SORL1 is Genetically Associated with Neuropathologically Characterized Late-Onset Alzheimer's Disease

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.

Elucidating Molecular Phenotypes Caused by the SORL1 Alzheimer’s Disease Genetic Risk Factor Using Human Induced Pluripotent Stem Cells

“…Multiple studies have confirmed a strong linkage disequilibrium in these regions using various population datasets (Bettens et al, 2008; Rogaeva et al, 2007; Wen et al, 2013). We genotyped our fibroblast lines for eight representative SORL1 variants, four SNPs in the 5′ region and four SNPs in the 3′ region.…”

Early Life Epidemiology of Alzheimer's Disease - A Critical Review

“…Mutations in the APOE receptor SORL1 have also been linked to late-onset AD and alter neural structure in AD-affected networks 17 . SORL1 variant children show white matter microstructural abnormalities, and the underexpression of SORL1 mRNA in brain occurs specifically during childhood and adolescence 10 .…”

Sortilin Fragments Deposit at Senile Plaques in Human Cerebrum

“…Variants in several loci of the sortilin-related receptor L1 gene ( SORL1 , also known as SORLA, SORLA1 or LR11 ) can increase the risk of AD (Rogaeva et al, 2007; Pottier et al, 2012; Wen et al, 2013; Felsky et al, 2014; Louwersheimer et al, 2015; Verheijen et al, 2016). Variants of single nucleotide polymorphisms (SNPs) of the sortilin related Vps10p domain containing receptor 1 ( SORCS1 ) may also relate to AD (Reitz et al, 2011).…”