TY - JOUR
T1 - Observational and genetic studies of short telomeres and Alzheimer’s disease in 67,000 and 152,000 individuals
T2 - a Mendelian randomization study
AU - Scheller Madrid, Alexander
AU - Rasmussen, Katrine L.
AU - Rode, Line
AU - Frikke-Schmidt, Ruth
AU - Nordestgaard, Børge G.
AU - Bojesen, Stig E.
PY - 2020
Y1 - 2020
N2 - Short telomeres might lead to increased risk of Alzheimer’s disease, but observational analyses have been inconclusive and potentially confounded by the strong association of both telomere length and risk of Alzheimer’s disease with age and adverse lifestyle. To circumvent this, analyses including single nucleotide polymorphisms associated with telomere length used in an instrumental variable analysis produces risk estimates likely free of distortions from reverse causation and of most confounding. We tested the hypothesis that short telomeres are associated with increased risk of Alzheimer’s disease, observationally and causal, genetically. Telomere length was measured in 66,567 individuals, and genotyped for rs2487999 in OBFC1, rs7726159 in TERT, and rs1317082 in TERC causing lifelong telomere shortening in 98,146 individuals from two Copenhagen studies. Genetic data on 54,162 individuals from the International Genomics of Alzheimer’s Project were also included. Observationally, multifactorially adjusted hazard ratio for Alzheimer’s disease was 1.02 (95% CI 1.00–1.03) per 200 base pair shorter telomeres. Telomere length was 335 base pairs shorter in individuals with 6 versus 0–1 alleles (p = 5 × 10−105). Genetically, odds ratio for Alzheimer’s disease was 1.08 (1.01–1.16) per 200 base pairs shorter telomeres. Similar results were found in strata of age and comorbidities. In comparative analyses, genetically predicted shorter telomeres were associated with increased risk of myocardial infarction, and with decreased risks of lung cancer and melanoma as previously reported. Short telomeres were associated observationally and causal, genetically with increased risk of Alzheimer’s disease. Telomere biology is therefore a potential pathway involved in the development of Alzheimer’s disease.
AB - Short telomeres might lead to increased risk of Alzheimer’s disease, but observational analyses have been inconclusive and potentially confounded by the strong association of both telomere length and risk of Alzheimer’s disease with age and adverse lifestyle. To circumvent this, analyses including single nucleotide polymorphisms associated with telomere length used in an instrumental variable analysis produces risk estimates likely free of distortions from reverse causation and of most confounding. We tested the hypothesis that short telomeres are associated with increased risk of Alzheimer’s disease, observationally and causal, genetically. Telomere length was measured in 66,567 individuals, and genotyped for rs2487999 in OBFC1, rs7726159 in TERT, and rs1317082 in TERC causing lifelong telomere shortening in 98,146 individuals from two Copenhagen studies. Genetic data on 54,162 individuals from the International Genomics of Alzheimer’s Project were also included. Observationally, multifactorially adjusted hazard ratio for Alzheimer’s disease was 1.02 (95% CI 1.00–1.03) per 200 base pair shorter telomeres. Telomere length was 335 base pairs shorter in individuals with 6 versus 0–1 alleles (p = 5 × 10−105). Genetically, odds ratio for Alzheimer’s disease was 1.08 (1.01–1.16) per 200 base pairs shorter telomeres. Similar results were found in strata of age and comorbidities. In comparative analyses, genetically predicted shorter telomeres were associated with increased risk of myocardial infarction, and with decreased risks of lung cancer and melanoma as previously reported. Short telomeres were associated observationally and causal, genetically with increased risk of Alzheimer’s disease. Telomere biology is therefore a potential pathway involved in the development of Alzheimer’s disease.
KW - Alzheimer’s disease
KW - Causal association
KW - General population
KW - Mendelian randomization
KW - Telomere length
U2 - 10.1007/s10654-019-00563-w
DO - 10.1007/s10654-019-00563-w
M3 - Journal article
C2 - 31564046
AN - SCOPUS:85073986104
VL - 35
SP - 147
EP - 156
JO - European Journal of Epidemiology
JF - European Journal of Epidemiology
SN - 0393-2990
IS - 2
ER -