title: A regulatory SNP of the BICD1 gene contributes to telomere length variation in humans.
abstract: Telomeres are repetitive sequences of variable length at the ends of chromosomes involved in maintaining their integrity. Telomere dysfunction is associated with increased risk of cancer and other age-related diseases. Telomere length is an important determinant of telomere function and has a strong genetic basis. We previously carried out a genome-wide linkage analysis of mean leukocyte telomere length, and identified a 12 cm quantitative-trait locus affecting telomere length on human chromosome 12. In the present study we confirmed linkage to this locus in an extended sample (380 families, 520 sib-pairs, maximum LOD score 4.3). Fine-mapping identified a 51 kb region of association within intron 1 of the Bicaudal-D homolog 1 (BICD1, MIM 602204) gene. The strongest association (P = 1.9 x 10(-5)) was with SNP rs2630578 where the minor allele C (frequency 0.21) was associated with telomeres that were shorter by 604 (+/-204) base pairs, equivalent to approximately 15-20 years of age-related attrition in telomere length. Subjects carrying the C allele for rs2630778 had 44% lower BICD1 mRNA levels in their leukocytes compared with GG homozygotes (P = 0.004). BICD1 is involved in Golgi-to-endoplasmic reticulum vacuolar transport. Previous studies have implicated vacuolar genes in telomere length homeostasis in yeast. Our study indicates that BICD1 plays a similar role in humans.
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
authors.forename: Massimo
authors.initials: M
authors.lastname: Mangino
authors.forename: Scott
authors.initials: S
authors.lastname: Brouilette
authors.forename: Peter
authors.initials: P
authors.lastname: Braund
authors.forename: Nighat
authors.initials: N
authors.lastname: Tirmizi
authors.forename: Mariuca
authors.initials: M
authors.lastname: Vasa-Nicotera
authors.forename: John R
authors.initials: JR
authors.lastname: Thompson
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000368:Aged; D002874:Chromosome Mapping; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D015894:Genome, Human; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D035781:Siblings; D016615:Telomere / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C109571:BICD1 protein, human; D003598:Cytoskeletal Proteins