Abstract
Genetic studies on telomere length are important for understanding age-related diseases. Prior GWASs 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 < 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 that 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 that our TL polygenic trait scores (PTSs) were associated with an increased risk of cancer-related phenotypes.
| Original language | English (US) |
|---|---|
| Article number | 100084 |
| Journal | Cell Genomics |
| Volume | 2 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 12 2022 |
Keywords
- telomere length genetics
- telomeres
- trans-population genome-wide association study
ASJC Scopus subject areas
- Genetics
- Biochemistry, Genetics and Molecular Biology (miscellaneous)
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In: Cell Genomics, Vol. 2, No. 1, 100084, 12.01.2022.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed
AU - Fernando D. Martinez on behalf of the NHLBI CARE Network
AU - NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
AU - TOPMed Hematology and Hemostasis Working Group
AU - TOPMed Structural Variation Working Group
AU - Taub, Margaret A.
AU - Conomos, Matthew P.
AU - Keener, Rebecca
AU - Iyer, Kruthika R.
AU - Weinstock, Joshua S.
AU - Yanek, Lisa R.
AU - Lane, John
AU - Miller-Fleming, Tyne W.
AU - Brody, Jennifer A.
AU - Raffield, Laura M.
AU - McHugh, Caitlin P.
AU - Jain, Deepti
AU - Gogarten, Stephanie M.
AU - Laurie, Cecelia A.
AU - Keramati, Ali
AU - Arvanitis, Marios
AU - Smith, Albert V.
AU - Heavner, Benjamin
AU - Barwick, Lucas
AU - Becker, Lewis C.
AU - Bis, Joshua C.
AU - Blangero, John
AU - Bleecker, Eugene R.
AU - Burchard, Esteban G.
AU - Celedón, Juan C.
AU - Chang, Yen Pei C.
AU - Custer, Brian
AU - Darbar, Dawood
AU - de las Fuentes, Lisa
AU - DeMeo, Dawn L.
AU - Freedman, Barry I.
AU - Garrett, Melanie E.
AU - Gladwin, Mark T.
AU - Heckbert, Susan R.
AU - Hidalgo, Bertha A.
AU - Irvin, Marguerite R.
AU - Islam, Talat
AU - Johnson, W. Craig
AU - Kaab, Stefan
AU - Launer, Lenore
AU - Lee, Jiwon
AU - Liu, Simin
AU - Moscati, Arden
AU - North, Kari E.
AU - Peyser, Patricia A.
AU - Rafaels, Nicholas
AU - Seidman, Christine
AU - Ruczinski, Ingo
AU - Armanios, Mary
AU - Mathias, Rasika A.
N1 - Funding Information: We thank Chen Li, Claudia Langernberg, and Veryan Codd for providing summary statistics from their TL GWAS for replication analysis. The whole-genome sequencing (WGS) 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 supplemental information . Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center ( 3R01HL-117626-02S1 ; contract HHSN268201800002I). Phenotype harmonization, data management, sample-identity QC, and general study coordination, were provided by the TOPMed Data Coordinating Center ( 3R01HL-120393-02S1 ; contract HHSN268201800001I). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. The full study specific acknowledgments, as well as individual acknowledgments, are detailed in the supplemental information . The BioVU projects at Vanderbilt University Medical Center are supported by numerous sources: institutional funding, private agencies, and federal grants. These include the NIH-funded Shared Instrumentation Grant S10OD017985 and S10RR025141 and CTSA grants UL1TR002243 , UL1TR000445 , and UL1RR024975 from the National Center for Advancing Translational Sciences . Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. Genomic data are also supported by investigator-led projects that include U01HG004798 , R01NS032830 , RC2GM092618 , P50GM115305 , U01HG006378 , U19HL065962 , R01HD074711 . and additional funding sources listed at https://victr.vumc.org/biovu-funding/ . Support for this work was provided by the National Institutes of Health, National Heart, Lung, and Blood Institute , through the BioData Catalyst program (awards 1OT3HL142479-01 , 1OT3HL142478-01 , 1OT3HL142481-01 , 1OT3HL142480-01 , and 1OT3HL147154 ). F.D.M. is supported by grants from NIH/NHLBI ( HL139054 , HL091889 , HL132523 , HL130045 , HL098112 , and HL056177 ), the NIH/NIEHS ( ES006614 ), the NIH/NIAID ( AI126614 ), and the NIH/Office of Director ( OD023282 ). Vifor Pharmaceuticals