SORL1 Single Nucleotide Polymorphisms Research Articles

SORL1 genetic variants and Alzheimer disease risk: a literature review and meta-analysis of sequencing data.

Massive parallel sequencing recently allowed the identification of three genes carrying a higher burden of rare, protein-truncating and missense predicted damaging variants in Alzheimer disease (AD) casesas compared to controls: TREM2, SORL1, and ABCA7. SORL1 encodes SorLA, a key protein involved in the processing of the amyloid-beta (Aβ) precursor protein (APP) and the secretion of the Aβ peptide, the aggregation of which triggers AD pathophysiology. Common SORL1 single nucleotide polymorphisms had originally been associated with AD with modest odds ratios (ORs). The association of AD with rare SORL1 coding variants has been demonstrated at the gene level by aggregating protein-truncating (PTV) and rare predicted damaging missense variants. In addition to the loss of SorLA function induced by PTVs, a few missense variants were studied in vitro, showing diverse degrees of decreased SorLA function andleading to increased Aβ secretion. However, the exact functional consequences of most of the missense variants remain to be determined as well as corresponding levels of AD risk. Hereby we review the evidence of the association of SORL1 common and rare variants with AD risk and conduct a meta-analysis of published data on SORL1 rare variants in five large sequencing studies. We observe a significant enrichment in PTVs with ORs of 12.29 (95% confidence interval = [4.22-35.78]) among all AD cases and 27.50 [7.38-102.42] among early-onset cases. Rare [minor allele frequency (MAF) < 1%] and ultra-rare (MAF < 10-4) missense variants that are predicted damaging by 3/3 bioinformatics tools also show significant associations with corresponding ORs of 1.87 [1.54-2.28] and 3.14 [2.30-4.28], respectively. Per-domain analyses show significant association with the APP-binding CR cluster class A repeats and the Aβ-binding VPS10P domains, as well as the fibronectin type III domain, the function of which remains to be specified. These results further support a critical role for SORL1 rare coding variants in AD, although functional and segregation analyses are required to allow an accurate use in a clinical setting.

An exploratory study of the association between SORL1 polymorphisms and sporadic Alzheimer's disease in the Han Chinese population.

In previous studies, we reported that the sortilin-related receptor, L (DLR class) A repeats containing (SORL1) gene single nucleotide polymorphisms (SNPs) are associated with the risk of sporadic Alzheimer’s disease (SAD) in the Han Chinese population. To further explore the relationships between SORL1 genetic variants and SAD, we conducted a two-step study. Sequencing analysis in 50 case samples identified 14 SNPs within the promoter and untranslated region of the SORL1 gene. Subsequent genotyping analysis in 106 patients with SAD and 179 healthy controls detected a significant association between the “G” allele of SNP rs1133174 in the 3′ untranslated region of the SORL1 gene and SAD risk (odds ratio =1.92, 95% confidence interval [95% CI] =1.28–2.90, adjusted P=0.028). In addition, “G” allele carriers of rs1133174 (GA + GG) have a 2.15-fold increased risk of SAD compared to noncarriers (AA) (adjusted P=0.042). However, no significant positive associations were observed in the other 13 SNPs within the SORL1 gene. These preliminary findings suggest that the SORL1 SNP rs1133174 may be a potential risk locus for SAD in the Han Chinese population.

Association of SORL1 gene variants with hippocampal and cerebral atrophy and Alzheimer's disease.

