Telomere length and aging‐related outcomes in humans: A Mendelian randomization study in 261,000 older participants

Abstract Inherited genetic variation influencing leukocyte telomere length provides a natural experiment for testing associations with health outcomes, more robust to confounding and reverse causation than observational studies. We tested associations between genetically determined telomere length and aging‐related health outcomes in a large European ancestry older cohort. Data were from n = 379,758 UK Biobank participants aged 40–70, followed up for mean of 7.5 years (n = 261,837 participants aged 60 and older by end of follow‐up). Thirteen variants strongly associated with longer telomere length in peripheral white blood cells were analyzed using Mendelian randomization methods with Egger plots to assess pleiotropy. Variants in TERC, TERT, NAF1, OBFC1, and RTEL1 were included, and estimates were per 250 base pairs increase in telomere length, approximately equivalent to the average change over a decade in the general white population. We highlighted associations with false discovery rate‐adjusted p‐values smaller than .05. Genetically determined longer telomere length was associated with lowered risk of coronary heart disease (CHD; OR = 0.95, 95% CI: 0.92–0.98) but raised risk of cancer (OR = 1.11, 95% CI: 1.06–1.16). Little evidence for associations were found with parental lifespan, centenarian status of parents, cognitive function, grip strength, sarcopenia, or falls. The results for those aged 60 and older were similar in younger or all participants. Genetically determined telomere length was associated with increased risk of cancer and reduced risk of CHD but little change in other age‐related health outcomes. Telomere lengthening may offer little gain in later‐life health status and face increasing cancer risks.


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FIG. 1: Per allele association with any fall in the last year: log of odds ratio for any fall in the last year per effect allele, allele associated with longer telomere length; Per allele association with mean telomere length: SD change in mean telomere length per effect allele. Inverse-variance weighted (IVW), likelihood-based (MaxLik), and MR-Egger (beta) p-values for associations with telomere length and MR-Egger (intercept) for pleiotropy.
FIG. 2: Per allele association with back pain for 3+ months: log of odds ratio for back pain for 3+ months per effect allele, allele associated with longer telomere length; Per allele association with mean telomere length: SD change in mean telomere length per effect allele. Inverse-variance weighted (IVW), likelihood-based (MaxLik), and MR-Egger (beta) p-values for associations with telomere length and MR-Egger (intercept) for pleiotropy.
FIG. 3: Per allele association with both parents top 10% survival: log of odds ratio for both parents top 10% survival per effect allele, allele associated with longer telomere length; Per allele association with mean telomere length: SD change in mean telomere length per effect allele. Inverse-variance weighted (IVW), likelihood-based (MaxLik), and MR-Egger (beta) p-values for associations with telomere length and MR-Egger (intercept) for pleiotropy.
FIG. 4: Per allele association with breast cancer: log of odds ratio for breast cancer per effect allele, allele associated with longer telomere length; Per allele association with mean telomere length: SD change in mean telomere length per effect allele. Inverse-variance weighted (IVW), likelihood-based (MaxLik), and MR-Egger (beta) p-values for associations with telomere length and MR-Egger (intercept) for pleiotropy.
FIG. 5: Per allele association with cancer: log of odds ratio for cancer excluding non-melanoma skin cancers per effect allele, allele associated with longer telomere length; Per allele association with mean telomere length: SD change in mean telomere length per effect allele. Inverse-variance weighted (IVW), likelihood-based (MaxLik), and MR-Egger (beta) p-values for associations with telomere length and MR-Egger (intercept) for pleiotropy.
FIG. 6: Per allele association with centenarian status of parents: log of odds ratio for centenarian status of parents per effect allele, allele associated with longer telomere length; Per allele association with mean telomere length: SD change in mean telomere length per effect allele. Inverse-variance weighted (IVW), likelihood-based (MaxLik), and MR-Egger (beta) p-values for associations with telomere length and MR-Egger (intercept) for pleiotropy. FIG. 7: Per allele association with colorectal cancer: log of odds ratio for colorectal cancer per effect allele, allele associated with longer telomere length; Per allele association with mean telomere length: SD change in mean telomere length per effect allele. Inverse-variance weighted (IVW), likelihood-based (MaxLik), and MR-Egger (beta) p-values for associations with telomere length and MR-Egger (intercept) for pleiotropy.
FIG. 8: Per allele association with CHD: log of odds ratio for coronary heart disease per effect allele, allele associated with longer telomere length; Per allele association with mean telomere length: SD change in mean telomere length per effect allele. Inverse-variance weighted (IVW), likelihood-based (MaxLik), and MR-Egger (beta) p-values for associations with telomere length and MR-Egger (intercept) for pleiotropy.
FIG. 9: Per allele association with depression over the last two weeks: log of odds ratio for depression over the last two weeks per effect allele, allele associated with longer telomere length; Per allele association with mean telomere length: SD change in mean telomere length per effect allele. Inverse-variance weighted (IVW), likelihood-based (MaxLik), and MR-Egger (beta) p-values for associations with telomere length and MR-Egger (intercept) for pleiotropy.
FIG. 10: Per allele association with diastolic blood pressure: log of odds ratio for diastolic blood pressure per effect allele, allele associated with longer telomere length; Per allele association with mean telomere length: SD change in mean telomere length per effect allele. Inverse-variance weighted (IVW), likelihood-based (MaxLik), and MR-Egger (beta) p-values for associations with telomere length and MR-Egger (intercept) for pleiotropy.
