TY - JOUR
T1 - Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks
T2 - The GR@ACE project
AU - GR@ACE consortium
AU - DEGESCO consortium
AU - Alzheimer's Disease Neuroimaging Initiative
AU - Moreno-Grau, Sonia
AU - de Rojas, Itziar
AU - Hernández, Isabel
AU - Quintela, Inés
AU - Montrreal, Laura
AU - Alegret, Montserrat
AU - Hernández-Olasagarre, Begoña
AU - Madrid, Laura
AU - González-Perez, Antonio
AU - Maroñas, Olalla
AU - Rosende-Roca, Maitée
AU - Mauleón, Ana
AU - Vargas, Liliana
AU - Lafuente, Asunción
AU - Abdelnour, Carla
AU - Rodríguez-Gómez, Octavio
AU - Gil, Silvia
AU - Santos-Santos, Miguel Ángel
AU - Espinosa, Ana
AU - Ortega, Gemma
AU - Sanabria, Ángela
AU - Pérez-Cordón, Alba
AU - Cañabate, Pilar
AU - Moreno, Mariola
AU - Preckler, Silvia
AU - Ruiz, Susana
AU - Aguilera, Nuria
AU - Pineda, Juan Antonio
AU - Macías, Juan
AU - Alarcón-Martín, Emilio
AU - Sotolongo-Grau, Oscar
AU - Abdelnour, C.
AU - Alarcon, E.
AU - Benaque, A.
AU - Boada, M.
AU - Buendia, M.
AU - Carracedo, A.
AU - Corbatón, A.
AU - Diego, S.
AU - Gailhajenet, A.
AU - García González, P.
AU - Guitart, M.
AU - Ibarria, M.
AU - Martín, E.
AU - Martínez, M. T.
AU - Marquié, M.
AU - Monté-Rubio, G.
AU - Orellana, A.
AU - Pancho, A.
AU - Ruiz, A.
N1 - Publisher Copyright:
© 2019 The Authors
PY - 2019/10/1
Y1 - 2019/10/1
N2 - Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series.
AB - Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series.
KW - Alzheimer's disease
KW - Biological pathway
KW - Cerebral amyloid angiopathy
KW - GWAS
KW - Vascular pathology
UR - https://www.scopus.com/pages/publications/85072869719
UR - https://www.scopus.com/pages/publications/85072869719#tab=citedBy
U2 - 10.1016/j.jalz.2019.06.4950
DO - 10.1016/j.jalz.2019.06.4950
M3 - Article
C2 - 31473137
AN - SCOPUS:85072869719
SN - 1552-5260
VL - 15
SP - 1333
EP - 1347
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
IS - 10
ER -