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

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

doi:10.1038/s41467-024-48394-y

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

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English (US)
Article number	4417
Journal	Nature communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-48394-y
State	Published - Dec 2024

Funding

The authors thank Chen Li, Claudia Langenberg, Veryan Codd, Dayana Delgado, Brandon Pierce, and Rajkumar Dorajoo, in addition to all the individuals who were sampled, for providing summary statistics from their telomere length GWAS that were included in this meta-analysis. The whole-genome sequencing for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI). Specific funding sources for each study and genomic center are given in the Supplementary Acknowledgements. px458 was a gift from Andrew Holland\u2019s lab. We acknowledge the ENCODE Consortium and the following ENCODE production laboratories: Michael Snyder and J. Michael Cherry. We would also like to thank Margaret Strong, Emily DeBoy, the JHU Synthesis & Sequencing Facility, and the JHU Ross Flow Cytometry Core for their technical assistance, Andrew Holland and Emmanouil Tampakakis for helpful discussion about CRISPR/Cas9 editing experiments, and the Mathias, Greider, and Battle labs for helpful discussion throughout the course of this work. Rebecca Keener was supported in part by NIH/NIGMS grant 5K12GM123914. This work was carried out at the Advanced Research Computing at Hopkins (ARCH) core facility (rockfish.jhu.edu), which is supported by the National Science Foundation (NSF) grant number OAC1920103. Matthew P. Conomos was supported by R01HL-120393; contract HHSN268201800001I; U01 HL137162. Brian E. Cade was supported by R01HL153805. Barry I. Freedman was supported by R01 DK071891. Lifang Hou was supported by R01AG081244, R01AG069120. Marilyn J. Telen was supported by NHLBI (R01HL68959, R01HL87681 and R01HL079915) for the collection of the samples. Allison E. Ashley-Koch was supported by NHLBI (R01HL68959, R01HL87681 and R01HL079915) for the collection of the samples. Joshua C. Bis was supported by R01HL105756. Zhanghua Chen was supported by P30ES007048, 5P01ES011627, ES021801, ES023262, P01ES009581, P01ES011627, P01ES022845, R01 ES016535, R03ES014046, P50 CA180905, R01HL061768, R01HL076647, R01HL087680, RC2HL101651, RD83544101, R826708, RD831861, R831845, R00ES027870, and the Hastings Foundation. Dr. Patrick T. Ellinor was supported by grants from the National Institutes of Health (1RO1HL092577, 1R01HL157635, 5R01HL139731), from the American Heart Association Strategically Focused Research Networks (18SFRN34110082), and from the European Union (MAESTRIA 965286). Myriam Fornage was supported by U01AG052409, U01AG058589. Bruce D. Gelb was supported by U01HL153009. Frank D. Gilliland was supported by P30ES007048, 5P01ES011627, ES021801, ES023262, P01ES009581, P01ES011627, P01ES022845, R01 ES016535, R03ES014046, P50 CA180905, R01HL061768, R01HL076647, R01HL087680, RC2HL101651, RD83544101, R826708, RD831861, R831845, R00ES027870, and the Hastings Foundation. Talat Islam was supported by P30ES007048, 5P01ES011627, ES021801, ES023262, P01ES009581, P01ES011627, P01ES022845, R01 ES016535, R03ES014046, P50 CA180905, R01HL061768, R01HL076647, R01HL087680, RC2HL101651, RD83544101, R826708, RD831861, R831845, R00ES027870, and the Hastings Foundation. Rajesh Kumar was supported by UM1AI160040, U01AI160018-01, UG1HL139125, R01AI153239. Ruth J.F. Looks was supported by R01DK107786; R01HG010297. Nicholette D. Palmer was supported by R01 AG058921. Susan Redline was supported by R35HL135818. David Schwartz was supported by P01-HL162607, R01-HL158668, R01-HL149836, IO1BX005295, UG3/UH3-HL151865, and X01-HL134585. The Johns Hopkins Genetic Study of Atherosclerosis Risk (GeneSTAR) was supported by grants from the National Institutes of Health through the National Heart, Lung, and Blood Institute (U01HL72518, HL087698, HL112064) and by a grant from the National Center for Research Resources (M01-RR000052) to the Johns Hopkins General Clinical Research Center. Dr. Rasika Mathias receives support as the Sarah Miller Coulson Scholar in the Johns Hopkins Center for Innovative Medicine. Carol W. Greider was supported by NIH R35 CA209974. Alexis Battle was supported by NIH/NIGMS R35GM139580.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-024-48394-y

