Genome‐wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project

Abstract

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.

Genetic Background Influences the Propagation of Tau Pathology in Transgenic Rodent Models of Tauopathy

“…Genome-wide association studies and their meta-analyses implicate more than 20 genetic loci, mainly involved in the immune system (directly or indirectly related to microglia), lipid metabolism, and endocytosis, as potential risk factors in sporadic late-onset Alzheimer's disease (Ridge et al, 2016;Jansen et al, 2019;Kunkle et al, 2019). However, clinic-pathological heterogeneity between AD cases complicate the understanding of the role these genetic components play in the manifestation of the disease (Moreno-Grau et al, 2019). It is suggested that genetic susceptibility may influence the effect of environmental and psychological factors on cognitive phenotypes during aging (Wang et al, 2019).…”

Common variants in Alzheimer’s disease: Novel association of six genetic variants with AD and risk stratification by polygenic risk scores

“…The GR@ACE study 28 recruited AD patients from Fundació ACE, Institut Català de Neurociències Aplicades (Catalonia, Spain) and control individuals from three centres: Fundació ACE (Barcelona, Spain), Valme University Hospital (Seville, Spain) and the Spanish National DNA Bank Carlos III (University of Salamanca, Spain) (http://www.bancoadn.org). Additional cases and controls were obtained from dementia cohorts included in the Dementia Genetics Spanish Consortium (DEGESCO) 30 .…”

“…Genotyping was conducted using the Axiom 815K Spanish Biobank array (Thermo Fisher) at the Spanish National Centre for Genotyping (CeGEN, Santiago de Compostela, Spain) (Supplementary information, methods). We conducted previously described standard quality control prior to imputation 28 . In brief, individual quality control includes genotype call rates > 97%, sex checks and no excess heterozygosity; we removed population outliers as well (European cluster of 1000 Genomes).…”

“…Rare variants (MAF < 0.001) and variants with low imputation quality (R 2 < 0.30) were excluded. Logistic regression models, adjusted for the first four ancestry principal components 28 , were fitted using Plink (v2.00a). Population-based controls were used; therefore, age was not included as a covariate (Supplementary Table 3).…”

“…Here we aimed to comprehend and expand the knowledge of the genetic landscape underlying AD. We first performed a meta-GWAS integrating all currently published GWAS case-control data, by-proxy case-control data and the data from the Genome Research at Fundació ACE (GR@ACE) study 28 . We confirm the novel observed associations in a large independent replication study.…”