Genome‐wide association study of rate of cognitive decline in Alzheimer's disease patients identifies novel genes and pathways
Richard Sherva, Alden L. Gross, Shubhabrata Mukherjee, Ryan Koesterer, Philippe Amouyel, Céline Bellenguez, Carole Dufouil, David Bennett, Lori B. Chibnik, Carlos Cruchaga, Jorge L. Del‐Aguila, Lindsay A. Farrer, Richard Mayeux, Leanne Munsie, Ashley R. Winslow, Stephen Newhouse, Andrew J. Saykin, John S.K. Kauwe, Paul K. Crane, Robert C. Green
Abstract
Abstract Introduction Variability exists in the disease trajectories of Alzheimer's disease (AD) patients. We performed a genome‐wide association study to examine rate of cognitive decline (ROD) in patients with AD. Methods We tested for interactions between genetic variants and time since diagnosis to predict the ROD of a composite cognitive score in 3946 AD cases and performed pathway analysis on the top genes. Results Suggestive associations ( P < 1.0 × 10 −6 ) were observed on chromosome 15 in DNA polymerase‐γ (rs3176205, P = 1.11 × 10 −7 ), chromosome 7 (rs60465337, P = 4.06 × 10 −7 ) in contactin‐associated protein‐2, in RP11‐384F7.1 on chromosome 3 (rs28853947, P = 5.93 × 10 −7 ), family with sequence similarity 214 member‐A on chromosome 15 (rs2899492, P = 5.94 × 10 −7 ), and intergenic regions on chromosomes 16 (rs4949142, P = 4.02 × 10 −7 ) and 4 (rs1304013, P = 7.73 × 10 −7 ). Significant pathways involving neuronal development and function, apoptosis, memory, and inflammation were identified. Discussion Pathways related to AD, intelligence, and neurological function determine AD progression, while previously identified AD risk variants, including the apolipoprotein ( APOE ) ε4 and ε2 variants, do not have a major impact.