provided medicine and additional funding to support recruitment for HL130045 . P.T.E. is supported by a grant from Bayer AG to the Broad Institute focused on the genetics and therapeutics of cardiovascular diseases. Any opinions expressed in this document are those of the authors and do not necessarily reflect the views of NHLBI, the National Institutes of Health, the US Department of Health and Human Services, individual BioData Catalyst Consortium members, or affiliated organizations and institutions. Funding Information: J.C.C. has received research materials from GlaxoSmithKline and Merck (inhaled steroids) and Pharmavite (vitamin D and placebo capsules) to provide medications free of cost to participants in NIH-funded studies, unrelated to the current work. B.I.F. is a consultant for AstraZeneca Pharmaceuticals and RenalytixAI. L.K.W. is on the advisory board of GlaxoSmithKline and receives grant funding from NIAID, NHLBI, and NIDDK (NIH). I.V.Y. is a consultant for ElevenP15. S.A. receives equity and salary from 23andMe. M.H.C. receives grant support from GlaxoSmithKline. S.T.W. receives royalties from UpToDate. E.K.S. received grant support from GlaxoSmithKline and Bayer in the past 3 years. B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. F.D.M. is a council member for the Council for the Developing Child. P.T.E. has served on the advisory boards of or consulted for Bayer AG, Quest Diagnostics, and Novartis. K.C.B. receives royalties from UpToDate. G.A. is an employee of Regeneron Pharmaceuticals and owns stock and stock options in Regeneron Pharmaceuticals. A.M. is an employee of Regeneron Pharmaceuticals and owns stock and stock options in Regeneron Pharmaceuticals. A.B. is a consultant for Third Rock Ventures, and holds stock in Google. D.A.S. is the founder and chief scientific officer of Eleven P15, a company focused on the early diagnosis and treatment of pulmonary fibrosis. Funding Information: We thank Chen Li, Claudia Langernberg, and Veryan Codd for providing summary statistics from their TL GWAS for replication analysis. The whole-genome sequencing (WGS) 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 supplemental information. Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Phenotype harmonization, data management, sample-identity QC, and general study coordination, were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1; contract HHSN268201800001I). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. The full study specific acknowledgments, as well as individual acknowledgments, are detailed in the supplemental information. The BioVU projects at Vanderbilt University Medical Center are supported by numerous sources: institutional funding, private agencies, and federal grants. These include the NIH-funded Shared Instrumentation Grant S10OD017985 and S10RR025141 and CTSA grants UL1TR002243, UL1TR000445, and UL1RR024975 from the National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, R01HD074711. and additional funding sources listed at https://victr.vumc.org/biovu-funding/. Support for this work was provided by the National Institutes of Health, National Heart, Lung, and Blood Institute, through the BioData Catalyst program (awards 1OT3HL142479-01, 1OT3HL142478-01, 1OT3HL142481-01, 1OT3HL142480-01, and 1OT3HL147154). F.D.M. is supported by grants from NIH/NHLBI (HL139054, HL091889, HL132523, HL130045, HL098112, and HL056177), the NIH/NIEHS (ES006614), the NIH/NIAID (AI126614), and the NIH/Office of Director (OD023282). Vifor Pharmaceuticals provided medicine and additional funding to support recruitment for HL130045. P.T.E. is supported by a grant from Bayer AG to the Broad Institute focused on the genetics and therapeutics of cardiovascular diseases. Any opinions expressed in this document are those of the authors and do not necessarily reflect the views of NHLBI, the National Institutes of Health, the US Department of Health and Human Services, individual BioData Catalyst Consortium members, or affiliated organizations and institutions. M.A.T. and R.A.M. conceived of and led the