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

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

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.

Publication types

  • Meta-Analysis
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / complications
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / psychology*
  • Apolipoproteins E / genetics
  • Case-Control Studies
  • Chromosomes, Human, Pair 4 / genetics
  • DNA, Intergenic / genetics
  • Female
  • Genetic Predisposition to Disease / genetics
  • Genome-Wide Association Study / methods
  • Genome-Wide Association Study / statistics & numerical data*
  • Glucose Transport Proteins, Facilitative / genetics*
  • Humans
  • Male
  • Middle Aged
  • Neurocalcin / genetics*
  • Polymorphism, Single Nucleotide / genetics
  • Psychiatric Status Rating Scales / statistics & numerical data
  • Psychotic Disorders / complications
  • Psychotic Disorders / diagnosis
  • Psychotic Disorders / genetics*

Substances

  • Apolipoproteins E
  • DNA, Intergenic
  • Glucose Transport Proteins, Facilitative
  • Neurocalcin
  • SLC2A9 protein, human
  • VSNL1 protein, human

Grant support