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Human Molecular Genetics Advance Access published online on May 16, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn152
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

A regulatory SNP of the BICD1 gene contributes to telomere length variation in humans

Massimo Mangino1, Scott Brouilette1, Peter Braund1, Nighat Tirmizi1, Mariuca Vasa-Nicotera1, John R. Thompson2 and Nilesh J. Samani1,*

1 Departments of Cardiovascular Sciences and University of Leicester, Leicester, United Kingdom 2 Departments of Health Sciences, University of Leicester, Leicester, United Kingdom

* Correspondence to: Professor Nilesh J. Samani Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences Wing, Glenfield Hospital, Groby Road, Leicester, LE3 9QP, UK. E-mail: njs{at}le.ac.uk Fax No: +44 116 2875792 Tel No: +44 116 2563021

Received March 13, 2008; Revised April 27, 2008; Accepted May 14, 2008

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 [OMIM] ) gene. The strongest association (P=1.9x10–5) was with SNP rs2630778 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 leucocytes 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.


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