Open AccessGenome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology
Author(s) -
Daniel Levy,
Susan L. Neuhausen,
Steven C. Hunt,
Masayuki Kimura,
Shih Jen Hwang,
Wei Chen,
Joshua C. Bis,
Annette L. Fitzpatrick,
Erin N. Smith,
Andrew D. Johnson,
J. P. Gardner,
Sathanur R. Srinivasan,
Nicholas J. Schork,
Jerome I. Rotter,
Utz Herbig,
Bruce M. Psaty,
Malinee Sastrasinh,
Sarah Murray,
Ramachandran S. Vasan,
Michael A. Province,
Nicole L. Glazer,
Xingrong Lu,
Xiaojian Cao,
Richard A. Kronmal,
Massimo Mangino,
Nicole Soranzo,
Tim D. Spector,
Gerald S. Berenson,
Abraham Aviv
Publication year - 2010
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0911494107
Subject(s) - telomere , biology , genetics , human genome , locus (genetics) , genome wide association study , genome , computational biology , dna , gene , single nucleotide polymorphism , genotype
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 forOBFC1 but notCXCR4 . In addition, we confirmed the telomerase RNA component(TERC) as a gene associated with LTL (P = 1.1 × 10−5 ). The identification ofOBFC1 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.