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

P. Hollingworth, R. Sweet*, R. Sims, D. Harold, G. Russo, R. Abraham, A. Stretton, N. Jones, A. Gerrish, J. Chapman, D. Ivanov, V. Moskvina, S. Lovestone, P. Priotsi, Michelle Lupton, C. Brayne, M. Gill, B. Lawlor, A. Lynch, D. CraigB. McGuinness, J. Johnston, C. Holmes, G. Livingston, N. J. Bass, H. Gurling, A. McQuillin, P. Holmans, L. Jones, B. Devlin, L. Klei, M. M. Barmada, F. Y. Demirci, S. T. DeKosky, O. L. Lopez, P. Passmore, M. J. Owen, M. C. O'Donovan, R. Mayeux, M. I. Kamboh, J. Williams, GERAD Consortium, Natl Inst Aging Late-Onset Alzheim

*Corresponding author for this work

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Abstract

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

Original languageEnglish
Article numberN/A
Pages (from-to)1316-1327
Number of pages12
JournalMolecular Psychiatry
Volume17
Issue number12
DOIs
Publication statusPublished - Dec 2012

Keywords

  • Alzheimer's disease
  • psychosis
  • behavioural symptoms
  • genome-wide association study
  • genetic
  • INCREASED FAMILIAL RISK
  • COMPLEMENT RECEPTOR 1
  • COMMON VARIANTS
  • BIPOLAR DISORDER
  • URIC-ACID
  • NEUROPSYCHIATRIC INVENTORY
  • COGNITIVE IMPAIRMENT
  • CEREBROSPINAL-FLUID
  • IDENTIFIES VARIANTS
  • NATIONAL INSTITUTE

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