Association of CR1, CLU and PICALM with Alzheimer's disease in a cohort of clinically characterized and neuropathologically verified individuals

Abstract

In this study, we assess 34 of the most replicated genetic associations for Alzheimer's disease (AD) using data generated on Affymetrix SNP 6.0 arrays and imputed at over 5.7 million markers from a unique cohort of over 1600 neuropathologically defined AD cases and controls (1019 cases and 591 controls). Testing the top genes from the AlzGene meta-analysis, we confirm the well-known association with APOE single nucleotide polymorphisms (SNPs), the CLU, PICALM and CR1 SNPs recently implicated in unusually large data sets, and previously implicated CST3 and ACE SNPs. In the cases of CLU, PICALM and CR1, as well as in APOE, the odds ratios we find are slightly larger than those previously reported in clinical samples, consistent with what we believe to be more accurate classification of disease in the clinically characterized and neuropathologically confirmed AD cases and controls.

Hippocampal Function in Healthy Carriers of theCLUAlzheimer's Disease Risk Variant

“…In 2009, through genome-wide association study, a single nucleotide polymorphism (SNP) within clusterine (CLU, also called APOJ ) on chromosome 8p21.1, rs11136000 was discovered to be significantly associated with AD in two independent studies (Harold et al, 2009;Lambert et al, 2009). This finding has since been replicated by several groups (Carrasquillo et al, 2010;Corneveaux et al, 2010;Jun et al, 2010;Kamboh et al, 2010;Seshadri et al, 2010), leading to CLU being the third top-ranking locus associated with Alzheimer's disease in the AlzGene database (http://www.alzgene.org). Carrying the minor allele T is assumed to establish a protective effect and reduces the risk to develop AD by 16% (Bertram and Tanzi, 2010); conversely, carrying the C-allele could be interpreted as an AD risk factor.…”

“…Recent genome-wide association studies have identified a SNP (11136000) within the Clusterin gene as strongly associated with risk for Alzheimers disease (Harold et al, 2009;Lambert et al, 2009;Carrasquillo et al, 2010;Corneveaux et al, 2010;Jun et al, 2010;Kamboh et al, 2010;Seshadri et al, 2010). CLU appears to be a biologically plausible candidate for AD as it binds amyloid beta peptide (A␤) and critically modifies A␤ Figure 1.…”

CR1-mediated ATP Release by Human Red Blood Cells Promotes CR1 Clustering and Modulates the Immune Transfer Process

“…The current findings on the functional consequence of RBC CR1 ligation in the immune-transfer process are important especially now when unexpected and non-redundant roles for human RBC CR1 in pathologies ranging from malaria (45) and sepsis (46) to Alzheimer disease (35,(47)(48)(49) are beginning to be unraveled.…”

Investigating Statistical Epistasis in Complex Disorders

“…Since 2009 and the completion of several large GWAS, strong evidence for additional candidate LOAD genes such as PICALM, CLU, CR1 have been identified, thus corroborating the utility of GWAS [8,9]. Recent meta-analyses and replication studies have provided further evidence for these genetic factors and added a previously suspected AD candidate, BIN1, to genome-wide significance level, again contributing to the overall heritability [10][11][12]. However these findings still do not account for the entire estimated genetic component.…”