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

Abstract

Psychotic symptoms occur in approximately 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 (GWAS) to identify loci that a) increase susceptibility to an AD and subsequent psychotic symptoms; or b) modify risk of psychotic symptoms in the presence of neurodegeneration caused by AD. 1299 AD cases with psychosis (AD+P), 735 AD cases without psychosis (AD-P) and 5659 controls were drawn from GERAD1, the NIA-LOAD family study and the University of Pittsburgh ADRC GWAS. Unobserved genotypes were imputed to provide data on > 1.8 million SNPs. Analyses in each dataset were completed comparing a) AD+P to AD-P cases, and b) AD+P cases with controls (GERAD1, ADRC only). Aside from the 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 to controls. These findings warrant further investigation in larger, appropriately powered samples in which the presence of psychotic symptoms in AD has been well characterised.