Alleles that increase risk for type 2 diabetes mellitus are not associated with increased risk for Alzheimer's disease

Petroula Proitsi, Michelle K. Lupton, Latha Velayudhan, Gillian Hunter, Stephen Newhouse, Kuang Lin, Isabella Fogh, Magda Tsolaki, Makrina Daniilidou, Megan Pritchard, David Craig, Stephen Todd, Janet A. Johnston, Bernadette McGuinness, Iwona Kloszewska, Hilkka Soininen, Patrizia Mecocci, Bruno Vellas, Peter A. Passmore, Rebecca SimsJulie Williams, Carol Brayne, Robert Stewart, Pak Sham, Simon Lovestone, John F. Powell

Research output: Contribution to journalArticle

Abstract

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.
Original languageEnglish
Pages (from-to)2883.e3-2883.e10
Number of pages8
JournalNeurobiology of Aging
Volume35
Issue number12
DOIs
Publication statusPublished - Dec 2014

Keywords

  • late-onset Alzheimer's disease
  • genetics
  • type 2 diabetes mellitus
  • genotype risk score
  • mediated pleiotropy
  • environment

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    Proitsi, P., Lupton, M. K., Velayudhan, L., Hunter, G., Newhouse, S., Lin, K., Fogh, I., Tsolaki, M., Daniilidou, M., Pritchard, M., Craig, D., Todd, S., Johnston, J. A., McGuinness, B., Kloszewska, I., Soininen, H., Mecocci, P., Vellas, B., Passmore, P. A., ... Powell, J. F. (2014). Alleles that increase risk for type 2 diabetes mellitus are not associated with increased risk for Alzheimer's disease. Neurobiology of Aging, 35(12), 2883.e3-2883.e10. https://doi.org/10.1016/j.neurobiolaging.2014.07.023