Possible association between SORL1 and Alzheimer disease? Reanalysing the data of Shibata et al.
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ABSTRACT:
SUBMITTER: Lee JH
PROVIDER: S-EPMC2703707 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:OBJECTIVE:To reexamine the association between the neuronal sortilin-related receptor gene (SORL1) and Alzheimer disease (AD). DESIGN:Comprehensive and unbiased meta-analysis of all published and unpublished data from case-control studies for the SORL1 single-nucleotide polymorphisms (SNPs) that had been repeatedly assessed across studies. SETTING:Academic research institutions in the United States, the Netherlands, Canada, Belgium, the United Kingdom, Singapore, Japan, Sweden, Germany, France, and Italy. PARTICIPANTS:All published white and Asian case-control data sets, which included a total of 12,464 cases and 17,929 controls. MAIN OUTCOME MEASURES:Alzheimer disease according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) and the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (now known as the Alzheimer's Association). RESULTS:In the white data sets, several markers were associated with AD after correction for multiple testing, including previously reported SNPs 8, 9, and 10 (P < .001). In addition, the C-G-C haplotype at SNPs 8 through 10 was associated with AD risk (P < .001). In the combined Asian data sets, SNPs 19 and 23 through 25 were associated with AD risk (P < .001). The disease-associated alleles at SNPs 8, 9, and 10 (120,873,131-120,886,175 base pairs [bp]; C-G-C alleles), at SNP 19 (120,953,300 bp; G allele), and at SNPs 24 through 25 (120,988,611 bp; T and C alleles) were the same previously reported alleles. The SNPs 4 through 5, 8 through 10, 12, and 19 through 25 belong to distinct linkage disequilibrium blocks. The same alleles at SNPs 8 through 10 (C-G-C), 19 (G), and 24 and 25 (T and C) have also been associated with AD endophenotypes, including white matter hyperintensities and hippocampal atrophy on magnetic resonance imaging, cerebrospinal fluid measures of amyloid ?-peptide 42, and full-length SORL1 expression in the human brain. CONCLUSION:This comprehensive meta-analysis provides confirmatory evidence that multiple SORL1 variants in distinct linkage disequilibrium blocks are associated with AD.
| S-EPMC3086666 | biostudies-literature
Project description:To investigate the association between Alzheimer disease (AD) and variant alleles in SORL1 using a series of single nucleotide polymorphisms (SNPs) in an urban, multiethnic, community-based population.We used a nested case-control analysis in a population-based, prospective study of aging and dementia in Medicare recipients, 65 years and older.Northern Manhattan, NY.There were 296 patients with probable AD and 428 healthy, elderly controls. The participants were African American (34%), Caribbean Hispanic (51%), or non-Hispanic white (15%).We genotyped all 29 SNPs in SORL1 that were examined in the earlier report. We assessed allelic association with AD using standard case-control methods, which included apolipoprotein E genotype as a covariate.Several individual SNPs and SNP haplotypes were significantly associated with AD in this prospectively collected community-based cohort, confirming the previously reported positive association of SORL1 with AD. Single nucleotide polymorphism 12, near the 5' region, was associated with AD in African American and Hispanic individuals. Two SNPs in the 3' region were also associated with AD in African American (SNP 26) and non-Hispanic white (SNP 20) individuals. A single haplotype in the 3' region was associated with AD in Hispanic individuals. However, several different haplotypes were associated with AD in African American and white individuals, including the TTC haplotypes at SNPs 23 through 25 (P = .035), which was significantly associated with AD in the North European white individuals in our previous report.This study confirms the association between genetic variants in SORL1 and AD. While the associations observed in these data sets overlap with those previously reported, the finding of novel SNP and haplotype associations suggests that there may be extensive allelic heterogeneity in SORL1. Broad regions of the SORL1 gene will therefore need to be scrutinized for functional pathogenic variants.
| S-EPMC2639214 | biostudies-literature
Project description:OBJECTIVE:Common single nucleotide polymorphisms in the SORL1 gene have been associated with late onset Alzheimer disease (LOAD), but causal variants have not been fully characterized nor has the mechanism been established. The study was undertaken to identify functional SORL1 mutations in patients with LOAD. METHODS:This was a family- and cohort-based genetic association study. Caribbean Hispanics with familial and sporadic LOAD and similarly aged controls were recruited from the United States and the Dominican Republic, and patients with sporadic disease of Northern European origin were recruited from Canada. Prioritized coding variants in SORL1 were detected by targeted resequencing and validated by genotyping in additional family members and unrelated healthy controls. Variants transfected into human embryonic kidney 293 cell lines were tested for A?40 and A?42 secretion, and the amount of the amyloid precursor protein (APP) secreted at the cell surface was determined. RESULTS:Seventeen coding exonic variants were significantly associated with disease. Two rare variants (rs117260922-E270K and rs143571823-T947M) with minor allele frequency (MAF)?<?1% and 1 common variant (rs2298813-A528T) with MAF?=?14.9% segregated within families and were deemed deleterious to the coding protein. Transfected cell lines showed increased A?40 and A?42 secretion for the rare variants (E270K and T947M) and increased A?42 secretion for the common variant (A528T). All mutants increased the amount of APP at the cell surface, although in slightly different ways, thereby failing to direct full-length APP into the retromer-recycling endosome pathway. INTERPRETATION:Common and rare variants in SORL1 elevate the risk of LOAD by directly affecting APP processing, which in turn can result in increased A?40 and A?42 secretion.
| S-EPMC4367199 | biostudies-literature
Project description: Not available
| S-EPMC7491402 | biostudies-literature
Project description:Comparative genomic hybridization experiments comparing DNA from experimentally evolved yeast strains to DNA from a euploid control.
