Article

Systematic Analysis of Candidate Genes for Alzheimer's Disease in a French, Genome-Wide Association Study

INSERM U744, Lille, France.
Journal of Alzheimer's disease: JAD (Impact Factor: 3.61). 04/2010; 20(4):1181-8. DOI: 10.3233/JAD-2010-100126
Source: PubMed

ABSTRACT We selected twenty genes from the "Top Results" list on the AlzGene database website and assessed their association with risk of developing Alzheimer's disease (AD) in a large, genome-wide association study (using 526 SNPs from 2,032 AD cases and 5,328 controls) performed in France. The APOE, CLU, PICALM, and CR1 loci were excluded, since they had already been extensively analyzed. Ten genes/loci (TFAM, SORL1, CHRNB2, SORCS1, DAPK1, MTHFR, GWA 14q32.13, BDNF, NEDD9, and CH25H) showed weak nominal association with AD risk, in line with previous studies. In the remaining ten genes/loci (TNK1, ACE, CST3, IL1B, hCG2039140, PRNP, GAB2, LOC651924, IL1A, and TF), no single nucleotide polymorphisms were associated in our dataset. Of the genes showing nominal association in our cohorts, TFAM and CHRNB2 appear particularly interesting and warrant further genetic and functional follow-up analyses.

1 Follower
 · 
264 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The retromer coat complex is a vital component of the intracellular trafficking mechanism sorting cargo from the endosomes to the trans-Golgi network or to the cell surface. In recent years, genes encoding components of the retromer coat complex and members of the vacuolar protein sorting 10 (Vps10) family of receptors, which play pleiotropic functions in protein trafficking and intracellular/intercellular signaling in neuronal and non-neuronal cells and are primary cargos of the retromer complex, have been implicated as genetic risk factors for sporadic and autosomal dominant forms of several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and frontotemporal lobar degeneration. In addition to their functions in protein trafficking, the members of the Vps10 receptor family (sortilin, SorL1, SorCS1, SorCS2, and SorCS3) modulate neurotrophic signaling pathways. Both sortilin and SorCS2 act as cell surface receptors to mediate acute responses to proneurotrophins. In addition, sortilin can modulate the intracellular response to brain-derived neurotrophic factor (BDNF) by direct control of BDNF levels and regulating anterograde trafficking of Trk receptors to the synapse. This review article summarizes the emerging data from this rapidly growing field of intracellular trafficking signaling in the pathogenesis of neurodegeneration.
    Molecular Genetics and Genomics 10/2014; 290(2). DOI:10.1007/s00438-014-0939-9 · 2.83 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer's disease (AD) is a chronic neurodegenerative disorder that is characterized by progressive neuropathology and cognitive decline. We performed a cross-tissue analysis of methylomic variation in AD using samples from four independent human post-mortem brain cohorts. We identified a differentially methylated region in the ankyrin 1 (ANK1) gene that was associated with neuropathology in the entorhinal cortex, a primary site of AD manifestation. This region was confirmed as being substantially hypermethylated in two other cortical regions (superior temporal gyrus and prefrontal cortex), but not in the cerebellum, a region largely protected from neurodegeneration in AD, or whole blood obtained pre-mortem from the same individuals. Neuropathology-associated ANK1 hypermethylation was subsequently confirmed in cortical samples from three independent brain cohorts. This study represents, to the best of our knowledge, the first epigenome-wide association study of AD employing a sequential replication design across multiple tissues and highlights the power of this approach for identifying methylomic variation associated with complex disease.
    Nature Neuroscience 08/2014; DOI:10.1038/nn.3782 · 14.98 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: No treatment strategies effectively limit the progression of Alzheimer’s disease (AD), a common and debilitating neurodegenerative disorder. The absence of viable treatment options reflects the fact that the pathophysiology and genotypic causes of the disease are not well understood. The advent of genome-wide association studies (GWAS) has made it possible to broadly investigate genotypic alterations driving phenotypic occurrences. Recent studies have associated single nucleotide polymorphisms (SNPs) in two paralogous scaffolding proteins, NEDD9 and CASS4, and the kinase PTK2B, with susceptibility to late-onset AD (LOAD). Intriguingly, NEDD9, CASS4, and PTK2B have been much studied as interacting partners regulating oncogenesis and metastasis, and all three are known to be active in the brain during development and in cancer. However, to date, the majority of studies of these proteins have emphasized their roles in the directly cancer relevant processes of migration and survival signaling. We here discuss evidence for roles of NEDD9, CASS4 and PTK2B in additional processes, including hypoxia, vascular changes, inflammation, microtubule stabilization and calcium signaling, as potentially relevant to the pathogenesis of LOAD. Reciprocally, these functions can better inform our understanding of the action of NEDD9, CASS4 and PTK2B in cancer.

Full-text (2 Sources)

Download
102 Downloads
Available from
May 19, 2014