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Keener, R., Chhetri, S. B., Connelly, C. J., Taub, M. A., Conomos, M. P., Weinstock, J., Ni, B., Strober, B., Aslibekyan, S., Auer, P. L., Barwick, L., Becker, L. C., Blangero, J., Bleecker, E. R., Brody, J. A., Cade, B. E., Celedon, J. C., Chang, Y. C., Cupples, L. A., ... Battle, A. (2024). Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes. Nature communications, 15(1), Article 4417. https://doi.org/10.1038/s41467-024-48394-y

@article{0e4c3d8d609a42f58f8d53a0b887858f,

title = "Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes",

abstract = "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.",

author = "Rebecca Keener and Chhetri, {Surya B.} and Connelly, {Carla J.} and Taub, {Margaret A.} and Conomos, {Matthew P.} and Joshua Weinstock and Bohan Ni and Benjamin Strober and Stella Aslibekyan and Auer, {Paul L.} and Lucas Barwick and Becker, {Lewis C.} and John Blangero and Bleecker, {Eugene R.} and Brody, {Jennifer A.} and Cade, {Brian E.} and Celedon, {Juan C.} and Chang, {Yi Cheng} and Cupples, {L. Adrienne} and Brian Custer and Freedman, {Barry I.} and Gladwin, {Mark T.} and Heckbert, {Susan R.} and Lifang Hou and Irvin, {Marguerite R.} and Isasi, {Carmen R.} and Johnsen, {Jill M.} and Kenny, {Eimear E.} and Charles Kooperberg and Minster, {Ryan L.} and Take Naseri and Satupa{\textquoteright}itea Viali and Sergei Nekhai and Nathan Pankratz and Peyser, {Patricia A.} and Taylor, {Kent D.} and Telen, {Marilyn J.} and Baojun Wu and Yanek, {Lisa R.} and Yang, {Ivana V.} and Christine Albert and Arnett, {Donna K.} and Ashley-Koch, {Allison E.} and Barnes, {Kathleen C.} and Bis, {Joshua C.} and Blackwell, {Thomas W.} and Eric Boerwinkle and Burchard, {Esteban G.} and Carson, {April P.} and Zhanghua Chen and Chen, {Yii Der Ida} and Dawood Darbar and {de Andrade}, Mariza and Ellinor, {Patrick T.} and Myriam Fornage and Gelb, {Bruce D.} and Gilliland, {Frank D.} and Jiang He and Talat Islam and Stefan Kaab and Kardia, {Sharon L.R.} and Shannon Kelly and Konkle, {Barbara A.} and Rajesh Kumar and Loos, {Ruth J.F.} and Martinez, {Fernando D.} and McGarvey, {Stephen T.} and Meyers, {Deborah A.} and Mitchell, {Braxton D.} and Montgomery, {Courtney G.} and North, {Kari E.} and Palmer, {Nicholette D.} and Peralta, {Juan M.} and Raby, {Benjamin A.} and Susan Redline and Rich, {Stephen S.} and Dan Roden and Rotter, {Jerome I.} and Ingo Ruczinski and David Schwartz and Frank Sciurba and Shoemaker, {M. Benjamin} and Silverman, {Edwin K.} and Sinner, {Moritz F.} and Smith, {Nicholas L.} and Smith, {Albert V.} and Tiwari, {Hemant K.} and Vasan, {Ramachandran S.} and Weiss, {Scott T.} and Williams, {L. Keoki} and Yingze Zhang and Elad Ziv and Raffield, {Laura M.} and Reiner, {Alexander P.} and Marios Arvanitis and Greider, {Carol W.} and Mathias, {Rasika A.} and Alexis Battle",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

doi = "10.1038/s41467-024-48394-y",

language = "English (US)",

volume = "15",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

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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, YC, 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, YDI, 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, Arvanitis, M, Greider, CW, Mathias, RA & Battle, A 2024, 'Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes', Nature communications, vol. 15, no. 1, 4417. https://doi.org/10.1038/s41467-024-48394-y

TY - JOUR

T1 - Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes

AU - Keener, Rebecca

AU - Chhetri, Surya B.

