Genome-wide Association Study of Alzheimer's disease with Psychotic Symptoms

Paul Hollingworth (1) , Robert Sweet (1) , Rebecca Sims (1) , Denise Harold (1) , Giancarlo Russo (1) , Richard Abraham (1) , Alexandra Stretton (1) , Nicola Jones (1) , Amy Gerrish (1) , Jade Chapman (1) , Dobril Ivanov (1) , Valentina Moskvina (1) , Simon Lovestone (1) , Michelle Lupton (1) , Carol Brayne (1) , Michael Gill (1) , Brian Lawlor (1) , Aoibhinn Lynch (1) , David Craig (1) , Bernadette Mcguinness (1) , Janet Johnston (1) , Clives Holmes (1) , Gill Livingston (1) , Nicholas Bass (1) , Hugh Gurling (1) , Andrew Mcquillin (1) , Peter Holmans (1) , Lesley Jones (1) , Bernard Devlin (1) , Lambertus Klei (1) , M. Michael Barmada (1) , F. Yesim Demirci (1) , Steven T. Dekosky (1) , Oscar L. Lopez (1) , Peter Passmore (1) , M Owen (1) , Michael O'Donovan (1) , Richard Mayeux (1) , M. Ilyas Kamboh (1) , Julie Williams (1)

1 Bioinformatics

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 x 10-7; 'AD+PvControls' P=1.11 x 10-4). SNPs upstream of SLC2A9 (rs6834555, P=3.0x10-7) and within VSNL1 (rs4038131, P=5.9x10-7) 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.

Mots clés: Alzheimer's disease; psychosis; behavioural symptoms; genome-wide association study; genetic

Domaines: Psychiatrie et santé mentale

Paul Hollingworth, Robert Sweet, Rebecca Sims, Denise Harold, Giancarlo Russo, et al.. Genome-wide Association Study of Alzheimer's disease with Psychotic Symptoms. Molecular Psychiatry, 2011, ⟨10.1038/mp.2011.125⟩. ⟨hal-00688561⟩