Among the participating COGS studies, the TL had been determined in cases and controls from the UK Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH) study (13 (
link),28 (
link)) (
http://ccge.medschl.cam.ac.uk/search/) controls from the Danish Copenhagen City Heart study (28 (
link),42 (
link),43 (
link)) (CCHS) and breast cancer cases from the Copenhagen General Population Study (18 (
link),44 (
link)) (CGPS). TL was measured using a real-time PCR methodology as described elsewhere (11 (
link)–13 (
link),45 (
link),46 (
link)) and a composite variable, putting the SEARCH, CCHS and CGPS data onto the same scale, was used for all analyses (28 (
link)) (see
Supplementary Material). All 187 647 SNPs with MAF >0.02 on the iCOGS chip that passed QC criteria were tested for association with TL in these subjects. Initially, analysis was confined to the healthy control subjects within each study (SEARCH females,
n = 6766; CCHS females,
n = 4537E and CCHS male,
n = 3762). A total of 272 SNPs were associated with TL, at
Ptrend < 10
−3, in these control subjects (
Supplementary Material, Table S1). All associations are consistent with a log-additive model.
In an exploratory attempt to increase the available sample size and thus the study power of this study, the above analysis was repeated using breast cancer cases as well as the healthy controls from these cancer studies. Therefore, SEARCH cases (
n = 8210) and CGPS cases (
n = 2814) were also included in the analysis. Of the 272 variants with per-allele
Ptrend < 10
−3 in the control-only analysis, 86 variants increased in significance upon inclusion of TL data from these breast cancer cases in our analysis (
Supplementary Material, Table S1). Among these were SNPs within all the loci previously and independently reported to be associated with TL; therefore, we feel confident that the inclusion of cancer cases is a valid way of increasing the study power.
Pooley K.A., Bojesen S.E., Weischer M., Nielsen S.F., Thompson D., Amin Al Olama A., Michailidou K., Tyrer J.P., Benlloch S., Brown J., Audley T., Luben R., Khaw K.T., Neal D.E., Hamdy F.C., Donovan J.L., Kote-Jarai Z., Baynes C., Shah M., Bolla M.K., Wang Q., Dennis J., Dicks E., Yang R., Rudolph A., Schildkraut J., Chang-Claude J., Burwinkel B., Chenevix-Trench G., Pharoah P.D., Berchuck A., Eeles R.A., Easton D.F., Dunning A.M, & Nordestgaard B.G. (2013). A genome-wide association scan (GWAS) for mean telomere length within the COGS project: identified loci show little association with hormone-related cancer risk. Human Molecular Genetics, 22(24), 5056-5064.