Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology.
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 x 10(-9)) and chemokine (C-X-C motif) receptor 4 gene (CXCR4; rs4452212; P = 2.9 x 10(-8)) were associated with LTL at a genome-wide significance level (P < 5 x 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 x 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.
Levy
Daniel
D
National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA. Levyd@nih.gov
Neuhausen
Susan L
SL
Hunt
Steven C
SC
Kimura
Masayuki
M
Hwang
Shih-Jen
SJ
Chen
Wei
W
Bis
Joshua C
JC
Fitzpatrick
Annette L
AL
Smith
Erin
E
Johnson
Andrew D
AD
Gardner
Jeffrey P
JP
Srinivasan
Sathanur R
SR
Schork
Nicholas
N
Rotter
Jerome I
JI
Herbig
Utz
U
Psaty
Bruce M
BM
Sastrasinh
Malinee
M
Murray
Sarah S
SS
Vasan
Ramachandran S
RS
Province
Michael A
MA
Glazer
Nicole L
NL
Lu
Xiaobin
X
Cao
Xiaojian
X
Kronmal
Richard
R
Mangino
Massimo
M
Soranzo
Nicole
N
Spector
Tim D
TD
Berenson
Gerald S
GS
Aviv
Abraham
A
D015331:Cohort Studies; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007962:Leukocytes / Q000737:chemistry / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D019718:Receptors, CXCR4 / Q000235:genetics / Q000502:physiology*; D016615:Telomere / Q000235:genetics / Q000502:physiology*; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000502:physiology*
C527276:CXCR4 protein, human; D019718:Receptors, CXCR4; C544946:Stn1 protein, human; D034501:Telomere-Binding Proteins