Dataset Information

Genetic variability in CLU and its association with Alzheimer's disease.

ABSTRACT: BACKGROUND:Recently, 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 FINDINGS:To 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/SIGNIFICANCE:We 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.

SUBMITTER: Guerreiro RJ

PROVIDER: S-EPMC2831070 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Genetic variability in CLU and its association with Alzheimer's disease.

Guerreiro Rita J RJ Beck John J Gibbs J Raphael JR Santana Isabel I Rossor Martin N MN Schott Jonathan M JM Nalls Michael A MA Ribeiro Helena H Santiago Beatriz B Fox Nick C NC Oliveira Catarina C Collinge John J Mead Simon S Singleton Andrew A Hardy John J

PloS one 20100303 3

<h4>Background</h4>Recently, 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.<h4>Methodology/principal findings</h4>To further characterize this association we have sequenced the coding region of this gene in a total of 495 AD cases and 330 healthy controls ...[more]

PMID: 20209083

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Project description:Late-onset Alzheimer's disease (LOAD) is the most common form of dementia in the elderly. The National Institute of Aging-Late Onset Alzheimer's Disease Family Study and the National Cell Repository for Alzheimer's Disease conducted a joint genome-wide association study (GWAS) of multiplex LOAD families (3,839 affected and unaffected individuals from 992 families plus additional unrelated neurologically evaluated normal subjects) using the 610 IlluminaQuad panel. This cohort represents the largest family-based GWAS of LOAD to date, with analyses limited here to the European-American subjects. SNPs near APOE gave highly significant results (e.g., rs2075650, p?=?3.2×10(-81)), but no other genome-wide significant evidence for association was obtained in the full sample. Analyses that stratified on APOE genotypes identified SNPs on chromosome 10p14 in CUGBP2 with genome-wide significant evidence for association within APOE ?4 homozygotes (e.g., rs201119, p?=?1.5×10(-8)). Association in this gene was replicated in an independent sample consisting of three cohorts. There was evidence of association for recently-reported LOAD risk loci, including BIN1 (rs7561528, p?=?0.009 with, and p?=?0.03 without, APOE adjustment) and CLU (rs11136000, p?=?0.023 with, and p?=?0.008 without, APOE adjustment), with weaker support for CR1. However, our results provide strong evidence that association with PICALM (rs3851179, p?=?0.69 with, and p?=?0.039 without, APOE adjustment) and EXOC3L2 is affected by correlation with APOE, and thus may represent spurious association. Our results indicate that genetic structure coupled with ascertainment bias resulting from the strong APOE association affect genome-wide results and interpretation of some recently reported associations. We show that a locus such as APOE, with large effects and strong association with disease, can lead to samples that require appropriate adjustment for this locus to avoid both false positive and false negative evidence of association. We suggest that similar adjustments may also be needed for many other large multi-site studies.

Dataset Information

Genetic variability in CLU and its association with Alzheimer's disease.

Publications

Genetic variability in CLU and its association with Alzheimer's disease.

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