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PMID: 21379329 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Genome-wide association of familial late-onset Alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE.

PLoS genetics ·Vol. 7 ·No. 2 ·2011-02-00 ·Pages e1001308

Wijsman EM, Pankratz ND, Choi Y, Rothstein JH, Faber KM, Cheng R, Lee JH, Bird TD, Bennett DA, Diaz-Arrastia R, Goate AM, Farlow M, Ghetti B, Sweet RA, Foroud TM, Mayeux R, NIA-LOAD/NCRAD Family Study Group

Abstract

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.

MeSH Terms
Adaptor Proteins, Signal Transducing/genetics Aged Alzheimer Disease/genetics Apolipoproteins E/genetics,metabolism CELF Proteins Case-Control Studies Clusterin/genetics Family Gene Frequency/genetics Genetic Predisposition to Disease Genome, Human/genetics Genome-Wide Association Study Heterozygote Humans Middle Aged Nerve Tissue Proteins/genetics,metabolism Nuclear Proteins/genetics Polymorphism, Single Nucleotide/genetics Population Dynamics Principal Component Analysis Protein Binding RNA-Binding Proteins/genetics,metabolism Reproducibility of Results Tumor Suppressor Proteins/genetics Whites/genetics
Chemicals
Adaptor Proteins, Signal Transducing Apolipoproteins E BIN1 protein, human CELF Proteins CELF2 protein, human CLU protein, human Clusterin Nerve Tissue Proteins Nuclear Proteins RNA-Binding Proteins Tumor Suppressor Proteins
Authors & Affiliations
17 authors, click to expand affiliations / ORCID
Wijsman Ellen M
Division of Medical Genetics, University of Washington, Seattle, Washington, United States of America.
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
NIA-LOAD/NCRAD Family Study Group
Conflict of Interest

The authors have declared that no competing interests exist.

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Article Info
Journal
PLoS genetics
Abbr.
PLoS Genet
ISSN
1553-7404
DOI
10.1371/journal.pgen.1001308
Published
2011-02-00
Epub
2011-00-17
Pages
e1001308
Language
English
Region
United States
NLM ID
101239074
PMCID
PMC3040659
Subset
IM
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PubMed source DOI: 10.1371/journal.pgen.1001308 PMC Full Text View journal details
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