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A genome-wide association study for late-onset Alzheimer's disease using DNA pooling.

ABSTRACT: Late-onset Alzheimer's disease (LOAD) is an age related neurodegenerative disease with a high prevalence that places major demands on healthcare resources in societies with increasingly aged populations. The only extensively replicable genetic risk factor for LOAD is the apolipoprotein E gene. In order to identify additional genetic risk loci we have conducted a genome-wide association (GWA) study in a large LOAD case - control sample, reducing costs through the use of DNA pooling.DNA samples were collected from 1,082 individuals with LOAD and 1,239 control subjects. Age at onset ranged from 60 to 95 and Controls were matched for age (mean = 76.53 years, SD = 33), gender and ethnicity. Equimolar amounts of each DNA sample were added to either a case or control pool. The pools were genotyped using Illumina HumanHap300 and Illumina Sentrix HumanHap240S arrays testing 561,494 SNPs. 114 of our best hit SNPs from the pooling data were identified and then individually genotyped in the case - control sample used to construct the pools.Highly significant association with LOAD was observed at the APOE locus confirming the validity of the pooled genotyping approach.For 109 SNPs outside the APOE locus, we obtained uncorrected p-values

SUBMITTER: Abraham R

PROVIDER: S-EPMC2570675 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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A genome-wide association study for late-onset Alzheimer's disease using DNA pooling.

Abraham Richard R Moskvina Valentina V Sims Rebecca R Hollingworth Paul P Morgan Angharad A Georgieva Lyudmila L Dowzell Kimberley K Cichon Sven S Hillmer Axel M AM O'Donovan Michael C MC Williams Julie J Owen Michael J MJ Kirov George G

BMC medical genomics 20080929

<h4>Background</h4>Late-onset Alzheimer's disease (LOAD) is an age related neurodegenerative disease with a high prevalence that places major demands on healthcare resources in societies with increasingly aged populations. The only extensively replicable genetic risk factor for LOAD is the apolipoprotein E gene. In order to identify additional genetic risk loci we have conducted a genome-wide association (GWA) study in a large LOAD case - control sample, reducing costs through the use of DNA poo ...[more]

PMID: 18823527

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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

A genome-wide association study for late-onset Alzheimer's disease using DNA pooling.

Publications

A genome-wide association study for late-onset Alzheimer's disease using DNA pooling.

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