Abstract

BackgroundRecently, two large genome wide association studies in Alzheimer disease (AD) have identified variants in three different genes (CLU, PICALM and CR1) as being associated with the risk of developing AD. The strongest association was reported for an intronic single nucleotide polymorphism (SNP) in CLU.Methodology/Principal FindingsTo further characterize this association we have sequenced the coding region of this gene in a total of 495 AD cases and 330 healthy controls. A total of twenty-four variants were found in both cases and controls. For the changes found in more than one individual, the genotypic frequencies were compared between cases and controls. Coding variants were found in both groups (including a nonsense mutation in a healthy subject), indicating that the pathogenicity of variants found in this gene must be carefully evaluated. We found no common coding variant associated with disease. In order to determine if common variants at the CLU locus effect expression of nearby (cis) mRNA transcripts, an expression quantitative loci (eQTL) analysis was performed. No significant eQTL associations were observed for the SNPs previously associated with AD.Conclusions/SignificanceWe conclude that common coding variability at this locus does not explain the association, and that there is no large effect of common genetic variability on expression in brain tissue. We surmise that the most likely mechanism underpinning the association is either small effects of genetic variability on resting gene expression, or effects on damage induced expression of the protein.

Highlights

  • Alzheimer’s disease (AD) is recognized as a complex and multifactorial disease, in which genetics represents a significant role

  • Eleven were observed in only one subject (Table 1). These eleven variants include synonymous changes (c.126C.G, p.T42T; c.132G.A, p.A44A; c.279C.T, p.Y93Y; c.348C.T, p.N116N; c.438G.A, p.K146K; and c.879C.T, p.H293H), suggesting no functional change for the protein; non-synonymous variants observed in controls and Alzheimer disease (AD) patients (c.284A.G, p.N95S; c.764C.T, p.T255I and c.1013G.A, p.R338Q); a nonsense mutation identified in a control individual (c.40G.T, p.E14X); and an in-frame deletion (c.812_814delTCT, p.F272del) present in a control individual

  • Four variants were found in both cohorts (p.T255I, p.H315H, rs3216167 and p.D380D)

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Summary

Introduction

Alzheimer’s disease (AD) is recognized as a complex and multifactorial disease, in which genetics represents a significant role. Several studies have tried to uncover the genetic basis of these late onset cases, but until recently, the only well established genetic risk factor associated with LOAD was ApoE [1]. The two largest AD GWAS reported three genes (CLU, PICALM and CR1) reaching genome wide significance when studying over 16000 individuals. In these studies, the most significant hit (rs11136000) is located in an intron of CLU, on chromosome 8 [3,4]. Two large genome wide association studies in Alzheimer disease (AD) have identified variants in three different genes (CLU, PICALM and CR1) as being associated with the risk of developing AD. The strongest association was reported for an intronic single nucleotide polymorphism (SNP) in CLU

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