AU - Connelly, Carla J.

AU - Taub, Margaret A.

AU - Conomos, Matthew P.

AU - Weinstock, Joshua

AU - Ni, Bohan

AU - Strober, Benjamin

AU - Aslibekyan, Stella

AU - Auer, Paul L.

AU - Barwick, Lucas

AU - Becker, Lewis C.

AU - Blangero, John

AU - Bleecker, Eugene R.

AU - Brody, Jennifer A.

AU - Cade, Brian E.

AU - Celedon, Juan C.

AU - Chang, Yi Cheng

AU - Cupples, L. Adrienne

AU - Custer, Brian

AU - Freedman, Barry I.

AU - Gladwin, Mark T.

AU - Heckbert, Susan R.

AU - Hou, Lifang

AU - Irvin, Marguerite R.

AU - Isasi, Carmen R.

AU - Johnsen, Jill M.

AU - Kenny, Eimear E.

AU - Kooperberg, Charles

AU - Minster, Ryan L.

AU - Naseri, Take

AU - Viali, Satupa’itea

AU - Nekhai, Sergei

AU - Pankratz, Nathan

AU - Peyser, Patricia A.

AU - Taylor, Kent D.

AU - Telen, Marilyn J.

AU - Wu, Baojun

AU - Yanek, Lisa R.

AU - Yang, Ivana V.

AU - Albert, Christine

AU - Arnett, Donna K.

AU - Ashley-Koch, Allison E.

AU - Barnes, Kathleen C.

AU - Bis, Joshua C.

AU - Blackwell, Thomas W.

AU - Boerwinkle, Eric

AU - Burchard, Esteban G.

AU - Carson, April P.

AU - Chen, Zhanghua

AU - Chen, Yii Der Ida

AU - Darbar, Dawood

AU - de Andrade, Mariza

AU - Ellinor, Patrick T.

AU - Fornage, Myriam

AU - Gelb, Bruce D.

AU - Gilliland, Frank D.

AU - He, Jiang

AU - Islam, Talat

AU - Kaab, Stefan

AU - Kardia, Sharon L.R.

AU - Kelly, Shannon

AU - Konkle, Barbara A.

AU - Kumar, Rajesh

AU - Loos, Ruth J.F.

AU - Martinez, Fernando D.

AU - McGarvey, Stephen T.

AU - Meyers, Deborah A.

AU - Mitchell, Braxton D.

AU - Montgomery, Courtney G.

AU - North, Kari E.

AU - Palmer, Nicholette D.

AU - Peralta, Juan M.

AU - Raby, Benjamin A.

AU - Redline, Susan

AU - Rich, Stephen S.

AU - Roden, Dan

AU - Rotter, Jerome I.

AU - Ruczinski, Ingo

AU - Schwartz, David

AU - Sciurba, Frank

AU - Shoemaker, M. Benjamin

AU - Silverman, Edwin K.

AU - Sinner, Moritz F.

AU - Smith, Nicholas L.

AU - Smith, Albert V.

AU - Tiwari, Hemant K.

AU - Vasan, Ramachandran S.

AU - Weiss, Scott T.

AU - Williams, L. Keoki

AU - Zhang, Yingze

AU - Ziv, Elad

AU - Raffield, Laura M.

AU - Reiner, Alexander P.

AU - Arvanitis, Marios

AU - Greider, Carol W.

AU - Mathias, Rasika A.

AU - Battle, Alexis

PY - 2024/12

Y1 - 2024/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85194218687&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85194218687&partnerID=8YFLogxK

U2 - 10.1038/s41467-024-48394-y

DO - 10.1038/s41467-024-48394-y

M3 - Article

C2 - 38789417

AN - SCOPUS:85194218687

SN - 2041-1723

VL - 15

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 4417

ER -

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

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