Article

Meta-Analysis for Genome-Wide Association Study Identifies Multiple Variants at the BIN1 Locus Associated with Late-Onset Alzheimer's Disease

Molecular Medicine, Pfizer Inc., Groton, Connecticut, United States of America.
PLoS ONE (Impact Factor: 3.23). 02/2011; 6(2):e16616. DOI: 10.1371/journal.pone.0016616
Source: PubMed

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.

Download full-text

Full-text

Available from: Stephanie Hall
  • Source
    • "and the rs3865444 C/C (CD33; minor allele 5 A, MAF 5 0.21) and rs670139 G/G (MS4A4E) genotypes (SF 5 5.31; P 5 .003). All three variants have been implicated in numerous AD GWAS studies [8] [9] [10] [11] [12] [13] and are on the " AlzGene Top Results " list [14], which summarizes the most established genes associated with AD. MS4A4E and CLU were recently replicated in a large meta-analysis of 74,046 individuals, but CD33 did not replicate [15]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Ebbert et al. reported gene-gene interactions between rs11136000-rs670139 (CLU-MS4A4E) and rs3865444-rs670139 (CD33-MS4A4E). We evaluate these interactions in the largest data set for an epistasis study. Methods: We tested interactions using 3837 cases and 4145 controls from Alzheimer's Disease Genetics Consortium using meta-analyses and permutation analyses. We repeated meta-analyses stratified by APOEε4 status, estimated combined odds ratio (OR) and population attributable fraction (cPAF), and explored causal variants. Results: Results support the CLU-MS4A4E interaction and a dominant effect. An association between CLU-MS4A4E and APOEε4 negative status exists. The estimated synergy factor, OR, and cPAF for rs11136000-rs670139 are 2.23, 2.45, and 8.0, respectively. We identified potential causal variants. Discussion: We replicated the CLU-MS4A4E interaction in a large case-control series, with APOEε4 and possible dominant effect. The CLU-MS4A4E OR is higher than any Alzheimer's disease locus except APOEε4, APP, and TREM2. We estimated an 8% decrease in Alzheimer's disease incidence without CLU-MS4A4E risk alleles and identified potential causal variants.
    Full-text · Article · Oct 2015 · Alzheimer's & dementia: the journal of the Alzheimer's Association
  • Source
    • "The GWAS included: the ADNI study [10], the GenADA study [11], the TGEN study [12], the NIA study [13] and the Murcia study [8]. Furthermore, we aggregated data from Harold et al. [14], Seshadri et al. [15], Hu et al. [16] and Naj et al. [17]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The objective of this study was to identify genetic variation in genes encoding death receptors and signals that modulate their activity. After conducting a meta-analysis with five previous genome-wide association studies and aggregated data, the most significant signals, (TNF locus: rs2395488, rs2534672, and rs9267445; and FASLG locus: rs730278), were replicated in 1,046 cases and 372 controls. The rs2395488 and rs2534672 markers showed a modest protective effect (OR = 0.849, p = 0.49780; OR = 0.687, p = 0.11335), in contrast to rs730278 marker (OR = 1.146, p = 0.17212), which did not follow the previous effect direction; in any case it reached the significance level. Final meta-analysis, adding the replication sample, confirmed these observations. We concluded that FASLG marker is not etiologically linked to Alzheimer's disease. However, single nucleotide polymorphisms around TNF locus require further analyses in order to explain the association between Alzheimer's disease and human leukocyte antigen.
    Full-text · Article · Jan 2015 · Journal of Alzheimer's disease: JAD
  • Source
    • "The most common risk factor for sporadic AD is the ApoE4 allele, which increases the risk of developing the disease by three times for heterozygous carriers and by 15 times for homozygous carriers [64]. Other genes, such as CLU, Bin1 or PICALM have also been identified as risk genes for AD [44, 52, 69, 105]. Among the genes identified as risk factors for AD were genes expressed by microglia. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Microglia, the tissue-resident macrophages of the brain, are attracting increasing attention as key players in brain homeostasis from development through aging. Recent works have highlighted new and unexpected roles for these once-enigmatic cells in both healthy central nervous system function and in diverse pathologies long thought to be primarily the result of neuronal malfunction. In this review, we have chosen to focus on Rett syndrome, which features early neurodevelopmental pathology, and Alzheimer's disease, a disorder associated predominantly with aging. Interestingly, receptor-mediated microglial phagocytosis has emerged as a key function in both developmental and late-life brain pathologies. In a mouse model of Rett syndrome, bone marrow transplant and CNS engraftment of microglia-like cells were associated with surprising improvements in pathology-these benefits were abrogated by block of phagocytic function. In Alzheimer's disease, large-scale genome-wide association studies have been brought to bear as a method of identifying previously unknown susceptibility genes, which highlight microglial receptors as promising novel targets for therapeutic modulation. Multi-photon in vivo microscopy has provided a method of directly visualizing the effects of manipulation of these target genes. Here, we review the latest findings and concepts emerging from the rapidly growing body of literature exemplified for Rett syndrome and late-onset, sporadic Alzheimer's disease.
    Full-text · Article · Jul 2014 · Acta Neuropathologica
Show more