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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    • "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.
    Journal of Alzheimer's disease: JAD 03/2013; 35(2). DOI:10.3233/JAD-122395 · 4.15 Impact Factor
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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.
    Journal of Alzheimer's disease: JAD 08/2009; 18(1):51-64. DOI:10.3233/JAD-2009-1137 · 4.15 Impact Factor
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    • "Seven other groups examined the relation between SORL1 and LOAD or LOAD endophenotypes in different populations (Bettens et al., 2008; Seshadri et al., 2007; Tan et al., 2007; Li H et al., 2008; Li M et al., 2008; Webster et al., 2008). Three replication studies supported the initial findings, while the remaining three showed either negative or weak results. "
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    ABSTRACT: Late-onset Alzheimer's disease is a common complex disorder of old age. Though these types of disorders can be highly heritable, they differ from single-gene (Mendelian) diseases in that their causes are often multifactorial with both genetic and environmental components. Genetic risk factors that have been firmly implicated in the cause are mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes, which are found in large multi-generational families with an autosomal dominant pattern of disease inheritance, the apolipoprotein E (APOE)epsilon4 allele and the sortilin-related receptor (SORL1) gene. Environmental factors that have been associated with late-onset Alzheimer's disease include depressive illness, various vascular risk factors, level of education, head trauma and estrogen replacement therapy. This complexity may help explain their high prevalence from an evolutionary perspective, but the etiologic complexity makes identification of disease-related genes much more difficult. The "endophenotype" approach is an alternative method for measuring phenotypic variation that may facilitate the identification of susceptibility genes for complexly inherited traits. The usefulness of endophenotypes in genetic analyses of normal brain morphology and, in particular for Alzheimer's disease will be reviewed as will the implications of these findings for models of disease causation. Given that the pathways from genotypes to end-stage phenotypes are circuitous at best, identifying endophenotypes more proximal to the effects of genetic variation may expedite the attempts to link genetic variants to disorders.
    Neuroscience 05/2009; 164(1):174-90. DOI:10.1016/j.neuroscience.2009.04.006 · 3.36 Impact Factor
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