SORL1 variants and risk of late-onset Alzheimer’s disease

Li, Yonghong; Rowland, Charles M.; Catanese, Joseph J.; Morris, John C.; Lovestone, Simon; O'Donovan, Michael Conlon; Goate, Alison M.; Williams, Julie; Grupe, Andrew

doi:10.1016/j.nbd.2007.09.001

Cited by 76 publications

(58 citation statements)

References 13 publications

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“…Li et al [9] examined several SNPs and haplotypes in a population of size and demographics similar to ours, and observed only marginal association with AD risk for a single SNP (rs2070045) which they dismissed because it is not statistically significant after correcting for multiple testing.…”

mentioning

confidence: 59%

No association of SORL1 SNPs with Alzheimer's disease

Minster¹,

DeKosky²,

Kamboh³

2008

Neuroscience Letters

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SORL1 is an element of the amyloid precursor protein processing pathway and is therefore a good candidate for affecting Alzheimer's disease (AD) risk. Indeed, there have been reports of associations between variation in SORL1 and AD risk. We examined six statistically significant single-nucleotide polymorphisms from the initial observation in a large Caucasian American case-controls cohort (1000 late-onset AD [LOAD] cases and 1000 older controls). Analysis of allele, genotype and haplotype frequencies revealed no association with LOAD risk in our cohort. KeywordsAlzheimer's disease; SORL1; genetics It is estimated that up to 79% of the risk for late-onset Alzheimer's disease (LOAD) is attributable to genetics [4]. Thus far, only variation in APOE has been definitively associated with LOAD [2], but only 20%-29% of risk is attributable to this variation [20,22]. Association between variation in an excellent biological candidate gene, sortilin-related receptor 1 (SORL1), and the risk of LOAD has been reported [18]. We genotyped and analyzed six of the single nucleotide polymorphisms (SNPs), listed in Table 1, that were reported to be associated with LOAD in a multiple case-control cohort or family-based samples [18] to verify this report.Case subjects were Caucasian Americans with LOAD (n = 1009; mean age-at-onset [AAO] 72.8 ± 6.2 [SD] years; 67.7% female; 7.3% autopsy-confirmed) recruited by the University of Pittsburgh Alzheimer's Disease Research Center. All cases were evaluated clinically and met criteria for probable or possible AD [11] or by autopsy and met neuropathological criteria for definite AD [13,14]. Controls were Caucasian Americans of age 60 or above with no psychiatric or neurological disorders (n = 1009; mean age-at-baseline 74.1 ± 6.2 [SD] years; 59.9% female; 1.3% autopsy-confirmed). All experiments on human subjects were conducted in accordance with the Declaration of Helsinki, and all procedures were carried out with the adequate understanding and written consent of the subjects. The genetic study was approved by the University of Pittsburgh Institutional Review Board.Genotypes for the six SORL1 SNPs were ascertained from genomic DNA using TaqMan SNP genotyping assays (Applied Biosystems, Foster City, California). Case and control samples were present on each 384-well plate used in genotyping. To estimate genotyping error rates, *Corresponding Author: University of Pittsburgh, Department of Human Genetics, Pittsburgh PA 15261, 412-624-3066, Fax: 412-383-7844, ikamboh@hgen.pitt.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 10% of the s...

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confidence: 59%

No association of SORL1 SNPs with Alzheimer's disease

Minster¹,

DeKosky²,

Kamboh³

2008

Neuroscience Letters

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“…Interestingly, association was observed in two distinct clusters of SORL1, suggesting multiple variations in this gene may contribute to late-onset AD genetic risk. Reinvestigation of the association supported this notion of allelic heterogeneity in an urban, multiethnic community-based cohort but not in a dataset collected from three Caucasian LOAD populations [Li et al, 2007]. Further, based on data from a publicly available genome-wide association study, association could be shown near the 3' region of SORL1 in an American AD population .…”

Section: Introductionmentioning

confidence: 86%

SORL1 is genetically associated with increased risk for late-onset Alzheimer disease in the Belgian population

et al. 2008

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SORL1 has recently been identified as a major genetic contributor to increased risk for lateonset Alzheimer disease (AD).Here we aimed at replicating this finding in a large, wellcharacterized group of 550 Belgian late-onset AD patients and 637 healthy control individuals using a gene-wide genotyping approach across the SORL1 locus. We observed significant associations, both for individual SNPs (SNPs 6, 8, 9, 10 and 27; p-values ranging from 0.001 to 0.040) and 3-SNP haplotypes (SNPs 5-6-7 and SNPs 25-26-27; p-values ranging from 0.008 to 0.035). Moreover, the associations at SNP 8, 9 and 10 represented a direct replication of the initial association data. Two signals in distinct regions of the gene were shown to be mutually independent, supporting allelic heterogeneity at the SORL1 locus in the Belgian population. Our findings confirm that genetic variants in SORL1 may be important risk factors for late-onset AD.

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“…Several groups have attempted to replicate these findings. One reports a “partial replication” using 2000 samples 29. A second study reports a replication of the original finding using an independent dataset including of 1408 individuals from the TGEN database (http://www.tgen.org/neurogenomics/data Translational Genomics Research Institute; TGEN) which included 1044 autopsied individuals (641 cases, 403 controls) and 364 clinically examined individuals from the Mayo Clinic (218 cases and 146 controls) 30.…”

Section: Chromosome 11mentioning

confidence: 99%

Genetic Aspects of Alzheimer Disease

Williamson

Goldman²,

Marder³

2009

The Neurologist

102

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Background Alzheimer disease (AD) is a genetically complex disorder. Mutations in 3 genes, presenilin 1, amyloid precursor protein, and presenilin 2, lead to early-onset familial AD in rare families with onset of disease occurring prior to age 65. Specific polymorphisms in apolipoprotein E are associated with the more common, late-onset AD occurring after age 65. In this review, we discuss current advances in AD genetics, the implications of the known AD genes, presenilin 1, presenilin 2, amyloid precursor protein, and apolipoprotein E, and other possible genes on the clinical diagnosis, treatment, and genetic counseling of patients and families with early- and late-onset AD. Review Summary In addition to the mutations in 4 known genes associated with AD, mutations in other genes may be implicated in the pathogenesis of the disease. Most recently, 2 different research groups have reported genetic association between 2 genes, sortilin-related receptor and GAB2, and AD. These associations have not changed the diagnostic and medical management of AD. Conclusions New research in the genetics of AD have implicated novel genes as having a role in the disease, but these findings have not been replicated nor have specific disease causing mutations been identified. To date, clinical genetic testing is limited to familial early-onset disease for symptomatic individuals and asymptomatic relatives and, although not recommended, amyloid precursor protein apolipoprotein E testing as an adjunct to diagnosis of symptomatic individuals.

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SORL1 variants and risk of late-onset Alzheimer’s disease

Cited by 76 publications

References 13 publications

No association of SORL1 SNPs with Alzheimer's disease

No association of SORL1 SNPs with Alzheimer's disease

SORL1 is genetically associated with increased risk for late-onset Alzheimer disease in the Belgian population

Genetic Aspects of Alzheimer Disease

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