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Research Letter |

Telomere Length Shortening and Alzheimer Disease—A Mendelian Randomization Study

Yiqiang Zhan, MD1; Ci Song, PhD1; Robert Karlsson, PhD1; Annika Tillander, PhD1; Chandra A. Reynolds, PhD2; Nancy L. Pedersen, PhD1; Sara Hägg, PhD1
[+] Author Affiliations
1Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
2Department of Psychology, University of California, Riverside
JAMA Neurol. 2015;72(10):1202-1203. doi:10.1001/jamaneurol.2015.1513.
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This study explores the causal effect of telomere length on Alzheimer disease by applying the mendelian randomization method to summary genome-wide association study data.

Telomeres are sequences of repetitive nucleotides at the end of the chromosomes, which protect them from fusion with neighboring chromosomes.1 Observational studies have found associations between shorter telomeres and Alzheimer disease (AD).2 However, these studies could have residual confounding or reverse causation, making it difficult to draw conclusions on whether telomere length (TL) is causally associated with AD. For the past decades, instrumental variable (IV) analysis has been developed for assessing causality using genetic variants in epidemiological research under the name of mendelian randomization (MR).3 In the present study, we investigated the causal effect of TL on AD by applying the MR method to summary genome-wide association study (GWAS) data from Codd et al4 and from the International Genomics of Alzheimer’s Project Consortium.5

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Genetic and Causal Effects of Leukocyte Telomere Length (TL) on Alzheimer Disease (AD), Odds Ratios (ORs), and 95% CIs

Mendelian randomization methods allow for causal interpretations of the effect of a phenotype, here TL, on an outcome, here AD, by the use of genetic variants to generate instrumental variable (IV) estimates. A, The effects of TL-associated variants and genetic risk score (GRS) on AD using data from the International Genomics of Alzheimer’s Project Consortium in the Lambert et al5 study. The OR could be interpreted as changes in odds per TL-decreasing allele for AD. B, IV estimates of TL on AD for each variant and GRS. The OR could be interpreted as changes in odds per SD increase of TL for AD. SNP indicates single-nucleotide polymorphism.

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