TY - JOUR
T1 - Genome-wide association study of rate of cognitive decline in Alzheimer's disease patients identifies novel genes and pathways
AU - the Alzheimer's Disease Genetics Consortium
AU - Sherva, Richard
AU - Gross, Alden
AU - Mukherjee, Shubhabrata
AU - Koesterer, Ryan
AU - Amouyel, Philippe
AU - Bellenguez, Celine
AU - Dufouil, Carole
AU - Bennett, David A.
AU - Chibnik, Lori
AU - Cruchaga, Carlos
AU - del-Aguila, Jorge
AU - Farrer, Lindsay A.
AU - Mayeux, Richard
AU - Munsie, Leanne
AU - Winslow, Ashley
AU - Newhouse, Stephen
AU - Saykin, Andrew J.
AU - Kauwe, John S.K.
AU - Crane, Paul K.
AU - Green, Robert C.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - 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.
AB - 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.
KW - cognitive decline
KW - disease progression
KW - genetic association
KW - pathway analysis
UR - http://www.scopus.com/inward/record.url?scp=85087185266&partnerID=8YFLogxK
U2 - 10.1002/alz.12106
DO - 10.1002/alz.12106
M3 - Article
AN - SCOPUS:85087185266
SN - 1552-5260
VL - 16
SP - 1134
EP - 1145
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
IS - 8
ER -
