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Genome-wide association study of Alzheimer's disease with psychotic symptoms

Hollingworth, Paul, Sweet, R., Sims, Rebecca ORCID:, Harold, Denise ORCID:, Russo, Giancarlo, Abraham, Richard Alun, Stretton, Alexandra, Denning, Nicola, Gerrish, Amy, Chapman, Jade Alice, Ivanov, Dobril ORCID:, Escott-Price, Valentina ORCID:, Lovestone, S., Priotsi, P., Lupton, M., Brayne, C., Gill, M., Lawlor, B., Lynch, A., Craig, D., McGuinness, B., Johnston, J., Holmes, C., Livingston, G., Bass, N. J., Gurling, H., McQuillin, A., Holmans, Peter Alan ORCID:, Jones, Lesley ORCID:, Devlin, B., Klei, L., Barmada, M. M., Demirci, F. Y., DeKosky, S. T., Lopez, O. L., Passmore, P., Owen, Michael John ORCID:, O'Donovan, Michael Conlon ORCID:, Mayeux, R., Kamboh, M. I. and Williams, Julie ORCID: 2012. Genome-wide association study of Alzheimer's disease with psychotic symptoms. Molecular Psychiatry 17 (12) , pp. 1316-1327. 10.1038/mp.2011.125

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Psychotic symptoms occur in ~40% of subjects with Alzheimer's disease (AD) and are associated with more rapid cognitive decline and increased functional deficits. They show heritability up to 61% and have been proposed as a marker for a disease subtype suitable for gene mapping efforts. We undertook a combined analysis of three genome-wide association studies (GWASs) to identify loci that (1) increase susceptibility to an AD and subsequent psychotic symptoms; or (2) modify risk of psychotic symptoms in the presence of neurodegeneration caused by AD. In all, 1299 AD cases with psychosis (AD+P), 735 AD cases without psychosis (AD–P) and 5659 controls were drawn from Genetic and Environmental Risk in AD Consortium 1 (GERAD1), the National Institute on Aging Late-Onset Alzheimer's Disease (NIA-LOAD) family study and the University of Pittsburgh Alzheimer Disease Research Center (ADRC) GWASs. Unobserved genotypes were imputed to provide data on >1.8 million single-nucleotide polymorphisms (SNPs). Analyses in each data set were completed comparing (1) AD+P to AD–P cases, and (2) AD+P cases with controls (GERAD1, ADRC only). Aside from the apolipoprotein E (APOE) locus, the strongest evidence for association was observed in an intergenic region on chromosome 4 (rs753129; ‘AD+PvAD–P’ P=2.85 × 10−7; ‘AD+PvControls’ P=1.11 × 10−4). SNPs upstream of SLC2A9 (rs6834555, P=3.0 × 10−7) and within VSNL1 (rs4038131, P=5.9 × 10−7) showed strongest evidence for association with AD+P when compared with controls. These findings warrant further investigation in larger, appropriately powered samples in which the presence of psychotic symptoms in AD has been well characterized.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Advanced Research Computing @ Cardiff (ARCCA)
Neuroscience and Mental Health Research Institute (NMHRI)
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > RZ Other systems of medicine
Uncontrolled Keywords: Alzheimer's disease; psychosis; behavioural symptoms; genome-wide association study; genetic
Publisher: Nature Publishing Group
ISSN: 1359-4184
Date of Acceptance: 25 August 2011
Last Modified: 04 Mar 2023 02:56

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