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

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Title: Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed
Authors: Margaret A. Taub, Matthew P. Conomos, Rebecca Keener, Kruthika R. Iyer, Joshua S. Weinstock, Lisa R. Yanek, John Lane, Tyne W. Miller-Fleming, Jennifer A. Brody, Laura M. Raffield, Caitlin P. McHugh, Deepti Jain, Stephanie M. Gogarten, Cecelia A. Laurie, Ali Keramati, Marios Arvanitis, Albert V. Smith, Benjamin Heavner, Lucas Barwick, Lewis C. Becker, Joshua C. Bis, John Blangero, Eugene R. Bleecker, Esteban G. Burchard, Juan C. Celedón, Yen Pei C. Chang, Brian Custer, Dawood Darbar, Lisa de las Fuentes, Dawn L. DeMeo, Barry I. Freedman, Melanie E. Garrett, Mark T. Gladwin, Susan R. Heckbert, Bertha A. Hidalgo, Marguerite R. Irvin, Talat Islam, W. Craig Johnson, Stefan Kaab, Lenore Launer, Jiwon Lee, Simin Liu, Arden Moscati, Kari E. North, Patricia A. Peyser, Nicholas Rafaels, Christine Seidman, Daniel E. Weeks, Fayun Wen, Marsha M. Wheeler, L. Keoki Williams, Ivana V. Yang, Wei Zhao, Stella Aslibekyan, Paul L. Auer, Donald W. Bowden, Brian E. Cade, Zhanghua Chen, Michael H. Cho, L. Adrienne Cupples, Joanne E. Curran, Michelle Daya, Ranjan Deka, Celeste Eng, Tasha E. Fingerlin, Xiuqing Guo, Lifang Hou, Shih-Jen Hwang, Jill M. Johnsen, Eimear E. Kenny, Albert M. Levin, Chunyu Liu, Ryan L. Minster, Take Naseri, Mehdi Nouraie, Muagututi‘a Sefuiva Reupena, Ester C. Sabino, Jennifer A. Smith, Nicholas L. Smith, Jessica Lasky-Su, James G. Taylor, VI, Marilyn J. Telen, Hemant K. Tiwari, Russell P. Tracy, Marquitta J. White, Yingze Zhang, Kerri L. Wiggins, Scott T. Weiss, Ramachandran S. Vasan, Kent D. Taylor, Moritz F. Sinner, Edwin K. Silverman, M. Benjamin Shoemaker, Wayne H.-H. Sheu, Frank Sciurba, David A. Schwartz, Jerome I. Rotter, Daniel Roden, Susan Redline, Benjamin A. Raby, Bruce M. Psaty, Juan M. Peralta, Nicholette D. Palmer, Sergei Nekhai, Courtney G. Montgomery, Braxton D. Mitchell, Deborah A. Meyers, Stephen T. McGarvey, Angel C.Y. Mak, Ruth J.F. Loos, Rajesh Kumar, Charles Kooperberg, Barbara A. Konkle, Shannon Kelly, Sharon L.R. Kardia, Robert Kaplan, Jiang He, Hongsheng Gui, Frank D. Gilliland, Bruce D. Gelb, Myriam Fornage, Patrick T. Ellinor, Mariza de Andrade, Adolfo Correa, Yii-Der Ida Chen, Eric Boerwinkle, Kathleen C. Barnes, Allison E. Ashley-Koch, Donna K. Arnett, Christine Albert, Cathy C. Laurie, Goncalo Abecasis, Deborah A. Nickerson, James G. Wilson, Stephen S. Rich, Daniel Levy, Ingo Ruczinski, Abraham Aviv, Thomas W. Blackwell, Timothy Thornton, Jeff O’Connell, Nancy J. Cox, James A. Perry, Mary Armanios, Alexis Battle, Nathan Pankratz, Alexander P. Reiner, Rasika A. Mathias
Source: Cell Genomics, Vol 2, Iss 1, Pp 100084- (2022)
Publisher Information: Elsevier, 2022.
