Our results reveal CD2AP neuronal requirements with relevance to AD susceptibility, including for proteostasis, calcium handling, and synaptic structure and function.
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.
Genetic variants in PICALM, BIN1, CD2AP, and RIN3 are associated with increased risk of Alzheimer's disease, all dementia, and suggested vascular dementia independent of the strong APOE ε4 allele.
To examine whether there is a genetic link for these diseases, we performed a case-control study in Chinese population to evaluate the association of AD genome-wide association studies top hits with both PD and cognitive function in PD, investigating 13 single-nucleotide polymorphisms in 9 genes (BIN1, CLU, ABCA7, CR1, PICALM, MS4A6A, CD33, MS4A4E, and CD2AP).
We have used exome and genome sequencing data to analyze the single independent and joint effect of rare and low-frequency protein coding variants in 9 AD GWAS loci with the strongest effect sizes after APOE (BIN1, CLU, CR1, PICALM, MS4A6A, ABCA7, EPHA1, CD33, and CD2AP) in a cohort of 332 sporadic AD cases and 676 elderly controls of British and North-American ancestry.
This article reviews possible links between AD pathogenic factors such as AβPP/Aβ and tau; novel risk genes including clusterin, phosphatidylinositol-binding clathrin assembly protein, complement receptor 1, bridging integrator 1, ATP-binding cassette transporter 7, membrane-spanning 4-domains subfamily A, CD2-associated protein, sialic acid-binding immunoglobulin-like lectin, and ephrin receptor A1; metabolic changes including insulin resistance and hypercholesterolemia; lipid changes including alterations in brain phospholipids, cholesterol and ceramides; glial changes affecting microglia and astrocytes; alterations in brain iron metallome and oxidative stress; and slow excitotoxicity.
Besides the previously reported APOE and CR1 loci, we found that the ABCA7 (rs3764650; P = .02) and CD2AP (rs9349407; P = .03) AD susceptibility loci are associated with neuritic plaque burden.
Five genomewide association studies (GWAS) in white populations have recently identified and confirmed 9 novel Alzheimer's disease (AD) susceptibility loci (CLU, CR1, PICALM, BIN1, ABCA7, MS4A gene cluster, CD2AP, CD33, and EPHA1).
The study prioritized new AD-associated biological mechanisms and focused the analysis on previously unreported interactions associated with the biological processes of polymorphisms that affect specific protein domains within characterized AD genes and their direct interactors using (1) concordant GO-BP and (2) domain interactions within STRING protein-protein interactions corresponding to the genomic location of the AD polymorphism (eg, EPHA1, APOE, and CD2AP).