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Observational and genetic studies of short telomeres and Alzheimer's disease in 67,000 and 152,000 individuals: a Mendelian randomization study

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@article{3cb0fa885963445e961d2b3f88ce0330,
title = "Observational and genetic studies of short telomeres and Alzheimer's disease in 67,000 and 152,000 individuals: a Mendelian randomization study",
abstract = "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.",
keywords = "Alzheimer’s disease, Causal association, General population, Mendelian randomization, Telomere length, Humans, Middle Aged, Risk Factors, Telomere Shortening/genetics, Genetic Predisposition to Disease/genetics, Male, Mendelian Randomization Analysis/methods, Alzheimer Disease/diagnosis, Telomere, Genetic Variation, Adult, Female",
author = "{Scheller Madrid}, Alexander and Rasmussen, {Katrine L} and Line Rode and Ruth Frikke-Schmidt and Nordestgaard, {B{\o}rge G} and Bojesen, {Stig E}",
year = "2020",
month = "2",
doi = "10.1007/s10654-019-00563-w",
language = "English",
volume = "35",
pages = "147--156",
journal = "European Journal of Epidemiology",
issn = "0393-2990",
publisher = "Springer Netherlands",
number = "2",

}

RIS

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 - 2020/2

Y1 - 2020/2

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

KW - Humans

KW - Middle Aged

KW - Risk Factors

KW - Telomere Shortening/genetics

KW - Genetic Predisposition to Disease/genetics

KW - Male

KW - Mendelian Randomization Analysis/methods

KW - Alzheimer Disease/diagnosis

KW - Telomere

KW - Genetic Variation

KW - Adult

KW - Female

U2 - 10.1007/s10654-019-00563-w

DO - 10.1007/s10654-019-00563-w

M3 - Journal article

VL - 35

SP - 147

EP - 156

JO - European Journal of Epidemiology

JF - European Journal of Epidemiology

SN - 0393-2990

IS - 2

ER -

ID: 59307757