Validation of human telomere length trans-ancestry meta-analysis association signals identifiesPOP5andKBTBD6as novel human telomere length regulation genes
Author:
Keener RebeccaORCID, Chhetri Surya, 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 JohnORCID, Bleecker Eugene R., Brody Jennifer A.ORCID, Cade Brian E.ORCID, Celedon Juan C., Chang Yi-Cheng, Cupples L. Adrienne, Custer BrianORCID, 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., Nekhai Sergei, Pankratz Nathan, Peyser Patricia A., Taylor Kent D., Telen Marilyn J., Wu Baojun, Yanek Lisa R.ORCID, 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.ORCID, Fornage MyriamORCID, Gelb Bruce D., Gilliland Frank D., He JiangORCID, Islam TalatORCID, 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.ORCID, Montgomery Courtney G., North Kari E., Palmer Nicholette D., Peralta Juan M., Raby Benjamin A., Redline Susan, Rich Stephen S., Roden DanielORCID, Rotter Jerome I., Ruczinski Ingo, Schwartz David, Sciurba Rank, Shoemaker M. Benjamin, Silverman Edwin K., Sinner Moritz F., Smith Nicholas L., Smith Albert V.ORCID, Tiwari Hemant K., Vasan Ramachandran S., Weiss Scott T.ORCID, Williams L. Keoki, Zhang Yingze, Ziv Elad, Raffield Laura M.ORCID, Reiner Alexander P., Arvanitis Marios, Greider Carol W., Mathias Rasika A., Battle Alexis, , ,
Abstract
AbstractTelomere length genome-wide association studies (GWAS) have become well-powered to detect novel genes in telomere length regulation. However, no prior work has validated these putative novel genes to confirm the contribution of GWAS loci to telomere length regulation. We conducted a trans-ancestry meta-analysis of 211,369 individuals. Through enrichment analyses of chromatin state and cell-type heritability we identified blood and immune cells as the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressingKBTBD6, a component of an E3 ubiquitin ligase complex, andPOP5, a component of the Ribonuclease P/MRP complex, and demonstrating that both lengthened telomeres as predicted by our statistical analyses. CRISPR/Cas9 deletion of the predicted causal regions of these association peaks in K562 immortalized blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation ofKBTBD6andPOP5, respectively. Together our results demonstrate the utility of telomere length GWAS in the identification of novel telomere length regulation mechanisms and highlight the importance of the proteasome-ubiquitin pathway in telomere length regulation.
Publisher
Cold Spring Harbor Laboratory
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