Sortilin-related receptor, Sorl1, is a neuronal receptor that interacts with the amyloid precursor protein to regulate amyloidogenesis. Variants in the gene encoding Sorl1 are associated with Alzheimer's disease (AD), as well as its neuroimaging markers. To investigate the relationship between SORL1 gene variants with ADrelated brain morphologies and AD, testing for sex-specific effects. The sample comprised 292 individuals aged ≥ 75 years participating in the longitudinal Sydney Older Persons Study. A sub-sample also underwent a brain MRI scan (n=102, 53 males; 49 females). The relationships of three SORL1 single nucleotide polymorphisms (SNPs): rs4935774, rs2298813, rs1133174 with brain MRI measures, and AD were determined. Significant associations of SORL1 variants with cross-sectional brain MRI measures and AD were observed only when the sample was stratified by sex. The most common haplotype (H1), comprising rs4935774-T, rs2298813-G, and rs1133174-G alleles (T/G/G) was associated with whole brain atrophy in both males and females (p=0.012 & p=0.013; respectively). Only SNP rs1133174 was individually associated with hippocampal atrophy in males (p= 0.039) and females (p=0.025). Of the 292 participants, 111 had either probable or possible AD. A significant association of H1 with AD (p = 0.017) was observed in females. A nominally significant association of SNP rs1133174 with AD (p = 0.051) was also observed in the whole cohort. The results provide evidence that the association of polymophisms in the sortilin-related receptor gene (SORL1) with AD and its MRI biomarkers of brain and hippocampal atrophy are moderated by sex.

REGULATION OF SORLA IN GENERAL AND IN ALZHEIMER'S DISEASE

The Sortillin-related receptor (sorLA) is involved in cellular trafficking and processing of the Amyloid precursor protein (APP). A decrease in sorLA expression has been identified in brain tissue from patients suffering from Alzheimer's disease (AD), suggesting that sorLA may be a key regulator of Aβ production and that sorLA activity protects against AD. Furthermore, association between Single Nucleotide Polymorphisms (SNPs) from the gene encoding sorLA (gene name: SORL1) and AD was recently identified; suggesting that transcription of SORL1 could be linked to the development of AD. The mechanism behind the regulation of SORL1 expression in general and how AD-associated SNPs influence sorLA levels during AD, has not yet been characterized. To identify cis - and trans -regulatory factors important for the expression of sorLA, we studied the proximal promoter of SORL1 using in silico analysis and generated promoter constructs for Dual Luciferase Assay. We precipitated proteins from nuclear cell extracts binding to the SORL1 promoter using Streptavidin magnetic beads and biotinylated oligomers. By introduction of constructs for over expression and siRNA molecules for under expression of transcription factors, we determined their effects on sorLA expression by qPCR and Western blotting. Using site-directed mutagenesis we mapped regulatory cis-element binding sites for verified transcription factors. We have identified regions in the SORL1 promoter, important for induction as well as repression of sorLA expression. We identified several trans cription factors that is directly involved in the regulation of sorLA expression, and mapped their binding sites within the proximal SORL1 promoter. Finally, we determined the level of these transcription factors in brain tissue from patients with Alzheimer's disease. We have investigated the regulation of sorLA expression and identified several cis - and trans-regulatory elements important for the proper expression of sorLA. These studies may help to elucidate the mechanisms underlying the observ ed down regulation of sorLA and the linkage to disease onset of SORL1 SNPs in AD patients.

The SORL1 polymorphism rs985421 may confer the risk for amnestic mild cognitive impairment and Alzheimer's disease in the Han Chinese population

Although the pathogenetic mechanisms driving Alzheimer's disease (AD) are unclear, genetic variations may play an important role. Previous studies have identified that single nucleotide polymorphisms (SNPs) in the sortilin-related receptor, L (DLR class) A repeats containing (SORL1) gene are associated with AD or amnestic mild cognitive impairment (aMCI) patients. However, the association of SORL1 variants with AD or aMCI susceptibility in the Han Chinese population has not been adequately reported. Thus, we conducted a case-control study in 106 sporadic AD patients, 67 aMCI patients, and 179 healthy control Han Chinese subjects to determine whether SORL1 genetic variations alter the risk for AD or aMCI. Using the LDR–PCR method to genotype five polymorphisms in SORL1, we found significant associations (for AD: OR=1.968, 95% CI=1.273–3.042; for aMCI: OR=2.210, 95% CI=1.353–3.610) between the ‘A’ allele of the SORL1 SNP rs985421 and AD and aMCI, which may represent an ApoE ɛ4-independent risk factor for SAD. These findings suggest that the SORL1 SNP rs985421 may alter the risk for sporadic AD and aMCI in the Han Chinese population.

