Genome-wide meta-analysis points to CTC1 and ZNf676 as genes regulating telomere homeostasis in humans

Massimo Mangino, Shih Jen Hwang, Timothy D. Spector, Steven C. Hunt, Masayuki Kimura, Annette L. Fitzpatrick, Lene Christiansen, Inge Petersen, Clara C. Elbers, Tamara Harris, Wei Chen, Sathanur R. Srinivasan, Jeremy D. Kark, Athanase Benetos, Said El shamieh, Sophie Visvikis-Siest, Kaare Christensen, Gerald S. Berenson, Ana M. Valdes, Ana VinuelaMelissa Garcia, Donna K. Arnett, Ulrich Broeckel, Michael A. Province, James S. Pankow, Candace Kammerer, Yongmei Liu, Michael Nalls, Sarah Tishkoff, Fridtjof Thomas, Elad Ziv, Bruce M. Psaty, Joshua C. Bis, Jerome I. Rotter, Kent D. Taylor, Erin Smith, Nicholas J. Schork, Daniel Levy, Abraham Aviv

Research output: Contribution to journalArticlepeer-review

129 Scopus citations

Abstract

Leukocyte telomere length (LTL) is associated with a number of common age-related diseases and is a heritable trait. Previous genome-wide association studies (GWASs) identified two loci on chromosomes 3q26.2 (TERC) and 10q24.33 (OBFC1) that are associated with the inter-individual LTL variation. We performed a meta-analysis of 9190 individuals from six independent GWAS and validated our findings in 2226 individuals from four additional studies. We confirmed previously reported associations with OBFC1 (rs9419958 P = 9.1 × 10-11) and with the telomerase RNA component TERC (rs1317082, P = 1.1 × 10-8). We also identified two novel genomic regions associated with LTL variation that map near a conserved telomere maintenance complex component 1 (CTC1; rs3027234, P = 3.6 × 10-8) on chromosome17p13.1 and zinc finger protein 676 (ZNF676; rs412658, P = 3.3 × 10-8) on 19p12. The minor allele of rs3027234 was associated with both shorter LTL and lower expression of CTC1. Our findings are consistent with the recent observations that point mutations in CTC1 cause short telomeres in both Arabidopsis and humans affected by a rare Mendelian syndrome. Overall, our results provide novel insights into the genetic architecture of inter-individual LTL variation in the general population.

Original languageEnglish (US)
Article numberdds382
Pages (from-to)5385-5394
Number of pages10
JournalHuman molecular genetics
Volume21
Issue number24
DOIs
StatePublished - Dec 2012

Bibliographical note

Funding Information:
TwinsUK. The study was funded by the Wellcome Trust; European Community’s Seventh Framework Programme (FP7/2007-2013), ENGAGE project grant agreement (HEALTH-F4-2007-201413). The study also receives support from the Dept of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London. T.D.S. is an NIHR senior Investigator and is holder of an ERC Advanced Principal Investigator award. Genotyping was performed by The Wellcome Trust Sanger Institute, support of the National Eye Institute via an NIH/CIDR genotyping project. The Bogalusa Heart Study. This study was supported by grants HD-061437 and HD-062783 from the National Institute of Child Health and Human Development, and AG-16592 from the National Institute on Aging. The Framingham Heart Study. Supported by NIH contract N01-HC-25195. This project was supported in part by intramural funding from the National Heart, Lung, and Blood Institute and the Center for Population Studies of the NHLBI. CHS. This CHS research was supported by NHLBI grant 1 R01 HL80698-01 and contracts N01-HC-85239, N01-HC-85079 through N01-HC-85086; N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HHSN268201200036C and NHLBI grants HL080295, HL087652, HL105756 with additional contribution from NINDS. Additional support was provided through AG-023629, AG-15928, AG-20098 and AG-027058 from the NIA. See also http://www.chs-nhlbi.org/pi.htm. DNA handling and genotyping were supported in part by National Center of Advancing Translational Technologies CTSI grant UL1TR000124 and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center and Cedars-Sinai Board of Governors’ Chair in Medical Genetics (J.I.R.). The Center of Human Development and Aging. A.A. grant support: NIH: Human Telomere Genetics R01AG20132; Telomeres & Vascular Aging, R01AG21593; Leukocyte Telomere Dynamics, Gender, Menopause, Insulin Resistance, R01AG030678. Jerusalem LRC Longitudinal Study The study was funded by the US-Israel Binational Science Foundation and the Israel Science Foundation. ADELAHYDE-Nancy study and ERA-France study. The study received support from the French Fondation pour la Recherche Médicale (FRM DCV2007-0409250) and the Plan Pluriformation (PPF815 PSVT-2005). Special thanks to Ms Cynthia Thiriot (INSERM U961, Nancy France) for her contribution to the geotyping of French cohorts. HyperGEN. HyperGEN was supported by cooperative agreements HL54471, HL54472, HL54473, HL54495, HL54496, HL54509, HL54515 and grant HL055673. HyperGEN investigators and institutions can be found at http://www.biostat. wustl.edu/hypergen/hypergen.shtml. Health ABC. This research was supported by NIA contracts N01AG62101, N01AG62103 and N01AG62106. The GWAS was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust.

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