Publication Year: 2022
Collection: LCC:Genetics
LCC:Internal medicine
Subject Terms: telomeres, telomere length genetics, trans-population genome-wide association study, Genetics, QH426-470, Internal medicine, RC31-1245
More Details: Summary: 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.
Document Type: article
File Description: electronic resource
Language: English
ISSN: 2666-979X
Relation: http://www.sciencedirect.com/science/article/pii/S2666979X21001051; https://doaj.org/toc/2666-979X
DOI: 10.1016/j.xgen.2021.100084
Access URL: https://doaj.org/article/9db9bc5c4cd74de38ea78d49281d0bb2
Accession Number: edsdoj.9db9bc5c4cd74de38ea78d49281d0bb2
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  Data: Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed
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– Name: TitleSource
  Label: Source
  Group: Src
  Data: Cell Genomics, Vol 2, Iss 1, Pp 100084- (2022)
– Name: Publisher
  Label: Publisher Information
  Group: PubInfo
  Data: Elsevier, 2022.
– Name: DatePubCY
  Label: Publication Year
  Group: Date
  Data: 2022
– Name: Subset
  Label: Collection
  Group: HoldingsInfo
  Data: LCC:Genetics&lt;br /&gt;LCC:Internal medicine
– Name: Subject
  Label: Subject Terms
  Group: Su
  Data: &lt;searchLink fieldCode=&quot;DE&quot; term=&quot;%22telomeres%22&quot;&gt;telomeres&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;DE&quot; term=&quot;%22telomere+length+genetics%22&quot;&gt;telomere length genetics&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;DE&quot; term=&quot;%22trans-population+genome-wide+association+study%22&quot;&gt;trans-population genome-wide association study&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;DE&quot; term=&quot;%22Genetics%22&quot;&gt;Genetics&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;DE&quot; term=&quot;%22QH426-470%22&quot;&gt;QH426-470&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;DE&quot; term=&quot;%22Internal+medicine%22&quot;&gt;Internal medicine&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;DE&quot; term=&quot;%22RC31-1245%22&quot;&gt;RC31-1245&lt;/searchLink&gt;
– Name: Abstract
  Label: Description
  Group: Ab
  Data: Summary: 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 &lt; 5 &#215; 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.
– Name: TypeDocument
  Label: Document Type
  Group: TypDoc
  Data: article
– Name: Format
  Label: File Description
  Group: SrcInfo
  Data: electronic resource
– Name: Language
  Label: Language
  Group: Lang
  Data: English
– Name: ISSN
  Label: ISSN
  Group: ISSN
  Data: 2666-979X
– Name: NoteTitleSource
  Label: Relation
  Group: SrcInfo
  Data: http://www.sciencedirect.com/science/article/pii/S2666979X21001051; https://doaj.org/toc/2666-979X
– Name: DOI
  Label: DOI
  Group: ID
  Data: 10.1016/j.xgen.2021.100084
– Name: URL
  Label: Access URL
  Group: URL
  Data: &lt;link linkTarget=&quot;URL&quot; linkTerm=&quot;https://doaj.org/article/9db9bc5c4cd74de38ea78d49281d0bb2&quot; linkWindow=&quot;_blank&quot;&gt;https://doaj.org/article/9db9bc5c4cd74de38ea78d49281d0bb2&lt;/link&gt;
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  Data: edsdoj.9db9bc5c4cd74de38ea78d49281d0bb2
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        Value: 10.1016/j.xgen.2021.100084
    Languages:
      – Text: English
    Subjects:
      – SubjectFull: telomeres
        Type: general
      – SubjectFull: telomere length genetics
        Type: general
      – SubjectFull: trans-population genome-wide association study
        Type: general
      – SubjectFull: Genetics
        Type: general
      – SubjectFull: QH426-470
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      – SubjectFull: Internal medicine
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      – SubjectFull: RC31-1245
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      – TitleFull: Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed
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              M: 01
              Type: published
              Y: 2022
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          Titles:
            – TitleFull: Cell Genomics
              Type: main
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