Mendelian randomization study of the association between telomere length and risk of cancer and non-neoplastic diseases

Abstract

$\textbf{Importance}$ The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain, due to the susceptibility of observational studies to confounding and reverse causation. $\textbf{Objective}$ To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. $\textbf{Data Sources}$ Genome-wide association studies (GWAS) published up to January 15 2015. $\textbf{Study Selection}$ GWAS of non-communicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of pre-existing diseases. Of 163 GWAS of non-communicable diseases identified, summary data from 103 were available. $\textbf{Data Extraction}$ Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. $\textbf{Main Outcomes}$ Odds ratios (ORs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. $\textbf{Results}$ Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420,081 cases (median 2,526 per disease) and 1,093,105 controls (median 6,789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations were observed for (ORs per 1-SD change in genetically increased telomere length): glioma 5.27 (3.15-8.81), serous low-malignant-potential ovarian cancer 4.35 (2.39-7.94), lung adenocarcinoma 3.19 (2.40-4.22), neuroblastoma 2.98 (1.92-4.62) , bladder cancer 2.19 (1.32-3.66), melanoma 1.87 (1.55-2.26), testicular cancer 1.76 (1.02- 3.04), kidney cancer 1.55 (1.08-2.23) and endometrial cancer 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division (P<0.05). There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic and other non-neoplastic diseases, except for coronary heart disease (0.78 [0.67-0.90]), abdominal aortic aneurysm (0.63 [0.49-0.81]), celiac disease (0.42 [0.28-0.61]) and interstitial lung disease (0.09 [0.05- 0.15]). $\textbf{Conclusions}$ It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.