Validation of human telomere length trans-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as novel human telomere length regulation genes

Telomere 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 overexpressing KBTBD6, a component of an E3 ubiquitin ligase complex, and POP5, 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 of KBTBD6 and POP5, 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. ### Competing Interest Statement The authors declare the following competing interests: Juan C. Celedon received inhaled steroids from Merck for an NIH_funded study, unrelated to this work. Ivana V. Yang is a consultant for Eleven P15, a company focused on the early diagnosis and treatment of lung fibrosis. Dr. Patrick T. Ellinor receives sponsored research support from Bayer AG, IBM Research, Bristol Myers Squibb and Pfizer; he has also served on advisory boards or consulted for Bayer AG, MyoKardia and Novartis. Dr. David Schwartz is a founder and chief scientific officer of Eleven P15, a company focused on the early diagnosis and treatment of lung fibrosis. Laura M. Raffield is a consultant for the TOPMed Admistrative Coordinating Center (through Westat). Alexis Battle is a shareholder in Alphabet, Inc.; consultant for Third Rock Ventures, LLC. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services.