Article

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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    • "Even in hypothesis-free genome-wide association studies (GWAS) of AD, when testing of gene-gene interactions has been incorporated, it has been restricted to interactions between APOE and other risk loci with known main effect associations. Belbin et al. (2011) investigated interactions among 21 LOAD candidate and confirmed risk genes, including APOE, BIN1, CLU, CR1, and PICALM but failed to detect any interactions with disease status or age-atonset that were significant after correction for multiple testing (Belbin et al., 2011). Similarly, Carrasquillo et al. (2011) failed to identify significant interactions between variants in BIN1 and other LOAD risk genes, including APOE, CLU, CR1, and PICALM (Carrasquillo et al., 2011). "
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    ABSTRACT: Late-onset Alzheimer disease (LOAD) has a complex genetic etiology, involving locus heterogeneity, polygenic inheritance and gene-gene interactions; however, the investigation of interactions in recent GWAS has been limited. We used a biological knowledge-driven approach to evaluate gene-gene interactions for consistency across thirteen datasets from the Alzheimer Disease Genetics Consortium. Fifteen SNP-SNP pairs within three gene-gene combinations were identified: SIRT1 x ABCB1, PSAP x PEBP4, and GRIN2B x ADRA1A. Additionally, we extend a previously identified interaction from an endophenotype analysis between RYR3 x CACNA1C. Finally, post hoc gene expression analyses of the implicated SNPs further implicate SIRT1 and ABCB1, and implicate CDH23 which was most recently identified as an AD risk locus in an epigenetic analysis of AD. The observed interactions in this manuscript highlight ways in which genotypic variation related to disease may depend on the genetic context in which it occurs. Further, our results highlight the utility of evaluating genetic interactions to explain additional variance in AD risk and identify novel molecular mechanisms of AD pathogenesis.
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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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    • "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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