FIG. 11: Per allele association with father's age at death: log of odds ratio for father's age at death per effect allele, allele associated with longer telomere length; Per allele association with mean telomere length: SD change in mean telomere length per effect allele. Inverse-variance weighted (IVW), likelihood-based (MaxLik), and MR-Egger (beta) p-values for associations with telomere length and MR-Egger (intercept) for pleiotropy.
FIG. 12: Per allele association with FEV1: log of odds ratio for FEV1 per effect allele, allele associated with longer telomere length; Per allele association with mean telomere length: SD change in mean telomere length per effect allele. Inverse-variance weighted (IVW), likelihood-based (MaxLik), and MR-Egger (beta) p-values for associations with telomere length and MR-Egger (intercept) for pleiotropy. FIG. 20: Per allele association with hip pain for 3+ months: log of odds ratio for hip pain for 3+ months per effect allele, allele associated with longer telomere length; Per allele association with mean telomere length: SD change in mean telomere length per effect allele. Inverse-variance weighted (IVW), likelihood-based (MaxLik), and MR-Egger (beta) p-values for associations with telomere length and MR-Egger (intercept) for pleiotropy.
FIG. 21: Per allele association with hypertension: log of odds ratio for hypertension per effect allele, allele associated with longer telomere length; Per allele association with mean telomere length: SD change in mean telomere length per effect allele. Inverse-variance weighted (IVW), likelihood-based (MaxLik), and MR-Egger (beta) p-values for associations with telomere length and MR-Egger (intercept) for pleiotropy.
FIG. 22: Per allele association with knee pain for 3+ months: log of odds ratio for knee pain for 3+ months per effect allele, allele associated with longer telomere length; Per allele association with mean telomere length: SD change in mean telomere length per effect allele. Inverse-variance weighted (IVW), likelihood-based (MaxLik), and MR-Egger (beta) p-values for associations with telomere length and MR-Egger (intercept) for pleiotropy.
FIG. 23: Per allele association with low hand grip strength: log of odds ratio for low hand grip strength per effect allele, allele associated with longer telomere length; Per allele association with mean telomere length: SD change in mean telomere length per effect allele. Inverse-variance weighted (IVW), likelihood-based (MaxLik), and MR-Egger (beta) p-values for associations with telomere length and MR-Egger (intercept) for pleiotropy.
FIG. 24: Per allele association with low muscle mass: log of odds ratio for low muscle mass per effect allele, allele associated with longer telomere length; Per allele association with mean telomere length: SD change in mean telomere length per effect allele. Inverse-variance weighted (IVW), likelihood-based (MaxLik), and MR-Egger (beta) p-values for associations with telomere length and MR-Egger (intercept) for pleiotropy.
FIG. 25: Per allele association with mother's age at death: log of odds ratio for mother's age at death per effect allele, allele associated with longer telomere length; Per allele association with mean telomere length: SD change in mean telomere length per effect allele. Inverse-variance weighted (IVW), likelihood-based (MaxLik), and MR-Egger (beta) p-values for associations with telomere length and MR-Egger (intercept) for pleiotropy.
FIG. 26: Per allele association with parents' age at death: log of odds ratio for parents' age at death (average of z-transformed father's and mother's age at death) per effect allele, allele associated with longer telomere length; Per allele association with mean telomere length: SD change in mean telomere length per effect allele. Inverse-variance weighted (IVW), likelihood-based (MaxLik), and MR-Egger (beta) p-values for associations with telomere length and MR-Egger (intercept) for pleiotropy.
FIG. 27: Per allele association with pneumonia: log of odds ratio for pneumonia per effect allele, allele associated with longer telomere length; Per allele association with mean telomere length: SD change in mean telomere length per effect allele. Inversevariance weighted (IVW), likelihood-based (MaxLik), and MR-Egger (beta) p-values for associations with telomere length and MR-Egger (intercept) for pleiotropy.
FIG. 28: Per allele association with prostate cancer: log of odds ratio for log of prostate cancer per effect allele, allele associated with longer telomere length; Per allele association with mean telomere length: SD change in mean telomere length per effect allele. Inverse-variance weighted (IVW), likelihood-based (MaxLik), and MR-Egger (beta) p-values for associations with telomere length and MR-Egger (intercept) for pleiotropy.
FIG. 29: Per allele association with log(reaction time): log of odds ratio for log of reaction time per effect allele, allele associated with longer telomere length; Per allele association with mean telomere length: SD change in mean telomere length per effect allele. Inverse-variance weighted (IVW), likelihood-based (MaxLik), and MR-Egger (beta) p-values for associations with telomere length and MR-Egger (intercept) for pleiotropy.
FIG. 30: Per allele association with sarcopenia: log of odds ratio for sarcopenia per effect allele, allele associated with longer telomere length; Per allele association with mean telomere length: SD change in mean telomere length per effect allele. Inversevariance weighted (IVW), likelihood-based (MaxLik), and MR-Egger (beta) p-values for associations with telomere length and MR-Egger (intercept) for pleiotropy.
FIG. 31: Per allele association with systolic blood pressure: log of odds ratio for systolic blood pressure per effect allele, allele associated with longer telomere length; Per allele association with mean telomere length: SD change in mean telomere length per effect allele. Inverse-variance weighted (IVW), likelihood-based (MaxLik), and MR-Egger (beta) p-values for associations with telomere length and MR-Egger (intercept) for pleiotropy.
FIG. 32: Per allele association with log(visual memory errors+1): log of odds ratio for visual memory errors per effect allele, allele associated with longer telomere length; Per allele association with mean telomere length: SD change in mean telomere length per effect allele. Inverse-variance weighted (IVW), likelihood-based (MaxLik), and MR-Egger (beta) p-values for associations with telomere length and MR-Egger (intercept) for pleiotropy.