Genome-Wide Association of Familial Late-Onset Alzheimer's Disease Replicates BIN1 and CLU and Nominates CUGBP2 in Interaction with APOE

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 mult...

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Vydáno v:	PLoS genetics Ročník 7; číslo 2; s. e1001308
Hlavní autoři:	Wijsman, Ellen M., Pankratz, Nathan D., Choi, Yoonha, Rothstein, Joseph H., Faber, Kelley M., Cheng, Rong, Lee, Joseph H., Bird, Thomas D., Bennett, David A., Diaz-Arrastia, Ramon, Goate, Alison M., Farlow, Martin, Ghetti, Bernardino, Sweet, Robert A., Foroud, Tatiana M., Mayeux, Richard
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Public Library of Science 01.02.2011 Public Library of Science (PLoS)
Témata:	Adaptor Proteins, Signal Transducing - genetics Aged Alzheimer Disease - genetics Alzheimer's disease Alzheimers disease Apolipoproteins Apolipoproteins E - genetics Apolipoproteins E - metabolism Binding proteins Case-Control Studies CELF Proteins Chromosome replication Clusterin - genetics Colleges & universities Family Gene Frequency - genetics Genetic aspects Genetic Predisposition to Disease Genetics Genetics and Genomics/Genetics of Disease Genetics and Genomics/Genome Projects Genetics and Genomics/Population Genetics Genome, Human - genetics Genome-Wide Association Study Heterozygote Hospitals Humans Middle Aged Nerve Tissue Proteins - genetics Nerve Tissue Proteins - metabolism Neurological Disorders/Alzheimer Disease Neurological Disorders/Cognitive Neurology and Dementia Nuclear Proteins - genetics Physiological aspects Polymorphism, Single Nucleotide - genetics Population Dynamics Principal Component Analysis Protein Binding Reproducibility of Results Risk factors RNA-Binding Proteins - genetics RNA-Binding Proteins - metabolism Tumor Suppressor Proteins - genetics White People - genetics United States
ISSN:	1553-7404, 1553-7390, 1553-7404
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Popis
Shrnutí:	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 ε4 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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Conceived and designed the experiments: EMW NDP JHL TMF RM. Analyzed the data: EMW NDP YC JHR KMF RC JHL. Contributed reagents/materials/analysis tools: TDB DAB RDA AMG MF BG RAS TMF RM. Wrote the paper: EMW NDP YC JHR JHL TDB DAB RDA AMG MF RAS TMF RM. Managed the data: KMF.
ISSN:	1553-7404 1553-7390 1553-7404
DOI:	10.1371/journal.pgen.1001308