No association of SORL1 SNPs with Alzheimer's disease

Abstract

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...

Association of SORL1 Alleles with Late-Onset Alzheimer's Disease. Findings from the GIGAS_LOAD Study and Mega-Analysis

“…Sample size may be a critical factor, as discussed above. However, the negative results of GIGAS_LOAD are consistent with those reported in previous studies with similar case-control designs [23]. In addition a genome screen for LOAD carried out in a genetically isolated population from Netherlands found linkage to chromosome 11q25 [44].…”

SORL1 gene polymorphism association with late-onset Alzheimer’s disease

“…In 2007, Rogaeva et al [8] suggested that SORL1 may be the second risk factor for AD onset, reporting SNP results of the SORL1 gene sequence in six different species, and association between a SNP in SORL1 and LOAD. Following this, successive studies have indicated the SORL1 may be genetically associated with increased risk for amnestic mild cognitive impairment and Alzheimer's disease in the Han Chinese population [9,10,11], although some studies have shown no obvious correlation [12,13]. In humans, the SORL1 gene is located on the long arm of chromosome 11 (q23.2 24.2) and is 177.49 kb in length.…”

Sortilin receptor 1 predicts longitudinal cognitive change

“…In 2007, variants of the SORL1 gene were associated with Alzheimer’s disease (AD) risk (Rogaeva, et al, 2007). Subsequent replication efforts, though mixed, have been predominantly positive (Alexopoulos, et al, 2010,Bettens, et al, 2008,Cousin, et al, 2011,Feulner, et al, 2009,Kimura, et al, 2009,Kölsch, et al, 2009,Lee, et al, 2007,Lee, et al, 2008,Li, et al, 2008,Liu, et al, 2009,Meng, et al, 2007,Minster, et al, 2008,Patel, et al, 2010,Reitz, et al, 2011,Reynolds, et al, 2010,Schjeide, et al, 2009,Tan, et al, 2009,Webster, et al, 2008). Recently, we reported no significant association of six SORL1 markers with dementia risk, age-of-onset, CSF Aβ or tau (Reynolds, et al, 2010).…”