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Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed.

Publication ,  Journal Article
Taub, MA; Conomos, MP; Keener, R; Iyer, KR; Weinstock, JS; Yanek, LR; Lane, J; Miller-Fleming, TW; Brody, JA; Raffield, LM; McHugh, CP; Lee, J ...
Published in: Cell Genom
January 12, 2022

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWAS for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally-diverse individuals (European, African, Asian and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n=109,122 individuals. We identified 59 sentinel variants (p-value <5×10-9) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at OBFC1 indicated the independent signals colocalized with cell-type specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated our TL polygenic trait scores (PTS) were associated with increased risk of cancer-related phenotypes.

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Published In

Cell Genom

DOI

EISSN

2666-979X

Publication Date

January 12, 2022

Volume

2

Issue

1

Location

United States
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Taub, M. A., Conomos, M. P., Keener, R., Iyer, K. R., Weinstock, J. S., Yanek, L. R., … Mathias, R. A. (2022). Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed. Cell Genom, 2(1). https://doi.org/10.1016/j.xgen.2021.100084
Taub, Margaret A., Matthew P. Conomos, Rebecca Keener, Kruthika R. Iyer, Joshua S. Weinstock, Lisa R. Yanek, John Lane, et al. “Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed.Cell Genom 2, no. 1 (January 12, 2022). https://doi.org/10.1016/j.xgen.2021.100084.
Taub MA, Conomos MP, Keener R, Iyer KR, Weinstock JS, Yanek LR, et al. Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed. Cell Genom. 2022 Jan 12;2(1).
Taub, Margaret A., et al. “Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed.Cell Genom, vol. 2, no. 1, Jan. 2022. Pubmed, doi:10.1016/j.xgen.2021.100084.
Taub MA, Conomos MP, Keener R, Iyer KR, Weinstock JS, Yanek LR, Lane J, Miller-Fleming TW, Brody JA, Raffield LM, McHugh CP, Jain D, Gogarten SM, Laurie CA, Keramati A, Arvanitis M, Smith AV, Heavner B, Barwick L, Becker LC, Bis JC, Blangero J, Bleecker ER, Burchard EG, Celedón JC, Chang YPC, Custer B, Darbar D, de Las Fuentes L, DeMeo DL, Freedman BI, Garrett ME, Gladwin MT, Heckbert SR, Hidalgo BA, Irvin MR, Islam T, Johnson WC, Kaab S, Launer L, Lee J, Liu S, Moscati A, North KE, Peyser PA, Rafaels N, Seidman C, Weeks DE, Wen F, Wheeler MM, Williams LK, Yang IV, Zhao W, Aslibekyan S, Auer PL, Bowden DW, Cade BE, Chen Z, Cho MH, Cupples LA, Curran JE, Daya M, Deka R, Eng C, Fingerlin TE, Guo X, Hou L, Hwang S-J, Johnsen JM, Kenny EE, Levin AM, Liu C, Minster RL, Naseri T, Nouraie M, Reupena MS, Sabino EC, Smith JA, Smith NL, Su JL, Taylor JG, Telen MJ, Tiwari HK, Tracy RP, White MJ, Zhang Y, Wiggins KL, Weiss ST, Vasan RS, Taylor KD, Sinner MF, Silverman EK, Shoemaker MB, Sheu WH-H, Sciurba F, Schwartz DA, Rotter JI, Roden D, Redline S, Raby BA, Psaty BM, Peralta JM, Palmer ND, Nekhai S, Montgomery CG, Mitchell BD, Meyers DA, McGarvey ST, NHLBI CARE Network, Mak AC, Loos RJ, Kumar R, Kooperberg C, Konkle BA, Kelly S, Kardia SL, Kaplan R, He J, Gui H, Gilliland FD, Gelb BD, Fornage M, Ellinor PT, de Andrade M, Correa A, Chen Y-DI, Boerwinkle E, Barnes KC, Ashley-Koch AE, Arnett DK, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Hematology and Hemostasis Working Group, TOPMed Structural Variation Working Group, Laurie CC, Abecasis G, Nickerson DA, Wilson JG, Rich SS, Levy D, Ruczinski I, Aviv A, Blackwell TW, Thornton T, O’Connell J, Cox NJ, Perry JA, Armanios M, Battle A, Pankratz N, Reiner AP, Mathias RA. Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed. Cell Genom. 2022 Jan 12;2(1).

Published In

Cell Genom

DOI

EISSN

2666-979X

Publication Date

January 12, 2022

Volume

2

Issue

1

Location

United States