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

Hollingworth, Paul, Sweet, R., Sims, Rebecca, Harold, Denise, Russo, Giancarlo, Abraham, Richard Alun, Stretton, Alexandra, Denning, Nicola, Gerrish, Amy, Chapman, Jade Alice, Ivanov, Dobril, Escott-Price, Valentina, 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, Jones, Lesley, Devlin, B., Klei, L., Barmada, M. M., Demirci, F. Y., DeKosky, S. T., Lopez, O. L., Passmore, P., Owen, Michael John, O'Donovan, Michael Conlon, Mayeux, R., Kamboh, M. I. and Williams, Julie 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: 07 Aug 2022 07:17

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