Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology
Open accessAbstract
Telomeres are engaged in a host of cellular functions, and their length is regulated by multiple genes. Telomere shortening, in the course of somatic cell replication, ultimately leads to replicative senescence. In humans, rare mutations in genes that regulate telomere length have been identified in monogenic diseases such as dyskeratosis congenita and idiopathic pulmonary fibrosis, which are associated with shortened leukocyte telomere length (LTL) and increased risk for aplastic anemia. Shortened LTL is observed in a host of aging-related complex genetic diseases and is associated with diminished survival in the elderly. We report results of a genome-wide association study of LTL in a consortium of four observational studies ( n = 3,417 participants with LTL and genome-wide genotyping). SNPs in the regions of the oligonucleotide/oligosaccharide-binding folds containing one gene ( OBFC1 ; rs4387287; P = 3.9 × 10 −9 ) and chemokine (C-X-C motif) receptor 4 gene (CXCR4 ; rs4452212; P = 2.9 × 10 −8 ) were associated with LTL at a genome-wide significance level ( P < 5 × 10 −8 ). We attempted replication of the top SNPs at these loci through de novo genotyping of 1,893 additional individuals and in silico lookup in another observational study ( n = 2,876), and we confirmed the association findings for OBFC1 but not CXCR4 . In addition, we confirmed the telomerase RNA component (TERC) as a gene associated with LTL ( P = 1.1 × 10 −5 ). The identification of OBFC1 through genome-wide association as a locus for interindividual variation in LTL in the general population advances the understanding of telomere biology in humans and may provide insights into aging-related disorders linked to altered LTL dynamics.
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The previously reported OBFC1 locus was replicated.
“We also replicated the previously reported OBFC1 locus18.”
From Identification of seven loci affecting mean telomere length and their association with disease (2013) · cites this paper as [18]
Common variants at two loci on Chr3q26 (TERC) and Chr10q24.33 (OBFC1), that explain <1% of the variance in TL, have shown a replicated association with mean LTL in genome-wide association studies.
“So far, common variants at two loci on Chr3q26 (TERC)17–19 and Chr10q24.33 (OBFC1)18, that explain <1% of the variance in TL, have shown a replicated association with mean LTL in genome-wide association (GWA) studies.”
From Identification of seven loci affecting mean telomere length and their association with disease (2013) · cites this paper as [18]
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- Authors
- Levy, D., Neuhausen, S. L., Hunt, S. C., Kimura, M., Hwang, S.-J., Chen, W., Bis, J. C., Fitzpatrick, A. L., Smith, E., Johnson, A. D., Gardner, J. P., Srinivasan, S. R., Schork, N., Rotter, J. I., Herbig, U., Psaty, B. M., Sastrasinh, M., Murray, S. S., Vasan, R. S., Province, M. A., Glazer, N. L., Lu, X., Cao, X., Kronmal, R., Mangino, M., Soranzo, N., Spector, T. D., Berenson, G. S., & Aviv, A.
- Affiliations
- Boston University (US)
- Beckman Research Institute (US)
- University of Utah (US)
- Rutgers New Jersey Medical School (US)
- Tulane University (US)
- Kaiser Permanente Washington Health Research Institute (US)
- University of Washington (US)
- Scripps Research Institute (US)
- Cedars-Sinai Medical Center (US)
- Washington University in St. Louis (US)
- King's College London (GB)
- ORCID
- Levy, Daniel
- Neuhausen, Susan L.
- Hunt, Steven C.
- Kimura, Masayuki
- Hwang, Shih-Jen
- Chen, Wei
- Bis, Joshua C.
- Smith, Erin
- Johnson, Andrew D.
- Schork, Nicholas
- Rotter, Jerome I.
- Herbig, Utz
- Psaty, Bruce M.
- Murray, Sarah S.
- Vasan, Ramachandran S.
- Province, Michael A.
- Glazer, Nicole L.
- Cao, Xiaojian
- Kronmal, Richard
- Mangino, Massimo
- Soranzo, Nicole
- Spector, Tim D.
- Aviv, Abraham
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-04-26
- Volume
- 107
- Issue
- 20
- Pages
- 9293-9298
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2889047
- OpenAlex
- W2037762348
- Cited by
- 259
- References
- 58
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 9 · 2023: 8 · 2022: 9 · 2021: 18 · 2020: 22 · 2019: 20 · 2018: 15 · 2017: 17 · 2016: 29 · 2015: 18 · 2014: 18 · 2013: 23 · 2012: 23
- FWCI
- 14.52
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- leukocyte telomere length, telomere biology, CXCR4, telomerase RNA, TERC, genetic susceptibility, replicative senescence, age-related diseases, dyskeratosis congenita, idiopathic pulmonary fibrosis, aplastic anemia
- MeSH terms
- Genotype, Humans, Leukocytes, Cohort Studies, Telomere, Receptors, CXCR4, Polymorphism, Single Nucleotide, Telomere-Binding Proteins, Genome-Wide Association Study
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