study. M.A.T. M.P.C. R. Keener, K.R.I. L.R.Y. C.P.M. D.J. S.M.G. C.A.L. A.K. M. Arvanitis, J.C.B. E.G.B. J.C.C. Y.C.C. L.M.R. M.H.C. J.E.C. M.D. B.M.P. C.C.L. D.L. I.R. T.W.B. J.A.P. M. Armanios, A.B. A.P.R. and R.A.M. drafted the manuscript. M.A.T. M.P.C. R. Keener, J.S.W. J.A.B. D.J. A.K. C.C.L. G.A. D.A.N. J.G.W. S.S.R. D.L. I.R. A.A. T.W.B. T.T. J.O. N.J.C. J.A.P. M. Armanios, A.B. N.P. A.P.R. and R.A.M. contributed substantive analytical guidance. M.A.T. M.P.C. R. Keener, K.R.I. J.S.W. L.R.Y. J. Lane, T.W.M. J.A.B. C.P.M. D.J. S.M.G. C.A.L. A.K. M. Arvanitis, A.V.S. B.H. T.T. N.J.C. M. Armanios, A.B. N.P. A.P.R. and R.A.M. performed and led the analysis. L.R.Y. L.B. L.C.B. J.C.B. J.B. E.R.B. E.G.B. J.C.C. Y.C.C. B.C. D.D. L.d.l.F. D.L.D. B.I.F. M.E.G. M.T.G. S.R.H. B.A.H. M.R.I. T.I. W.C.J. S. Kaab, L.L. J. Lee, S.L. A.M. K.E.N. P.A.P. N.R. L.M.R. C.S. D.E.W. M.M.W. L.W. I.V.Y. W.Z. S.A. P.L.A. D.W.B. B.E.C. Z.C. M.H.C. L.A.C. J.E.C. M.D. R.D. C.E. T.E.F. X.G. L.H. S.H. J.M.J. E.E.K. A.M.L. C.L. R.L.M. T.N. M.N. M.S.R. E.C.S. J.A.S. N.L.S. J.L.S. M.J.T. H.K.T. R.P.T. M.J.W. Y.Z. K.L.W. S.T.W. R.S.V. K.D.T. M.F.S. E.K.S. M.B.S. W.H.-H.S. F.S. D.A.S. J.I.R. D.R. S.R. B.A.R. B.M.P. J.M.P. N.D.P. S.N. C.G.M. B.D.M. D.A.M. S.T.M. F.D.M. A.C.Y.M. R.J.F.L. R. Kumar, C.K. B.A.K. S. Kelly, S.L.R.K. R. Kaplan, J.H. H.G. F.D.G. B.D.G. M.F. P.T.E. M.d.A. A.C. Y.-D.I.C. E.B. K.C.B. A.E.A.-K. D.K.A. C.A. N.J.C. and M. Armanios were involved in the guidance, collection, and analysis of one or more of the studies that contributed data to this article. All of the authors read and approved the final draft. J.C.C. has received research materials from GlaxoSmithKline and Merck (inhaled steroids) and Pharmavite (vitamin D and placebo capsules) to provide medications free of cost to participants in NIH-funded studies, unrelated to the current work. B.I.F. is a consultant for AstraZeneca Pharmaceuticals and RenalytixAI. L.K.W. is on the advisory board of GlaxoSmithKline and receives grant funding from NIAID, NHLBI, and NIDDK (NIH). I.V.Y. is a consultant for ElevenP15. S.A. receives equity and salary from 23andMe. M.H.C. receives grant support from GlaxoSmithKline. S.T.W. receives royalties from UpToDate. E.K.S. received grant support from GlaxoSmithKline and Bayer in the past 3 years. B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. F.D.M. is a council member for the Council for the Developing Child. P.T.E. has served on the advisory boards of or consulted for Bayer AG, Quest Diagnostics, and Novartis. K.C.B. receives royalties from UpToDate. G.A. is an employee of Regeneron Pharmaceuticals and owns stock and stock options in Regeneron Pharmaceuticals. A.M. is an employee of Regeneron Pharmaceuticals and owns stock and stock options in Regeneron Pharmaceuticals. A.B. is a consultant for Third Rock Ventures, and holds stock in Google. D.A.S. is the founder and chief scientific officer of Eleven P15, a company focused on the early diagnosis and treatment of pulmonary fibrosis. Publisher Copyright: © 2021
PY - 2022/1/12
Y1 - 2022/1/12
N2 - Genetic studies on telomere length are important for understanding age-related diseases. Prior GWASs 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 < 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 that 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 that our TL polygenic trait scores (PTSs) were associated with an increased risk of cancer-related phenotypes.
AB - Genetic studies on telomere length are important for understanding age-related diseases. Prior GWASs 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 < 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 that 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 that our TL polygenic trait scores (PTSs) were associated with an increased risk of cancer-related phenotypes.
KW - telomere length genetics
KW - telomeres
KW - trans-population genome-wide association study
UR - http://www.scopus.com/inward/record.url?scp=85133272831&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85133272831&partnerID=8YFLogxK
U2 - 10.1016/j.xgen.2021.100084
DO - 10.1016/j.xgen.2021.100084
M3 - Article
C2 - 35530816
AN - SCOPUS:85133272831
SN - 2666-979X
VL - 2
JO - Cell Genomics
JF - Cell Genomics
IS - 1
M1 - 100084
ER -