Sorl1 as an Alzheimer’s Disease Predisposition Gene?

Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Ariz., USA.
Neurodegenerative Diseases (Impact Factor: 3.51). 02/2008; 5(2):60-4. DOI: 10.1159/000110789
Source: PubMed


Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressively disabling impairments in memory, cognition, and non-cognitive behavioural symptoms. Sporadic AD is multifactorial and genetically complex. While several monogenic mutations cause early-onset AD and gene alleles have been suggested as AD susceptibility factors, the only extensively validated susceptibility gene for late-onset AD is the apolipoprotein E (APOE) epsilon4 allele. Alleles of the APOE gene do not account for all of the genetic load calculated to be responsible for AD predisposition. Recently, polymorphisms across the neuronal sortilin-related receptor (SORL1) gene were shown to be significantly associated with AD in several cohorts. Here we present the results of our large case-control whole-genome scan at over 500,000 polymorphisms which presents weak evidence for association and potentially narrows the association interval.

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    • "A recent study failed to recapitulate the reduced expression of SORLA in yet another set of post-mortem AD brain samples (Sager et al., 2012), and, therefore, additional studies might be necessary to resolve this issue. Nevertheless, there is strong support for the involvement of SORLA in sporadic AD, which stems from population-based studies that document association of genetic variants of SORL1 (the gene encoding SORLA) with sporadic AD in several ethnicities (Rogaeva et al., 2007; Bettens et al., 2008; Cuenco et al., 2008; Lee et al., 2008; Webster et al., 2008). Cumulative meta-analyses encompassing in excess of 30,000 individuals (Reitz et al., 2011) and genomewide association studies (Meng et al., 2007; Naj et al., 2011) confirm the association of single nucleotide polymorphisms (SNPs) in SORL1 with AD. "
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    ABSTRACT: Excessive proteolytic breakdown of the amyloid precursor protein (APP) to neurotoxic amyloid β peptides (Aβ) by secretases in the brain is a molecular cause of Alzheimer disease (AD). According to current concepts, the complex route whereby APP moves between the secretory compartment, the cell surface and endosomes to encounter the various secretases determines its processing fate. However, the molecular mechanisms that control the intracellular trafficking of APP in neurons and their contribution to AD remain poorly understood. Here, we describe the functional elucidation of a new sorting receptor SORLA that emerges as a central regulator of trafficking and processing of APP. SORLA interacts with distinct sets of cytosolic adaptors for anterograde and retrograde movement of APP between the trans-Golgi network and early endosomes, thereby restricting delivery of the precursor to endocytic compartments that favor amyloidogenic breakdown. Defects in SORLA and its interacting adaptors result in transport defects and enhanced amyloidogenic processing of APP, and represent important risk factors for AD in patients. As discussed here, these findings uncovered a unique regulatory pathway for the control of neuronal protein transport, and provide clues as to why defects in this pathway cause neurodegenerative disease.
    Preview · Article · Jun 2013 · Journal of Cell Science
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    • "Together, these genetic and biological findings show that SORL1 could be one of the susceptibility genes for LOAD. After the initial study by Rogaeva et al. [5], subsequent replication studies were carried out on various cohorts, especially on Caucasians [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30]. Concerning Asians, there have been five replication studies: two on Chinese [31] [32] and the others on Japanese [33] [34] [35]. "
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    ABSTRACT: SORL1 was shown to be genetically associated with late-onset Alzheimer's disease (LOAD) in a large-scale genome-wide association study (GWAS) involving clinically verified subjects. Here, we attempted to replicate the association of SORL1 in Japanese neuropathologically characterized brain donor subjects (LOAD, 213; control, 370) through a single-nucleotide polymorphism (SNP)-based genetic study involving 19 SNPs: 11 SNPs were selected from the initial study reported by Rogaeva et al. (2007), and the other eight were from our GWAS. Among these SNPs, five exhibited a significant association with LOAD after multiple test correction (p < 2.63E-03 [ = 0.05/19]), which was supported by means of multiple logistic regression analysis with adjustment for age, gender, and carrier status of the APOE ε4 allele. Three of these SNPs (rs985421, rs12364988 [Rogaeva's SNP 7], and rs4598682) were encompassed by a 5' linkage disequilibrium (LD) region, and the remaining two (rs3781834 and rs3781836) by a 3' LD region. Strong LD among SNPs was observed within each LD region, implying that there are two genomic regions showing association with LOAD in SORL1. Case-control haplotype analysis demonstrated that some haplotypes are associated with LOAD in both LD regions. Our replication study strongly supports the preceding evidence that SORL1 is likely one of the genes associated with LOAD.
    Full-text · Article · Mar 2013 · Journal of Alzheimer's disease: JAD
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    • "Although there is some marginal evidence for association, when adjusted for multiple testing no SNP was significantly associated. Other studies also have genotyped a dense series of SNPs to evaluate additional genetic variants in the SORL1 gene [1] [5] [7] [30] [32]. None of these studies showed significant evidence of association with AD with adjustment for multiple testing. "
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    ABSTRACT: Several studies have investigated the role of the neuronal sortilin-related receptor (SORL1) gene in Alzheimer's disease (AD), but findings have been inconsistent. We conducted a study of 7 single nucleotide polymorphisms (SNPs), rs668387, rs689021, rs641120, rs1699102, rs3824968, rs2282649, and rs1010159, in the SORL1 gene that were associated to AD in previous studies. We tested for association with AD and cognitive function in 6741 participants of the Rotterdam Study and in 2883 individuals from the Erasmus Rucphen Family study. We performed meta-analyses on AD using our data together with those of previous studies published prior to September 2008 in Caucasians. Further, we studied up to 76 SNPs in a 400 kb region within and flanking the gene to evaluate the evidence that other genetic variants are associated with AD or cognitive function. There was no significant evidence for association between SORL1 SNPs and incident AD patients in the Rotterdam Study. In a meta-analysis of our data with those of others, six out of seven SNPs attained borderline significance. However, removal of the first study reporting association from the meta-analysis resulted in non-significant odds ratios for all SNPs. SNPs rs668387, rs689021, and rs641120 were associated with cognitive function in non-demented individuals at borderline statistical significance in two independent Dutch cohorts, but in the opposite direction. Testing for association using dense SNPs in the SORL1 gene did not reveal significant association with AD, or with cognitive function when adjusting for multiple testing. In conclusion, our data do not support the hypothesis that genetic variants in SORL1 are related to the risk of AD.
    Full-text · Article · Aug 2009 · Journal of Alzheimer's disease: JAD
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