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

Publication ,  Journal Article
Keener, R; Chhetri, SB; Connelly, CJ; Taub, MA; Conomos, MP; Weinstock, J; Ni, B; Strober, B; Aslibekyan, S; Auer, PL; Barwick, L; Becker, LC ...
Published in: Nat Commun
May 24, 2024

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.

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Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

May 24, 2024

Volume

15

Issue

1

Start / End Page

4417

Location

England

Related Subject Headings

  • Telomere Homeostasis
  • Telomere
  • Polymorphism, Single Nucleotide
  • K562 Cells
  • Humans
  • Genome-Wide Association Study
  • Gene Expression Regulation
  • CRISPR-Cas Systems
 

Citation

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Chicago
ICMJE
MLA
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Keener, R., Chhetri, S. B., Connelly, C. J., Taub, M. A., Conomos, M. P., Weinstock, J., … Battle, A. (2024). Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes. Nat Commun, 15(1), 4417. https://doi.org/10.1038/s41467-024-48394-y
Keener, Rebecca, Surya B. Chhetri, Carla J. Connelly, Margaret A. Taub, Matthew P. Conomos, Joshua Weinstock, Bohan Ni, et al. “Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes.Nat Commun 15, no. 1 (May 24, 2024): 4417. https://doi.org/10.1038/s41467-024-48394-y.
Keener R, Chhetri SB, Connelly CJ, Taub MA, Conomos MP, Weinstock J, et al. Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes. Nat Commun. 2024 May 24;15(1):4417.
Keener, Rebecca, et al. “Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes.Nat Commun, vol. 15, no. 1, May 2024, p. 4417. Pubmed, doi:10.1038/s41467-024-48394-y.
Keener R, Chhetri SB, Connelly CJ, Taub MA, Conomos MP, Weinstock J, Ni B, Strober B, Aslibekyan S, Auer PL, Barwick L, Becker LC, Blangero J, Bleecker ER, Brody JA, Cade BE, Celedon JC, Chang Y-C, Cupples LA, Custer B, Freedman BI, Gladwin MT, Heckbert SR, Hou L, Irvin MR, Isasi CR, Johnsen JM, Kenny EE, Kooperberg C, Minster RL, Naseri T, Viali S, Nekhai S, Pankratz N, Peyser PA, Taylor KD, Telen MJ, Wu B, Yanek LR, Yang IV, Albert C, Arnett DK, Ashley-Koch AE, Barnes KC, Bis JC, Blackwell TW, Boerwinkle E, Burchard EG, Carson AP, Chen Z, Chen Y-DI, Darbar D, de Andrade M, Ellinor PT, Fornage M, Gelb BD, Gilliland FD, He J, Islam T, Kaab S, Kardia SLR, Kelly S, Konkle BA, Kumar R, Loos RJF, Martinez FD, McGarvey ST, Meyers DA, Mitchell BD, Montgomery CG, North KE, Palmer ND, Peralta JM, Raby BA, Redline S, Rich SS, Roden D, Rotter JI, Ruczinski I, Schwartz D, Sciurba F, Shoemaker MB, Silverman EK, Sinner MF, Smith NL, Smith AV, Tiwari HK, Vasan RS, Weiss ST, Williams LK, Zhang Y, Ziv E, Raffield LM, Reiner AP, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Hematology and Hemostasis Working Group, TOPMed Structural Variation Working Group, Arvanitis M, Greider CW, Mathias RA, Battle A. Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes. Nat Commun. 2024 May 24;15(1):4417.

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

May 24, 2024

Volume

15

Issue

1

Start / End Page

4417

Location

England

Related Subject Headings

  • Telomere Homeostasis
  • Telomere
  • Polymorphism, Single Nucleotide
  • K562 Cells
  • Humans
  • Genome-Wide Association Study
  • Gene Expression Regulation
  • CRISPR-Cas Systems