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PMID: 21390209 Published · epublish English Journal Article Meta-Analysis Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Meta-analysis for genome-wide association study identifies multiple variants at the BIN1 locus associated with late-onset Alzheimer's disease.

PloS one ·Vol. 6 ·No. 2 ·2011-02-24 ·Pages e16616

Hu X, Pickering E, Liu YC, Hall S, Fournier H, Katz E, Dechairo B, John S, Van Eerdewegh P, Soares H, Alzheimer's Disease Neuroimaging Initiative

Abstract

Recent GWAS studies focused on uncovering novel genetic loci related to AD have revealed associations with variants near CLU, CR1, PICALM and BIN1. In this study, we conducted a genome-wide association study in an independent set of 1034 cases and 1186 controls using the Illumina genotyping platforms. By coupling our data with available GWAS datasets from the ADNI and GenADA, we replicated the original associations in both PICALM (rs3851179) and CR1 (rs3818361). The PICALM variant seems to be non-significant after we adjusted for APOE e4 status. We further tested our top markers in 751 independent cases and 751 matched controls. Besides the markers close to the APOE locus, a marker (rs12989701) upstream of BIN1 locus was replicated and the combined analysis reached genome-wide significance level (p = 5E-08). We combined our data with the published Harold et al. study and meta-analysis with all available 6521 cases and 10360 controls at the BIN1 locus revealed two significant variants (rs12989701, p = 1.32E-10 and rs744373, p = 3.16E-10) in limited linkage disequilibrium (r²  =  0.05) with each other. The independent contribution of both SNPs was supported by haplotype conditional analysis. We also conducted multivariate analysis in canonical pathways and identified a consistent signal in the downstream pathways targeted by Gleevec (P = 0.004 in Pfizer; P = 0.028 in ADNI and P = 0.04 in GenADA). We further tested variants in CLU, PICALM, BIN1 and CR1 for association with disease progression in 597 AD patients where longitudinal cognitive measures are sufficient. Both the PICALM and CLU variants showed nominal significant association with cognitive decline as measured by change in Clinical Dementia Rating-sum of boxes (CDR-SB) score from the baseline but did not pass multiple-test correction. Future experiments will help us better understand potential roles of these genetic loci in AD pathology.

MeSH Terms
Adaptor Proteins, Signal Transducing/genetics Age of Onset Aged Alleles Alzheimer Disease/epidemiology,genetics Case-Control Studies Chromosome Mapping Disease Progression Female Gene Frequency Genetic Loci/genetics Genetic Predisposition to Disease Genome-Wide Association Study/statistics & numerical data Genotype Humans Linkage Disequilibrium Male Nuclear Proteins/genetics Polymorphism, Single Nucleotide/physiology Signal Transduction/genetics Tumor Suppressor Proteins/genetics
Chemicals
Adaptor Proteins, Signal Transducing BIN1 protein, human Nuclear Proteins Tumor Suppressor Proteins
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Hu Xiaolan
Molecular Medicine, Pfizer Inc., Groton, Connecticut, United States of America. [email protected]
Pickering Eve
Liu Yingxue Cathy
Hall Stephanie
Fournier Helene
Katz Elyse
Dechairo Bryan
John Sally
Van Eerdewegh Paul
Soares Holly
Alzheimer's Disease Neuroimaging Initiative
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Article Info
Journal
PloS one
Abbr.
PLoS One
ISSN
1932-6203
DOI
10.1371/journal.pone.0016616
Email
[email protected]
Published
2011-02-24
Epub
2011-00-24
Pages
e16616
Language
English
Region
United States
NLM ID
101285081
PMCID
PMC3044719
Subset
IM
Grants
NIA NIH HHS · U01 AG024904 · United States
NIA NIH HHS · U19 AG010483 · United States
External Links
PubMed source DOI: 10.1371/journal.pone.0016616 PMC Full Text View journal details
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