Genome-wide Association Analysis Reveals Putative Alzheimer's Disease Susceptibility Loci in Addition to APOE

Abstract

Alzheimer's disease (AD) is a genetically complex and heterogeneous disorder. To date four genes have been established to either cause early-onset autosomal-dominant AD (APP, PSEN1, and PSEN2(1-4)) or to increase susceptibility for late-onset AD (APOE5). However, the heritability of late-onset AD is as high as 80%, (6) and much of the phenotypic variance remains unexplained to date. We performed a genome-wide association (GWA) analysis using 484,522 single-nucleotide polymorphisms (SNPs) on a large (1,376 samples from 410 families) sample of AD families of self-reported European descent. We identified five SNPs showing either significant or marginally significant genome-wide association with a multivariate phenotype combining affection status and onset age. One of these signals (p = 5.7 x 10(-14)) was elicited by SNP rs4420638 and probably reflects APOE-epsilon4, which maps 11 kb proximal (r2 = 0.78). The other four signals were tested in three additional independent AD family samples composed of nearly 2700 individuals from almost 900 families. Two of these SNPs showed significant association in the replication samples (combined p values 0.007 and 0.00002). The SNP (rs11159647, on chromosome 14q31) with the strongest association signal also showed evidence of association with the same allele in GWA data generated in an independent sample of approximately 1,400 AD cases and controls (p = 0.04). Although the precise identity of the underlying locus(i) remains elusive, our study provides compelling evidence for the existence of at least one previously undescribed AD gene that, like APOE-epsilon4, primarily acts as a modifier of onset age.

An Overview of Genome-Wide Association Studies in Alzheimer’s Disease

“…Meanwhile, another combined GWAS identified MS4A4A, CD2AP, EPHA1, and CD33 as AD-associated genes [33]. These results together with the study by Bertram et al [22] in 2008 made CD33 the only gene (except for APOE) with significance in GWASs in AD with both case-control and family-based approaches [34]. Using GWAS datasets, Jun et al [35] looked into the APOE region and found no association of SNPs in this region with AD or AAO after adjusting for APOE status, suggesting that APOE could explain all the genetic risk in the APOE region.…”

“…ATXN1, CD33, and APOC1 were identified in the first family-based GWAS in 2008 [22]. The second family-based GWAS by Poduslo et al was performed among extended pedigrees of AD.…”

The Evolving Biology of Microglia in Alzheimer's Disease

“…Upon binding its sialic acid ligand [114], CD33 was shown to promote downregulation of myeloid cell activation in the periphery [115]. CD33 function in the CNS, however, was not well studied until a series of genome-wide association studies identified CD33 variants that modified risk for developing AD [116][117][118]. It was later shown that CD33 expression levels correlate with cognitive decline in AD patients [119], and that the protective CD33 variant reduces CD33 expression [120].…”

P2‐030: Investigating the Role of Clu, Picalm, and Cr1 in Alzheimer's Disease

“…CD33 was first implicated in AD when in a study looking at families with multiple affected individuals, Bertram et al found an association between a variant (rs3826656) ~3kb upstream of the gene and AD risk (p = 4x10 -6 ), but which failed replication in an independent cohort (Bertram et al 2008). In 2011, two companion GWAS papers were published, with meta-analysis of the combined data revealing a genome wide significant association between SNP rs3865444 and AD (p = 1.6x10 -9 , OR 0.91 (95% CI 0.88-0.93)) (Hollingworth et al 2011;Naj et al 2011), a finding which has subsequently been replicated ).…”