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.

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Available from: Stephanie Hall, Sep 28, 2015
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    • "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. "
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    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.
    Acta Neuropathologica 07/2014; 128(3). DOI:10.1007/s00401-014-1321-z · 10.76 Impact Factor
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    • "GWAS with fewer than 1000 cases or control subjects have implicated novel AD risk single nucleotide polymorphisms (SNPs) in GOLPH2, GAB2, and PCDH11X genes [153] [154] [155] [156]. More powerful, higher number case and control GWAS have identified or replicated novel AD risk SNPs in BIN1, CLU, CR1 and PICALM genes [157] [158] [159] [160] [161] [162] [163] [164], and a recent meta-analysis of GWAS identified a total of 20 genetic susceptibility loci (11 new genes, in addition to 9 previously-identified risk genes) [156]. However, interpretation of GWAS findings to reveal diseaserelevant biological mechanisms remains a challenge because the genetic architecture of AD is incomplete [165]. "
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    ABSTRACT: Although Alzheimer's Disease (AD) is the most common neurodegenerative disease, the etiology of AD is not well understood. In some cases, genetic factors explain AD risk, but a high percentage of late-onset AD is unexplained. The fact that AD is associated with a number of physical and systemic manifestations suggests that AD is a multifactorial disease that affects both the CNS and periphery. Interestingly, a common feature of many systemic processes linked to AD is involvement in energy metabolism. The goals of this review are to 1) explore the evidence that peripheral processes contribute to AD risk, 2) explore ways that AD modulates whole-body changes, and 3) discuss the role of genetics, mitochondria, and vascular mechanisms as underlying factors that could mediate both central and peripheral manifestations of AD. Despite efforts to strictly define AD as a homogeneous CNS disease, there may be no single etiologic pathway leading to the syndrome of AD dementia. Rather, the neurodegenerative process may involve some degree of baseline genetic risk that is modified by external risk factors. Continued research into the diverse but related processes linked to AD risk is necessary for successful development of disease -modifying therapies.
    Biochimica et Biophysica Acta 04/2014; 1842(9). DOI:10.1016/j.bbadis.2014.04.012 · 4.66 Impact Factor
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    • "Mutations in BIN1 may be associated with autosomal recessive centronuclear myopathy. Caenorhabditis elegans experiments have suggested that BIN1 protein might have a role in trafficking APP, ApoE proteins, and Abeta through the endolysosomal pathways, thus BIN1 mutations may be a putative risk factor for LOAD.162 "
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    ABSTRACT: Alzheimer's disease (AD) is a complex and heterogeneous neurodegenerative disorder, classified as either early onset (under 65 years of age), or late onset (over 65 years of age). Three main genes are involved in early onset AD: amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2). The apolipoprotein E (APOE) E4 allele has been found to be a main risk factor for late-onset Alzheimer's disease. Additionally, genome-wide association studies (GWASs) have identified several genes that might be potential risk factors for AD, including clusterin (CLU), complement receptor 1 (CR1), phosphatidylinositol binding clathrin assembly protein (PICALM), and sortilin-related receptor (SORL1). Recent studies have discovered additional novel genes that might be involved in late-onset AD, such as triggering receptor expressed on myeloid cells 2 (TREM2) and cluster of differentiation 33 (CD33). Identification of new AD-related genes is important for better understanding of the pathomechanisms leading to neurodegeneration. Since the differential diagnoses of neurodegenerative disorders are difficult, especially in the early stages, genetic testing is essential for diagnostic processes. Next-generation sequencing studies have been successfully used for detecting mutations, monitoring the epigenetic changes, and analyzing transcriptomes. These studies may be a promising approach toward understanding the complete genetic mechanisms of diverse genetic disorders such as AD.
    Clinical Interventions in Aging 04/2014; 9:535-551. DOI:10.2147/CIA.S51571 · 2.08 Impact Factor
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