TY - JOUR
T1 - Alleles that increase risk for type 2 diabetes mellitus are not associated with increased risk for Alzheimer's disease
AU - Proitsi, Petroula
AU - Lupton, Michelle K
AU - Velayudhan, Latha
AU - Hunter, Gillian
AU - Newhouse, Stephen
AU - Lin, Kuang
AU - Fogh, Isabella
AU - Tsolaki, Magda
AU - Daniilidou, Makrina
AU - Pritchard, Megan
AU - Craig, David
AU - Todd, Stephen
AU - Johnston, Janet A
AU - McGuinness, Bernadette
AU - Kloszewska, Iwona
AU - Soininen, Hilkka
AU - Mecocci, Patrizia
AU - Vellas, Bruno
AU - Passmore, Peter A
AU - Sims, Rebecca
AU - Williams, Julie
AU - Brayne, Carol
AU - Stewart, Robert
AU - Sham, Pak
AU - Lovestone, Simon
AU - Powell, John F
AU - Alzheimer's Disease Neuroimaging Initiative
N1 - Copyright © 2014 Elsevier Inc. All rights reserved.
PY - 2014/12
Y1 - 2014/12
N2 - Although epidemiological studies suggest that type 2 diabetes mellitus (T2DM) increases the risk of late-onset Alzheimer's disease (LOAD), the biological basis of this relationship is not well understood. The aim of this study was to examine the genetic comorbidity between the 2 disorders and to investigate whether genetic liability to T2DM, estimated by a genotype risk scores based on T2DM associated loci, is associated with increased risk of LOAD. This study was performed in 2 stages. In stage 1, we combined genotypes for the top 15 T2DM-associated polymorphisms drawn from approximately 3000 individuals (1349 cases and 1351 control subjects) with extracted and/or imputed data from 6 genome-wide studies (>10,000 individuals; 4507 cases, 2183 controls, 4989 population controls) to form a genotype risk score and examined if this was associated with increased LOAD risk in a combined meta-analysis. In stage 2, we investigated the association of LOAD with an expanded T2DM score made of 45 well-established variants drawn from the 6 genome-wide studies. Results were combined in a meta-analysis. Both stage 1 and stage 2 T2DM risk scores were not associated with LOAD risk (odds ratio = 0.988; 95% confidence interval, 0.972-1.004; p = 0.144 and odds ratio = 0.993; 95% confidence interval, 0.983-1.003; p = 0.149 per allele, respectively). Contrary to expectation, genotype risk scores based on established T2DM candidates were not associated with increased risk of LOAD. The observed epidemiological associations between T2DM and LOAD could therefore be a consequence of secondary disease processes, pleiotropic mechanisms, and/or common environmental risk factors. Future work should focus on well-characterized longitudinal cohorts with extensive phenotypic and genetic data relevant to both LOAD and T2DM.
AB - Although epidemiological studies suggest that type 2 diabetes mellitus (T2DM) increases the risk of late-onset Alzheimer's disease (LOAD), the biological basis of this relationship is not well understood. The aim of this study was to examine the genetic comorbidity between the 2 disorders and to investigate whether genetic liability to T2DM, estimated by a genotype risk scores based on T2DM associated loci, is associated with increased risk of LOAD. This study was performed in 2 stages. In stage 1, we combined genotypes for the top 15 T2DM-associated polymorphisms drawn from approximately 3000 individuals (1349 cases and 1351 control subjects) with extracted and/or imputed data from 6 genome-wide studies (>10,000 individuals; 4507 cases, 2183 controls, 4989 population controls) to form a genotype risk score and examined if this was associated with increased LOAD risk in a combined meta-analysis. In stage 2, we investigated the association of LOAD with an expanded T2DM score made of 45 well-established variants drawn from the 6 genome-wide studies. Results were combined in a meta-analysis. Both stage 1 and stage 2 T2DM risk scores were not associated with LOAD risk (odds ratio = 0.988; 95% confidence interval, 0.972-1.004; p = 0.144 and odds ratio = 0.993; 95% confidence interval, 0.983-1.003; p = 0.149 per allele, respectively). Contrary to expectation, genotype risk scores based on established T2DM candidates were not associated with increased risk of LOAD. The observed epidemiological associations between T2DM and LOAD could therefore be a consequence of secondary disease processes, pleiotropic mechanisms, and/or common environmental risk factors. Future work should focus on well-characterized longitudinal cohorts with extensive phenotypic and genetic data relevant to both LOAD and T2DM.
KW - Alleles
KW - Alzheimer Disease
KW - Comorbidity
KW - Diabetes Mellitus, Type 2
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study
KW - Genotype
KW - Humans
KW - Meta-Analysis as Topic
KW - Risk
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
UR - http://www.scopus.com/inward/record.url?scp=84911455173&partnerID=8YFLogxK
U2 - 10.1016/j.neurobiolaging.2014.07.023
DO - 10.1016/j.neurobiolaging.2014.07.023
M3 - Article
C2 - 25150574
AN - SCOPUS:84911455173
SN - 0197-4580
VL - 35
SP - 2883.e3-2883.e10
JO - Neurobiology of Aging
JF - Neurobiology of Aging
IS - 12
M1 - 2883
ER -