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

• Published in: Molecular psychiatry Vol. 17; no. 12; pp. 1316 - 1327
• Main Authors: Hollingworth, P, Sweet, R, Sims, R, Harold, D, Russo, G, Abraham, R, Stretton, A, Jones, N, Gerrish, A, Chapman, J, Ivanov, D, Moskvina, V, 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, P, Jones, L, Devlin, B, Klei, L, Barmada, M M, Demirci, F Y, DeKosky, S T, Lopez, O L, Passmore, P, Owen, M J, O'Donovan, M C, Mayeux, R, Kamboh, M I, Williams, J
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2012; Nature Publishing Group
• Subjects: 631/208/205/2138; 631/378/1689/1761; 692/699/375/132/1283; Adult and adolescent clinical studies; Aged; Aged, 80 and over; Aging; Alzheimer Disease - complications; Alzheimer Disease - genetics; Alzheimer Disease - psychology; Alzheimer's disease; Apolipoprotein E; Apolipoproteins E - genetics; Behavioral Sciences; Biological and medical sciences; Biological Psychology; Bipolar disorder; Case-Control Studies; Chromosome 4; Chromosomes, Human, Pair 4 - genetics; Cognitive ability; Consortia; Data processing; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Development and progression; Disease; DNA, Intergenic - genetics; Family studies; Female; Gene mapping; Genes; Genetic aspects; Genetic Predisposition to Disease - genetics; Genetics; Genome-wide association studies; Genome-Wide Association Study - methods; Genome-Wide Association Study - statistics & numerical data; Genomes; Genomics; Glucose Transport Proteins, Facilitative - genetics; Heritability; Human health and pathology; Humans; Life Sciences; Male; Medical sciences; Medicine; Medicine & Public Health; Mental disorders; Mental health; Middle Aged; Neurocalcin - genetics; Neurodegeneration; Neurodegenerative diseases; Neurology; Neurosciences; Organic mental disorders. Neuropsychology; original-article; Pharmacotherapy; Physiological aspects; Polymorphism, Single Nucleotide - genetics; Proteins; Psychiatric Status Rating Scales - statistics & numerical data; Psychiatrics and mental health; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychoses; Psychosis; Psychotic Disorders - complications; Psychotic Disorders - diagnosis; Psychotic Disorders - genetics; Public health; Single-nucleotide polymorphism; United States; United Kingdom; United Kingdom > UK; United States > US; Pittsburgh Pennsylvania; genetic; behavioural symptoms; Alzheimer's disease; psychosis; genome-wide association study; Nervous system diseases; Alzheimer disease; Cerebral disorder; Behavioral disorder; Psychosis; Symptomatology; Central nervous system disease; Genetics; Degenerative disease
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/mp.2011.125

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.