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


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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    • "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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    • "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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