Genetic determinants of telomere length and risk of common cancers: a Mendelian randomization study

Chenan Zhang, Jennifer A. Doherty, Stephen Burgess, Rayjean J. Hung, Sara Lindström, Peter Kraft, Jian Gong, Christopher I. Amos, Thomas A. Sellers, Alvaro N.A. Monteiro, Georgia Chenevix-Trench, Heike Bickeböller, Angela Risch, Paul Brennan, James D. Mckay, Richard S. Houlston, Maria Teresa Landi, Maria N. Timofeeva, Yufei Wang, Joachim Heinrich, Zsofia Kote-Jarai, Rosalind A. Eeles, Ken Muir, Fredrik Wiklund, Henrik Grönberg, Sonja I. Berndt, Stephen J. Chanock, Fredrick Schumacher, Christopher A. Haiman, Brian E. Henderson, Ali Amin Al Olama, Irene L. Andrulis, John L. Hopper, Jenny Chang-Claude, Esther M. John, Kathleen E. Malone, Marilie D. Gammon, Giske Ursin, Alice S. Whittemore, David J. Hunter, Stephen B. Gruber, Julia A. Knight, Lifang Hou, Loic Le Marchand, Polly A. Newcomb, Thomas J. Hudson, Andrew T. Chan, Li Li, Michael O. Woods, Habibul Ahsan, Brandon L. Pierce

Epidemiological studies have reported inconsistent associations between telomere length (TL) and risk for various cancers. These inconsistencies are likely attributable, in part, to biases that arise due to post-diagnostic and post-treatment TL measurement. To avoid such biases, we used a Mendelian randomization approach and estimated associations between nine TL-associated SNPs and risk for five common cancer types (breast, lung, colorectal, ovarian and prostate cancer, including subtypes) using data on 51,725 cases and 62,035 controls. We then used an inverse-variance weighted average of the SNP-specific associations to estimate the association between a genetic score representing long TL and cancer risk. The long TL genetic score was significantly associated with increased risk of lung adenocarcinoma (P=6.3x10(-15)), even after exclusion of a SNP residing in a known lung cancer susceptibility region (TERT-CLPTM1L) P=6.6x10(-6)). Under Mendelian randomization assumptions, the association estimate (odds ratio (OR)=2.78) is interpreted as the OR for lung adenocarcinoma corresponding to a 1000 base pair increase in TL. The weighted TL SNP score was not associated with other cancer types or subtypes. Our finding that genetic determinants of long TL increase lung adenocarcinoma risk avoids issues with reverse causality and residual confounding that arise in observational studies of TL and disease risk. Under Mendelian randomization assumptions, our finding suggests that longer TL increases lung adenocarcinoma risk. However, caution regarding this causal interpretation is warranted in light of the potential issue of pleiotropy, and a more general interpretation is that SNPs influencing telomere biology are also implicated in lung adenocarcinoma risk.