Investigation of 15 of the top candidate genes for late-onset Alzheimer’s disease

MRC Human Genetics Unit, The Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, EH4 2XU UK
Human Genetics (Impact Factor: 4.82). 03/2011; 129(3):273-282. DOI: 10.1007/s00439-010-0924-2
Source: PubMed

ABSTRACT The 12 genome-wide association studies (GWAS) published to-date for late-onset Alzheimer’s disease (LOAD) have identified
over 40 candidate LOAD risk modifiers, in addition to apolipoprotein (APOE) ε4. A few of these novel LOAD candidate genes, namely BIN1, CLU, CR1, EXOC3L2 and PICALM, have shown consistent replication, and are thus credible LOAD susceptibility genes. To evaluate other promising LOAD candidate
genes, we have added data from our large, case–control series (n=5,043) to meta-analyses of all published follow-up case–control association studies for six LOAD candidate genes that have
shown significant association across multiple studies (TNK1, GAB2, LOC651924, GWA_14q32.13, PGBD1 and GALP) and for an additional nine previously suggested candidate genes. Meta-analyses remained significant at three loci after
addition of our data: GAB2 (OR=0.78, p=0.007), LOC651924 (OR=0.91, p=0.01) and TNK1 (OR=0.92, p=0.02). Breslow–Day tests revealed significant heterogeneity between studies for GAB2 (p<0.0001) and GWA_14q32.13 (p=0.006). We have also provided suggestive evidence that PGBD1 (p=0.04) and EBF3 (p=0.03) are associated with age-at-onset of LOAD. Finally, we tested for interactions between these 15 genes, APOE ε4 and the five novel LOAD genes BIN1, CLU, CR1, EXOC3L2 and PICALM but none were significant after correction for multiple testing. Overall, this large, independent follow-up study for 15
of the top LOAD candidate genes provides support for GAB2 and LOC651924 (6q24.1) as risk modifiers of LOAD and novel associations between PGBD1 and EBF3 with age-at-onset.

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Available from: Olivia Belbin, Sep 28, 2015
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    • "Among the more important of these are apolipoproteins E and J (ApoE and ApoJ) [26]. ApoE is the strongest known genetic risk factor for AD [27], and a human molecular genetic study recently identified ApoJ as an important factor as well [28], suggesting that transcellular trafficking of Aβ is particularly relevant to AD pathogenesis. Although there are numerous hypotheses about the physiological function or functions of ApoE and ApoJ, there is general agreement that they are involved in the clearance of Aβ, likely by mediating the delivery of extracellular Aβ to intracellular compartments responsible for Aβ degradation (that is, lysosomes) [27]. "
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    ABSTRACT: Alzheimer's disease (AD) is a progressive, age-related neurodegenerative disorder characterized by extracellular and intracellular deposition of the amyloid β-protein (Aβ). The study of rare, familial forms of AD has shown that sustained elevations in the production of Aβ (either all forms or specific pathogenic variants thereof) are sufficient to trigger the full spectrum of cognitive and histopathological features of the disease. Although the exact cause or causes remain unknown, emerging evidence suggests that impairments in the clearance of Aβ, after it is produced, may underlie the vast majority of sporadic AD cases. This review focuses on Aβ-degrading proteases (AβDPs), which have emerged as particularly important mediators of Aβ clearance. A wide variety of proteases that - by virtue of their particular regional and subcellular localization profiles - define distinct pools of Aβ have been identified. Different pools of Aβ, in turn, may contribute differentially to the pathogenesis of the disease. The study of individual AβDPs, therefore, promises to offer new insights into the mechanistic basis of AD pathogenesis and, ultimately, may facilitate the development of effective methods for its prevention or treatment or both.
    Alzheimer's Research and Therapy 08/2013; 5(4):37. DOI:10.1186/alzrt194 · 3.98 Impact Factor
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    • "A genome-wide association study of family-based case-control studies suggested that PGBD1 is involved in AD [15,16]. In addition, although weak (the minor allele was associated with an age of onset 1 year earlier than the major allele), a single nucleotide polymorphism (SNP) in PGBD1, rs3800324, has been shown to be associated with the age of onset in AD, as a risk modifier in a meta-analysis study [17]. However, no Japanese AD patients were examined in any of these studies. "
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    ABSTRACT: PiggyBac transposable element derived 1 (PGBD1) encodes a molecule involved in epigenetic mechanisms that have been implicated in Alzheimer's disease (AD), and recent genome-wide association studies and meta-analyses have indicated that a single nucleotide polymorphism (SNP), rs3800324, in PGBD1 could be associated with AD and the age of onset. However, no Japanese patients were examined in these studies. The aim of the present study was to replicate the previous finding in Japanese AD cases. We performed a case-control study (211 cases and 156 controls) to investigate the association between PGBD1 and Japanese AD using 4 tag SNPs including rs3800324. Single SNP and haplotype analysis showed no association between AD and age of onset, whereas genotypic and allelic frequencies of the ∊4 of apolipoprotein E (APOE) showed an association with AD as expected. In Japanese AD, we observed no influence of PGBD1, as either a risk factor or a modifier, even though APOE was associated with AD in this population.
    11/2012; 2(1):496-502. DOI:10.1159/000345085
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    • "The last several decades of research have yielded only 1 genetic risk factor of large effect for late-onset AD (LOAD)dapolipoprotein- E (APOE)dwith 2 copies of the ε4 allele conferring approximately 6- to 30-fold risk for the disease (Akiyama et al., 1993). More recent genome-wide association studies (GWAS) have identified and replicated 9 additional AD susceptibility genes, including BIN1, CLU, ABCA7, CR1, PICALM, MS4A6A, CD33, MS4A4E, and CD2AP (Belbin et al., 2011; Carrasquillo et al., 2011; Harold et al., 2009; Hollingworth et al., 2011; Naj et al., 2011; Shi et al., 2012). However, all of these have low effect sizes (odds ratios of 0.87e1.23) "
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    ABSTRACT: Missing heritability in late onset Alzheimer disease can be attributed, at least in part, to heterogeneity in disease status and to the lack of statistical analyses exploring genetic interactions. In the current study, we use quantitative intermediate phenotypes derived from magnetic resonance imaging data available from the Alzheimer's Disease Neuroimaging Initiative, and we test for association with gene-gene interactions within biological pathways. Regional brain volumes from the hippocampus (HIP) and entorhinal cortex (EC) were estimated from baseline and 12-month magnetic resonance imaging scans. Approximately 560,000 single nucleotide polymorphisms (SNPs) were available genome-wide. We tested all pairwise SNP-SNP interactions (approximately 151 million) within 212 Kyoto Encyclopedia of Genes and Genomes pathways for association with 12-month regional atrophy rates using linear regression, with sex, APOE ε4 carrier status, age, education, and clinical status as covariates. A total of 109 SNP-SNP interactions were associated with right HIP atrophy, and 125 were associated with right EC atrophy. Enrichment analysis indicated significant SNP-SNP interactions were overrepresented in the calcium signaling and axon guidance pathways for both HIP and EC atrophy and in the ErbB signaling pathway for HIP atrophy.
    Neurobiology of aging 10/2012; 34(5). DOI:10.1016/j.neurobiolaging.2012.09.020 · 5.01 Impact Factor
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