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Mol Psychiatry. 2012 Dec;17(12):1316-27. doi: 10.1038/mp.2011.125. Epub 2011 Oct 18.

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

Collaborators (147)

Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere M, Pahwa JS, Moskvina V, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan A, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown K, Passmore P, Craig D, McGuinness B, Todd S, Johnston J, Holmes C, Mann D, Smith A, Love S, Kehoe PG, Hardy J, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Heun R, Kölsch H, Schürmann B, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frölich L, Hampel H, Hüll M, Rujescu D, Goate A, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Singleton AB, Guerreiro R, Mühleisen TW, Nöthen MM, Moebus S, Jöckel KH, Klopp N, Wichmann HE, Carrasquillo MM, Pankratz V, Younkin SG, Holmans P, O'Donovan M, Owen MJ, Williams J, Green R, Kowall N, Farrer L, Williamson J, Santana V, Schmechel D, Gaskel P, Ghetti B, Farlow MR, Horner K, Growdon JH, Blacker D, Tanzi RE, Hyman BT, Boeve B, Kuntz K, Norgaard L, Larson N, Kistler D, Parfitt F, Haddow J, Silverman J, Schnaider Beeri M, Sano M, Wang J, Lally R, Johnson N, Mesulum M, Weintraub S, Bigio E, Kaye J, Kramer P, Payne-Murphy J, Bennett D, Jacobs H, Chang JS, Arends D, Harrell L, Bartzokis G, Cummings J, Lu PH, Toland U, Smith C, Brickhouse A, Trojanowski J, Van Deerlin V, McCarty Wood E, Lopez OL, Sweet RA, Chui IH, Varpetian A, Diaz-Arrastia R, Rosenberg R, Davis B, Bird T, Rumbaugh M, Schellenberg GD, Raskind M, Goate A, Morris J, Norton J, Levitch D, Grant B, Coats M.

Author information

1
Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Neurosciences and Mental Health Research Institute, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK.

Abstract

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.

PMID:
22005930
PMCID:
PMC3272435
DOI:
10.1038/mp.2011.125
[Indexed for MEDLINE]
Free PMC Article

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