Validation of Human Telomere Length Multi-ancestry Meta-analysis Association Signals Identifies POP5 and KBTBD6 As Human Telomere Length Regulation Genes

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.

Citing Articles

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

Keener R, Chhetri S, Connelly C, Taub M, Conomos M, Weinstock J Nat Commun. 2024; 15(1):4417.

PMID: 38789417 PMC: 11126610. DOI: 10.1038/s41467-024-48394-y.

References

. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012; 489(7414):57-74. PMC: 3439153. DOI: 10.1038/nature11247. View

Keener R, Chhetri S, Connelly C, Taub M, Conomos M, Weinstock J . Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes. Nat Commun. 2024; 15(1):4417. PMC: 11126610. DOI: 10.1038/s41467-024-48394-y. View

Li C, Stoma S, Lotta L, Warner S, Albrecht E, Allione A . Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length. Am J Hum Genet. 2020; 106(3):389-404. PMC: 7058826. DOI: 10.1016/j.ajhg.2020.02.006. View

Arvanitis M, Tayeb K, Strober B, Battle A . Redefining tissue specificity of genetic regulation of gene expression in the presence of allelic heterogeneity. Am J Hum Genet. 2022; 109(2):223-239. PMC: 8874223. DOI: 10.1016/j.ajhg.2022.01.002. View

Hukku A, Sampson M, Luca F, Pique-Regi R, Wen X . Analyzing and reconciling colocalization and transcriptome-wide association studies from the perspective of inferential reproducibility. Am J Hum Genet. 2022; 109(5):825-837. PMC: 9118134. DOI: 10.1016/j.ajhg.2022.04.005. View

Pike A, Strong M, Ouyang J, Greider C . TIN2 Functions with TPP1/POT1 To Stimulate Telomerase Processivity. Mol Cell Biol. 2019; 39(21). PMC: 6791651. DOI: 10.1128/MCB.00593-18. View

Huang F, Hodis E, Xu M, Kryukov G, Chin L, Garraway L . Highly recurrent TERT promoter mutations in human melanoma. Science. 2013; 339(6122):957-9. PMC: 4423787. DOI: 10.1126/science.1229259. View

Schmiedel B, Singh D, Madrigal A, Valdovino-Gonzalez A, White B, Zapardiel-Gonzalo J . Impact of Genetic Polymorphisms on Human Immune Cell Gene Expression. Cell. 2018; 175(6):1701-1715.e16. PMC: 6289654. DOI: 10.1016/j.cell.2018.10.022. View

Gupta A, Sharma S, Reichenbach P, Marjavaara L, Nilsson A, Lingner J . Telomere length homeostasis responds to changes in intracellular dNTP pools. Genetics. 2013; 193(4):1095-105. PMC: 3606089. DOI: 10.1534/genetics.112.149120. View

10.

Gusev A, Ko A, Shi H, Bhatia G, Chung W, Penninx B . Integrative approaches for large-scale transcriptome-wide association studies. Nat Genet. 2016; 48(3):245-52. PMC: 4767558. DOI: 10.1038/ng.3506. View

11.

Stanley S, Gable D, Wagner C, Carlile T, Hanumanthu V, Podlevsky J . Loss-of-function mutations in the RNA biogenesis factor NAF1 predispose to pulmonary fibrosis-emphysema. Sci Transl Med. 2016; 8(351):351ra107. PMC: 5351811. DOI: 10.1126/scitranslmed.aaf7837. View

12.

Thomas P, Ebert D, Muruganujan A, Mushayahama T, Albou L, Mi H . PANTHER: Making genome-scale phylogenetics accessible to all. Protein Sci. 2021; 31(1):8-22. PMC: 8740835. DOI: 10.1002/pro.4218. View

13.

Codd V, Mangino M, van der Harst P, Braund P, Kaiser M, Beveridge A . Common variants near TERC are associated with mean telomere length. Nat Genet. 2010; 42(3):197-9. PMC: 3773906. DOI: 10.1038/ng.532. View

14.

Viikari J, Akerblom H, Nikkari T, Rasanen L, Vuori I, Pyorala K . Multicenter study of atherosclerosis precursors in Finnish children--pilot study of 8-year-old boys. Ann Clin Res. 1982; 14(2):103-10. View

15.

Levy D, Neuhausen S, Hunt S, Kimura M, Hwang S, Chen W . Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology. Proc Natl Acad Sci U S A. 2010; 107(20):9293-8. PMC: 2889047. DOI: 10.1073/pnas.0911494107. View

16.

Taub M, Conomos M, Keener R, Iyer K, Weinstock J, Yanek L . Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed. Cell Genom. 2022; 2(1). PMC: 9075703. DOI: 10.1016/j.xgen.2021.100084. View

17.

van Steensel B, de Lange T . Control of telomere length by the human telomeric protein TRF1. Nature. 1997; 385(6618):740-3. DOI: 10.1038/385740a0. View

18.

van Eenennaam H, Lugtenberg D, Vogelzangs J, van Venrooij W, Pruijn G . hPop5, a protein subunit of the human RNase MRP and RNase P endoribonucleases. J Biol Chem. 2001; 276(34):31635-41. DOI: 10.1074/jbc.M103399200. View

19.

Askree S, Yehuda T, Smolikov S, Gurevich R, Hawk J, Coker C . A genome-wide screen for Saccharomyces cerevisiae deletion mutants that affect telomere length. Proc Natl Acad Sci U S A. 2004; 101(23):8658-63. PMC: 423251. DOI: 10.1073/pnas.0401263101. View

20.

Liu Y, Cao L, Li Z, Zhou D, Liu W, Shen Q . A genome-wide association study identifies a locus on TERT for mean telomere length in Han Chinese. PLoS One. 2014; 9(1):e85043. PMC: 3897378. DOI: 10.1371/journal.pone.0085043. View