Independent and epistatic effects of variants in VPS10-d receptors on Alzheimer disease risk and processing of the amyloid precursor protein (APP)

Genetic variants in the sortilin-related receptor (SORL1) and the sortilin-related vacuolar protein sorting 10 (VPS10) domain-containing receptor 1 (SORCS1) are associated with increased risk of Alzheimer's disease (AD), declining cognitive function and altered amyloid precursor protein (APP) processing. We explored whether other members of the (VPS10) domain-containing receptor protein family (the sortilin-related VPS10 domain-containing receptors 2 and 3 (SORCS2 and SORCS3) and sortilin (SORT1)) would have similar effects either independently or together. We conducted the analyses in a large Caucasian case control data set (n=11 840 cases, 10 931 controls) to determine the associations between single nucleotide polymorphisms (SNPs) in all the five homologous genes and AD risk. Evidence for interactions between SNPs in the five VPS10 domain receptor family genes was determined in epistatic statistical models. We also compared expression levels of SORCS2, SORCS3 and SORT1 in AD and control brains using microarray gene expression analyses and assessed the effects of these genes on γ-secretase processing of APP. Several SNPs in SORL1, SORCS1, SORCS2 and SORCS3 were associated with AD. In addition, four specific linkage disequilibrium blocks in SORCS1, SORCS2 and SORCS3 showed additive epistatic effects on the risk of AD (P⩽0.0006). SORCS3, but not SORCS2 or SORT1, showed reduced expression in AD compared with control brains, but knockdown of all the three genes using short hairpin RNAs in HEK293 cells caused a significant threefold increase in APP processing (from P<0.001 to P<0.05). These findings indicate that in addition to SORL1 and SORCS1, variants in other members of the VPS10 domain receptor family (that is, SORCS1, SORCS2, SORCS3) are associated with AD risk and alter APP processing. More importantly, the results indicate that variants within these genes have epistatic effects on AD risk.

Neuronal LR11 Expression Does Not Differentiate between Clinically-Defined Alzheimer's Disease and Control Brains

Alzheimer's disease (AD) is the leading cause of dementia in the elderly. Because the pathological changes underlying this disease can begin decades prior to the onset of cognitive impairment, identifying the earliest events in the AD pathological cascade has critical implications for both the diagnosis and treatment of this disease. We previously reported that compared to autopsy confirmed healthy control brain, expression of LR11 (or SorLA) is markedly reduced in AD brain as well as in a subset of people with mild cognitive impairment (MCI), a prodromal clinical stage of AD. Recent studies of the LR11 gene SORL1 have suggested that the association between SORL1 single nucleotide polymorphisms (SNPs) and AD risk may not be universal. Therefore, we sought to confirm our earlier findings in a population chosen solely based on clinical criteria, as in most genetic studies. Quantitative immunohistochemistry was used to measure LR11 expression in 43 cases from the Religious Orders Study that were chosen based on a final pre-mortem clinical diagnosis of MCI, mild/moderate AD or no cognitive impairment (NCI). LR11 expression was highly variable in all three diagnostic groups, with no significant group differences. Low LR11 cases were identified using the lowest tertile of LR11 expression observed across all cases as a threshold. Contrary to previous reports, low LR11 expression was found in only 29% of AD cases. A similar proportion of both the MCI and NCI cases also displayed low LR11 expression. AD-associated lesions were present in the majority of cases regardless of diagnostic group, although we found no association between LR11 levels and pathological variables. These findings suggest that the relationship between LR11 expression and the development of AD may be more complicated than originally believed.

