Telomere length and health outcomes: A two-sample genetic instrumental variables analysis.
Previous studies linking telomere length (TL) and health have been largely associational. We apply genetic instrumental variables (IV) analysis, also known as Mendelian randomization, to test the hypothesis that shorter TL leads to poorer health. This method reduces bias from reverse causation or confounding.



We used two approaches in this study that rely on two separate data sources: (1) individual-level data from the Health and Retirement Study (HRS) (N=3734), and (2) coefficients from genome-wide association studies (GWAS). We employed two-sample genetic IV analyses, constructing a polygenic risk score (PRS) of TL-associated single nucleotide polymorphisms. The first approach examined the association of the PRS with nine individual health outcomes in HRS. The second approach took advantage of estimates available in GWAS databases to estimate the impact of TL on five health outcomes using an inverse variance-weighted meta-analytic technique.



Using individual-level data, shorter TL was marginally statistically significantly associated with decreased risk of stroke and increased risk of heart disease. Using the meta-analytic approach, shorter TL was associated with increased risk of coronary artery disease (OR 1.02 per 100 base pairs, 95%CI: 1.00, 1.03).



With the exception of a small contribution to heart disease, our findings suggest that TL may be a marker of disease rather than a cause. They also demonstrate the utility of the inverse variance-weighted meta-analytic approach when examining small effect sizes.
Stanford University, Department of Medicine, 1070 Arastradero Road, Palo Alto, CA 94304, USA. Electronic address: rhamad@stanford.edu.
Rita
R
Hamad
University of California San Francisco, Department of Epidemiology & Biostatistics, 550 16th Street, San Francisco, CA 94158, USA.
Stefan
S
Walter
Stanford University, Department of Medicine, 1070 Arastradero Road, Palo Alto, CA 94304, USA.
David H
DH
Rehkopf
D000368:Aged; D000375:Aging / Q000235:genetics* / Q000502:physiology*; D003324:Coronary Artery Disease / Q000453:epidemiology* / Q000235:genetics; D016208:Databases, Factual; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D017720:Molecular Epidemiology; D020641:Polymorphism, Single Nucleotide; D057566:Self Report; D016615:Telomere / Q000648:ultrastructure*; D059505:Telomere Homeostasis / Q000502:physiology*; D014481:United States
Aging; Cardiovascular disease; Genetic instrumental variables; Mendelian randomization; Telomere length