2022-12-08 | GSE220549 | GEO
Project description:BACKGROUND:Single-nucleotide polymorphisms (SNPs) in 2 distinct regions of the gene for the sortilin-related receptor (SORL1) (bounded by consecutively numbered SNPs 8-10 and 22-25) were shown to be associated with Alzheimer disease (AD) in multiple ethnically diverse samples. OBJECTIVE:To test the hypothesis that SORL1 is associated with brain magnetic resonance imaging (MRI) measurements of atrophy and/or vascular disease. DESIGN, SETTING, AND PATIENTS:We evaluated the association of 30 SNPs spanning SORL1 with MRI measures of general cerebral atrophy, hippocampal atrophy, white matter hyperintensities, and overall cerebrovascular disease in 44 African American and 182 white sibships from the MIRAGE Study. We performed single- and 3-SNP haplotype association analyses using family-based tests. Haplotypes found to be significantly associated with at least 1 MRI trait were tested for association with 6 pathological traits in a separate sample of 69 white patients with autopsy-confirmed AD. RESULTS:In white patients, white matter hyperintensities were associated with multiple markers in the region encompassing SNPs 6 to 10, whereas cerebral and hippocampal atrophy were associated with markers from the region including SNPs 21 to 26. Examination of specific 3-SNP haplotypes from these 2 regions in the autopsy-confirmed cases of AD revealed association of white matter disease with SNPs 8 to 10 and association of hippocampal atrophy with SNPs 22 to 26. The haplotype CGC at SNPs 8 to 10 was associated with fewer white matter changes in the clinical (P<.001) and autopsy (P=.02) samples. CONCLUSIONS:Variants of SORL1 previously associated with AD are also associated with MRI and neuropathological measures of neurodegenerative and cerebrovascular disease. These findings not only support the hypothesis that multiple areas in SORL1 are of functional importance but also raise the possibility that multiple SORL1 variants influence amyloid precursor protein or endothelial lipoprotein processing or both in different regions of the brain.
| S-EPMC2719762 | biostudies-literature
Project description: Not available
| S-EPMC4696596 | biostudies-literature
Project description:The transcriptome profiles of sporulating vs non-sporulating cells, within an isogenic culture were compared. Keywords: isogenic subpopulation comparison Bacillus subtilis sporulation
2007-10-23 | GSE9266 | GEO
Project description:Several studies have reported an association of Alzheimer's disease (AD) with polymorphic markers in SORL1. Data from a recently published genome-wide association study in AD have been made publicly available. We tested the association of AD with SORL1 in this dataset (Translational Genomics Research Institute; TGEN), which included 31 SORL1 single nucleotide polymorphisms (SNPs), eight of which overlapped the original study. Six SNPs, near the 3' region of SORL1 containing SNPs which were strongly associated with AD in previous studies, showed significant association in the TGEN dataset. These results provide an independent replication of the association between AD and SORL1.
| S-EPMC2631643 | biostudies-literature
Project description:ObjectiveTo characterize the clinical and molecular effect of mutations in the sortilin-related receptor (SORL1) gene.MethodsWe performed whole-exome sequencing in early-onset Alzheimer disease (EOAD) and late-onset Alzheimer disease (LOAD) families followed by functional studies of select variants. The phenotypic consequences associated with SORL1 mutations were characterized based on clinical reviews of medical records. Functional studies were completed to evaluate β-amyloid (Aβ) production and amyloid precursor protein (APP) trafficking associated with SORL1 mutations.ResultsSORL1 alterations were present in 2 EOAD families. In one, a SORL1 T588I change was identified in 4 individuals with AD, 2 of whom had parkinsonian features. In the second, an SORL1 T2134 alteration was found in 3 of 4 AD cases, one of whom had postmortem Lewy bodies. Among LOAD cases, 4 individuals with either SORL1 A528T or T947M alterations had parkinsonian features. Functionally, the variants weaken the interaction of the SORL1 protein with full-length APP, altering levels of Aβ and interfering with APP trafficking.ConclusionsThe findings from this study support an important role for SORL1 mutations in AD pathogenesis by way of altering Aβ levels and interfering with APP trafficking. In addition, the presence of parkinsonian features among select individuals with AD and SORL1 mutations merits further investigation.
| S-EPMC5082932 | biostudies-literature