Evidence For An Effect of Single Nucleotide Polymorphisms In Sorl1 on Cerebrospinal Fluid Markers of Alzheimer‘s Disease

Evaluation of: Alexopoulos P, Guo LH, Kratzer M, Westerteicher C, Kurz A, Perneczky R. Impact of SORL1 single nucleotide polymorphisms on Alzheimer’s disease cerebrospinal fluid markers. Dement. Geriatr. Cogn. Disord. 32, 164–170 (2011). This study explores the effect of previously reported SORL1 variants on cerebrospinal fluid (CSF) levels of Aβ1–42, phosphorylated tau181 and total tau in 100 nondemented people, 166 people with mild cognitive impairment and 87 people with probable Alzheimer’s disease. In individuals with Alzheimer’s disease, the A allele of single nucleotide polymorphism 23 and the T allele of single nucleotide polymorphism 24 were associated with lower CSF Aβ1–42, the latter association becoming marginally insignificant after correction for multiple testing. Both associations showed an interaction with the APOE genotype. There were no significant associations of SORL1 single nucleotide polymorphisms with CSF Aβ1–42 levels in the mild cognitive impairment group or with phosphorylated tau181 or total tau in any of the groups.

Impact of SORL1 Single Nucleotide Polymorphisms on Alzheimer’s Disease Cerebrospinal Fluid Markers

Background: Recently, genetic variants of the neuronal sortilin-related receptor with A-type repeats (SORL1, also called LR11 or sorLA) have emerged as risk factors for the development of Alzheimer’s disease (AD). Methods: In this study, SORL1 gene polymorphisms, which have been shown to be related to AD, were analyzed for associations with cerebrospinal fluid (CSF) amyloid beta1–42 (Aβ_1–42), phosphorylated tau181, and total tau levels in a non-Hispanic Caucasian sample, which encompassed 100 cognitively healthy elderly individuals, 166 patients with mild cognitive impairment, and 87 patients with probable AD. The data were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (www.loni.ucla.edu/ADNI). Moreover, the impact of gene-gene interactions between SORL1 single nucleotide polymorphisms (SNPs) and the apolipoprotein E (APOE) Ε4 allele, the major genetic risk factor for sporadic AD, on Aβ_1–42 concentrations was investigated. Results: Significant associations between CSF Aβ_1–42 levels and the SORL1 SNPs 23 (rs3824968) and 24 (rs2282649) were detected in the AD group. The latter association became marginally statistically insignificant after Bonferroni correction for multiple comparisons. Carriers of the SORL1 SNP24 T allele and the SNP23 A allele both had lower CSF Aβ_1–42 concentrations than non-carriers of these alleles. The analysis of the impact of interactions between APOE Ε4 allele and SORL1 SNPs on CSF Aβ_1–42 levels unraveled significant influences of APOE. Conclusions: Our findings provide further support for the notion that SORL1 genetic variants are related to AD pathology, probably by regulating the amyloid cascade.

Meta-analysis of the Association Between Variants in SORL1 and Alzheimer Disease

To reexamine the association between the neuronal sortilin-related receptor gene (SORL1) and Alzheimer disease (AD). 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. Academic research institutions in the United States, the Netherlands, Canada, Belgium, the United Kingdom, Singapore, Japan, Sweden, Germany, France, and Italy. All published white and Asian case-control data sets, which included a total of 12,464 cases and 17,929 controls. 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). 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 β-peptide 42, and full-length SORL1 expression in the human brain. This comprehensive meta-analysis provides confirmatory evidence that multiple SORL1 variants in distinct linkage disequilibrium blocks are associated with AD.

Amyloid-β-Related Genes SORL1 and ACE are Genetically Associated With Risk for Late-onset Alzheimer Disease in the Chinese Population

