title: Alleles that increase risk for type 2 diabetes mellitus are not associated with increased risk for Alzheimer's disease.
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.
authors.affiliation: King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK; Department of Psychiatry, State Key Laboratory of Brain and Cognitive Sciences, and Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong. Electronic address: petroula.proitsi@kcl.ac.uk.
authors.forename: Petroula
authors.initials: P
authors.lastname: Proitsi
authors.affiliation: King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
authors.forename: Michelle K
authors.initials: MK
authors.lastname: Lupton
authors.affiliation: King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
authors.forename: Latha
authors.initials: L
authors.lastname: Velayudhan
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, UK.
authors.forename: Gillian
authors.initials: G
authors.lastname: Hunter
authors.affiliation: King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Newhouse
authors.affiliation: King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
authors.forename: Kuang
authors.initials: K
authors.lastname: Lin
authors.affiliation: King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
authors.forename: Isabella
authors.initials: I
authors.lastname: Fogh
authors.affiliation: Memory and Dementia Centre, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Magda
authors.initials: M
authors.lastname: Tsolaki
authors.affiliation: Laboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Makrina
authors.initials: M
authors.lastname: Daniilidou
authors.affiliation: King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
authors.forename: Megan
authors.initials: M
authors.lastname: Pritchard
authors.affiliation: Ageing group, Centre for Public Health, School of Medicine and Dentistry, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors.forename: David
authors.initials: D
authors.lastname: Craig
authors.affiliation: Ageing group, Centre for Public Health, School of Medicine and Dentistry, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Todd
authors.affiliation: Ageing group, Centre for Public Health, School of Medicine and Dentistry, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors.forename: Janet A
authors.initials: JA
authors.lastname: Johnston
authors.affiliation: Ageing group, Centre for Public Health, School of Medicine and Dentistry, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors.forename: Bernadette
authors.initials: B
authors.lastname: McGuinness
authors.affiliation: Department of Old Age Psychiatry & Psychotic Disorders, Medical University of Lodz, Lodz, Poland.
authors.forename: Iwona
authors.initials: I
authors.lastname: Kloszewska
authors.affiliation: Department of Neurology, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland.
authors.forename: Hilkka
authors.initials: H
authors.lastname: Soininen
authors.affiliation: Section of Gerontology and Geriatrics, Department of Medicine, University of Perugia, Perugia, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Mecocci
authors.affiliation: Department of Internal and Geriatrics Medicine, INSERM U 1027, Gerontopole, Hôpitaux de Toulouse, Toulouse, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Vellas
authors.affiliation: Ageing group, Centre for Public Health, School of Medicine and Dentistry, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Passmore
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Sims
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Julie
authors.initials: J
authors.lastname: Williams
authors.affiliation: Department of Public Health and Primary Care, Cambridge Institute of Public Health, University of Cambridge, Cambridge, UK.
authors.forename: Carol
authors.initials: C
authors.lastname: Brayne
authors.affiliation: King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Stewart
authors.affiliation: Department of Psychiatry, State Key Laboratory of Brain and Cognitive Sciences, and Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong.
authors.forename: Pak
authors.initials: P
authors.lastname: Sham
authors.affiliation: King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK; Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX3 7JX, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Lovestone
authors.affiliation: King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
authors.forename: John F
authors.initials: JF
authors.lastname: Powell
mesh_terms: D000483:Alleles; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics*; D015897:Comorbidity; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D015201:Meta-Analysis as Topic; D012306:Risk
keywords: Environmental; Genetics; Genotype risk score; Late-onset Alzheimer's disease; Mediated pleiotropy; Type 2 diabetes mellitus