Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer’s disease and three causality networks of AD: the GR@ACE project
Authors: Moreno-Grau Sonia , de Rojas Itziar , Hernández Isabel , Quintela Inés , Montrreal Laura , Alegret Montserrat , Hernández-Olasagarre Begoña , Madrid Laura , González-Perez Antonio , Maroña Olalla , Rosende-Roca Maitée , Mauleón Ana , Vargas Liliana , Lafuente Asunción , Abdelnour Carla , Rodríguez-Gómez Octavio , Gil Silvia , Ángel Santos-Santos Miguel , Espinosa Ana , Ortega Gemma , Sanabria Ángela , Pérez-Cordón Alba , Ruiz Susana , Aguilera Nuria , Pineda Juan Antonio , Macías Juan , Alarcón Emilio , Sotolongo-Grau Oscar ,   GR@ACE/DEGESCO consortium,   Alzheimer’s Disease Neuroimaging Initiative, Marquié Marta , Montè-Rubio Gemma , Valero Sergi , Clarimón Jordi , Bullido Maria Jesus , García-Ribas Guillermo , Pástor Pau , Sánchez-Juan Pascual , Álvarez Victoria , Piñol-Ripoll Gerard , García-Alberca Jose Maria , Royo José Luis , Franco Emilio , Mir Pablo , Calero Miguel , Medina Miguel , Rábano Alberto , Ávila Jesús , Antúnez Carmen , Real Luis Miguel , Orellana Adelina , Carracedo Ángel , Sáez María Eugenia , Tárraga Lluís , Boada Mercé , Ruiz Agustín 
Published: January 2019

AbstractBackgroundGenetics plays a major role in Alzheimer’s Disease (AD). To date, 40 genes associated with AD have been identified, although most remain undiscovered. Clinical, neuropathological and genetic variability might impact genetic discoveries and complicate dissection of the biological pathways underlying AD.MethodsGR@ACE is a genome-wide study of dementia and its clinical endophenotypes that encompasses 4,120 cases and 3,289 controls from Spain. GR@ACE phenotypes were defined according to AD’s clinical certainty and the presence of vascular co-morbidity. To explore whether clinical endophenotypes reflect variation in underlying biological pathways, we first assessed the impact of known AD loci across endophenotypes to generate three loci categories. Next, we incorporated gene co-expression data and conducted pathway analysis on each category. To assess the impact of heterogeneity in the GWAS findings, the GR@ACE series were meta-analyzed with: 1) genotype-level data from dbGaP (N=21,235); and 2) summary statistics from IGAP Stages I and II (n=61,571 and n=81,455 respectively).FindingsWe classified known AD loci in three categories, which might reflect the disease clinical heterogeneity, from vascular and mixed forms to pure AD pathology. Immune system pathways were detected in all categories. Intriguingly, vascular processes were only detected as a causal mechanism in probable AD. A meta-analysis of GR@ACE with additional GWAS datasets revealed theANKRD31-rs4704171signal in theHMGCRgenomic region. We confirmed NDUFAF6-rs10098778 andSCIMP-rs7225151, which were previously detected by IGAP, to be suggestive signals. We also confirmed CD33-rs3865444 to be genome-wide significant.InterpretationThe regulation of vasculature is a prominent causal component of probable AD. In that context, cerebral amyloid angiopathy, the unique identified link between the vascular and amyloid hypotheses, deserves further investigation. The GR@ACE meta-analysis revealed novel AD genetic signals. GWAS results are strongly driven by the presence of clinical heterogeneity in the AD series.FundingGrifols SA, Fundación bancaria “La Caixa”, Fundació ACE and ISCIII (Instituto de Salud Carlos III).