Late-onset Alzheimer Disease (LOAD) is a common neurodegenerative disease, and one of its major pathologic characteristics is senile plaques. Proteins encoded by SORL1 and ACE have been shown to be related to the processing, trafficking, and degradation of Amyloid-β, the principal component of senile plaques. In this paper, we investigated whether SORL1 and ACE are associated with LOAD. We recruited 144 LOAD patients and 476 controls from Shanghai, China and conducted a case-control study on 9 single-nucleotide polymorphisms (SNPs): 6 in SORL1 (rs2070045, rs661057, rs668387, rs689021, rs3824968, rs2282649) and 3 in ACE (rs1800764, rs4343, rs1799752). Despite the small case sample size (144), we observed that rs1800764, rs4343, rs1799752 in ACE, and rs2070045, rs3824968, rs2282649 in SORL1 showed significantly different allele frequencies between patients and controls (P=4.57×10, 5.24×10, 1.95×10, 1.77×10, 6.44×10, and 3.11×10, respectively). Moreover, haplotypes on ACE and on SORL1 were significantly associated with LOAD (all P-value<0.009 in ACE and all P-value <0.003 in SORL1). In ACE, we found the most significant protective haplotype encompasses SNPs rs2070045, rs3824968, and rs2282649 (C-G-D: OR=0.20, P=8.96×10). In SORL1, we detected a "complementary" haplotype (G-A-T: OR=1.54, P=2.67×10; T-T-C: OR=0.63, P=2.36×10) composed of SNPs rs2070045, rs3824968, and rs2282649. In addition, we carried out meta-analysis with 3 other Asian populations on 3 SNPs in SORL1 (rs2070045, rs3824968, and rs2282649). Results supported our initial finding that these 3 SNPs were associated with LOAD. Our data suggested that SORL1 and ACE might play a role in LOAD susceptibility among Han Chinese.

Validating predicted biological effects of Alzheimer's disease associated SNPs using CSF biomarker levels.

Recent large-scale genetic studies of late-onset Alzheimer's disease have identified risk variants in CALHM1, GAB2, and SORL1. The mechanisms by which these genes might modulate risk are not definitively known. CALHM1 and SORL1 may alter amyloid-β (Aβ) levels and GAB2 may influence phosphorylation of the tau protein. In this study we have analyzed disease associated genetic variants in each of these genes for association with cerebrospinal fluid (CSF) Aβ or tau levels in 602 samples from two independent CSF series. We failed to detect association between CSF Aβ42 levels and single nucleotide polymorphisms in SORL1 despite substantial statistical power to detect association. While we also failed to detect association between variants in GAB2 and CSF tau levels, power to detect this association was limited. Finally, our data suggest that the minor allele of rs2986017, in CALHM1, is marginally associated with CSF Aβ42 levels. This association is consistent with previous reports that this non-synonymous coding substitution results in increased Aβ levels in vitro and provides support for an Aβ-related mechanism for modulating risk for Alzheimer's disease.

Implication of Sex and SORL1 Variants in Italian Patients With Alzheimer Disease

To investigate the association of genetic variants in sortilin-related receptor (SORL1), which has been proposed as an important genetic contributor to late-onset Alzheimer disease (LOAD). We analyzed 13 SORL1 single-nucleotide polymorphisms (SNPs) and the relative haplotypes in a case-control association study. The sample included 708 Italian subjects: 251 unrelated, sporadic patients with LOAD, 99 sporadic patients with early-onset Alzheimer disease (AD), and 358 healthy controls. We analyzed the 13 SNPs in the SORL1 gene that had been studied in previous reports using case-control methods and included sex, apolipoprotein E (APOE) genotype, and age at AD onset as covariates. The SNPs 4 (rs661057), 7 (rs12364988), and 10 (rs641120) were significantly associated with LOAD compared with controls. We found an association between these 3 variants and sex, suggesting that SORL1 may possibly affect LOAD through a female-specific mechanism. Of interest, the association of these SNPs with LOAD was confined to APOE epsilon4 noncarriers. Several haplotypic associations at the 5' end of SORL1 were found, including the previously associated CGC haplotype at SNPs 8 through 10. Our results confirm the association of SORL1 with AD and show a possible effect of female sex, suggesting that this gene may be a promising susceptibility factor for LOAD. Further studies to detect pathogenic variants and further elucidate the effect of SORL1 on the development of AD are necessary.

A Study of the SORL1 Gene in Alzheimer's Disease and Cognitive Function

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.

Association between SORL1 and Alzheimer's disease in a genome-wide study.

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.

The Association Between Genetic Variants in SORL1 and Alzheimer Disease in an Urban, Multiethnic, Community-Based Cohort

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.