Jerome I.
name: Telen, Marilyn J.
name: Gilliland, Frank D.
name: Heckbert, Susan R.
name: North, Kari E.
name: Islam, Talat
name: Greider, Carol W.
name: Kooperberg, Charles
name: Chen, Yii-Der Ida
name: Albert, Christine
name: Burchard, Esteban G.
name: Vasan, Ramachandran S.
name: He, Jiang
name: Weinstock, Joshua
name: Roden, Dan
name: Cupples, L. Adrienne
name: Chhetri, Surya B.
name: Ni, Bohan
name: Hou, Lifang
name: Tiwari, Hemant K.
name: Palmer, Nicholette D.
name: Rich, Stephen S.
name: Barwick, Lucas
name: Bleecker, Eugene R.
name: Nekhai, Sergei
name: Reiner, Alexander P.
name: Johnsen, Jill M.
name: Aslibekyan, Stella
name: Montgomery, Courtney G.
name: Fornage, Myriam
name: Custer, Brian
name: Viali, Satupa’itea
name: Shoemaker, M. Benjamin
name: Connelly, Carla J.
name: Strober, Benjamin
name: Becker, Lewis C.
name: Yang, Ivana V.
name: Cade, Brian E.
name: Naseri, Take
name: Keener, Rebecca
name: Freedman, Barry I.
name: Silverman, Edwin K.
name: Conomos, Matthew P.
name: Auer, Paul L.
name: Weiss, Scott T.
name: Ruczinski, Ingo
Publisher: name: Springer Nature
Year: 2024

description: 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.