Journal
MOLECULAR PSYCHIATRY
Volume 17, Issue 12, Pages 1316-1327Publisher
SPRINGERNATURE
DOI: 10.1038/mp.2011.125
Keywords
Alzheimer's disease; psychosis; behavioural symptoms; genome-wide association study; genetic
Funding
- MRC
- Wellcome Trust
- Alzheimer's Research Trust
- Welsh Assembly Government
- Alzheimer's Society
- Ulster Garden Villages
- N Ireland RD Office
- Royal College of Physicians/Dunhill Medical Trust
- Mercer's Institute for Research on Ageing
- Lundbeck SA
- MRC [G0800509]
- National Institutes of Health [HHSN268200782096C]
- NIA-LOAD Family Study [U24AG026395]
- University of Pittsburgh [R01AG027224, R01AG030653, P50AG005133]
- Rush University Medical Center [P30AG10161]
- Boston Universit [P30AG013846]
- Columbia University [P50AG08702]
- Duke University [P30AG028377]
- Indiana University [P30AG010133]
- Massachusetts General Hospital [P50AG05134]
- Mayo Clinic, Rochester [P50AG165574]
- Mayo Clinic, Jacksonville [P50AG165574]
- Mount Sinai School of Medicine [P01AG05138, P01AG02219, P50AG05138]
- Northwestern University Medical School [P30AG13854]
- Oregon Health and Science University [P30AG008017]
- University of Alabama at Birmingham [P50AG016582]
- David Geffen School of Medicine, University of California, Los Angeles [P50AG016579]
- University of Kentucky, Lexington [P30AG028383]
- University of Pennsylvania [P30AG10124]
- University of Southern California [P50AG05142]
- University of Texas Southwestern Medical Center [P30AG12300]
- University of Washington [P50AG05136]
- Washington University School of Medicine [P50AG05681, P01AG03991]
- USPHS [AG027224]
- [U24AG021886]
- Alzheimers Research UK [ART-RF2007-3, ART-BIG2009-1] Funding Source: researchfish
- Medical Research Council [MC_U123160657, G0801418B, G0300429, MC_U123160651, G0800509, G0902227] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0611-10084] Funding Source: researchfish
- MRC [G0902227, G0800509, G0300429, MC_U123160651, MC_U123160657] Funding Source: UKRI
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Psychotic symptoms occur in similar to 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 x 10(-7); 'AD+PvControls' P=1.11 x 10(-4)). SNPs upstream of SLC2A9 (rs6834555, P=3.0 x 10(-7)) and within VSNL1 (rs4038131, P=5.9 x 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. Molecular Psychiatry (2012) 17, 1316-1327; doi: 10.1038/mp.2011.125; published online 18 October 2011
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