Investigating psychosis candidate genes in Alzheimer's disease with psychosis using genome-wide association studies

Abstract

As Alzheimer's disease (AD) progresses many sufferers experience additional behavioural and psychological symptoms such as psychosis. Psychotic symptoms are reported to affect 40-60% of individuals with AD and are associated with more rapid cognitive and functional decline, more severe cognitive impairment, premature institutionalization, and increased risks for agitated and aggressive behaviour. Several studies demonstrate excess aggregation of psychosis in families, suggesting that psychosis in Alzheimer disease (AD+P) represents a distinct subtype that is, in part, genetically determined. Recent studies in schizophrenia, bipolar affective disorder (BPAD) and AD+P suggest that psychosis susceptibility or modifier genes may act across the “disease divide”. Our study investigates susceptibility genes for psychosis related disorders identified through genome-wide association (GWA) studies, in our large GWA study of AD which includes 1,971 cases stratified for the presence or absence of psychotic symptoms. Psychosis candidate genes were chosen for investigation on the basis that at least one polymorphism within the gene (or within the flanking regions) had been identified as showing significant association to a psychosis related disorder in a published GWA study. These genes/markers were compared to data produced from analysis of our AD GWA study data using presence/absence of psychotic symptoms as a categorical variable. Our GWA study is a large resource containing 4,047 AD cases and 8,863 controls. All AD cases met criteria for either probable (NINCDS-AARDA, DSM-IV) or definite (CERAD) AD. Elderly controls were aged 60 years or over and were screened for cognitive decline or neuropathological signs of AD. Population controls were drawn from large existing cohorts with available GWA study data. 4572 samples were genotyped at the Sanger Institute on the Illumina 610-quad chip. The remaining samples were genotyped using either the Illumina 317k or 550k whole-genome single-nucleotide polymorphism arrays. Results of the study will be presented at ICAD 2009. Previous evidence suggests that psychosis susceptibility or modifier genes may act across the traditional “disease divide”. Identification of genetic variation associated with psychosis in AD will further our understanding of the disease mechanisms which underlie this sub-type of AD and may have implications for other neurodegenerative disorders where psychotic symptoms are common.