Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121586253 C>T
Position: (GRCh37/hg19):Chr11:121456962 C>T
dbSNP ID: rs1699102
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Silent
Codon Change: AAC to AAT
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 27

Findings

This synonymous variant is one of the 29 SNPs reported by Rogaeva et al. in 2007 and has been reported subsequently in several other studies (see table). While C is the reference allele at this position, it generally has been reported as the minor allele in populations of European descent (Caucasian populations), while T was found to be the minor allele in Asian cohorts. The two alleles were found with nearly equal frequency in African Americans. Homozygous carriers have been found among both AD cases and controls. Allelic variation at this position was not found to associate with AD in several individual studies of cohorts of various ancestries, nor in meta-analyses.

The variant also was not associated with cognitive impairment in the Women’s Health Initiative Memory Study (Driscoll et al., 2019), incident AD or cognitive function in Dutch subjects followed longitudinally for more than a decade (Liu et al., 2009), or risk or age of onset of AD in adults with Down syndrome (Lee et al., 2007). However, in a sample of non-demented Han Chinese, the T allele was associated with accelerated age-related changes in episodic memory and processing speed (Li et al., 2017).

The N1246N variant is classified as likely benign by the criteria of Holstege et al. (Holstege et al., 2017).

Biomarkers and Endophenotypes

Several studies investigated the association of the allele with fluid and imaging biomarkers.

One study found no association of the allele with levels of CSF core biomarkers— Aβ42, t-tau, and p-tau —in a group of non-Hispanic Caucasians that contained control, MCI, and AD subjects (Alexopoulos, et al., 2011). However, in a group of German AD subjects, carriers of the C allele had lower levels of CSF Aβ42 than did non-carriers (Guo et al., 2012).  In the same study, CSF levels of other biomarkers related to APP metabolism—sAPPα, sAPPβ, and BACE1—and of SORL1 itself did not differ between genotypes in cognitively impaired (AD, MCI) subjects.

SNP 22 was not associated with brain atrophy or cerebrovascular disease assessed using MRI in Caucasian and African-American sibships from the MIRAGE study (Cuenco et al., 2008). However, in a sample of non-demented Han Chinese, the T allele was associated with atrophy of the right middle temporal pole (Li et al., 2017).

Linkage Disequilibrium

SNP 22 is in linkage disequilibrium with several other variants, including rs2070045 (SNP 19), rs3824966 (SNP 20), rs73595277 (SNP 21), rs3824968 (SNP 23), rs2282649 (SNP 24), rs726601, rs1784931, rs1010159 (SNP 25) in cohorts of European ancestry (Caglayan et al., 2012; Jin et al., 2013; Rogaeva et al., 2007) and rs2070045 (SNP 19), rs3824968 (SNP 23), rs2282649 (SNP 24), rs1010159 (SNP 25) in Asian cohorts (Jin et al., 2013).

Functional Consequences

In a set of autopsy specimens from Caucasian donors with AD, the level of SORL1 protein in the frontal cortex was lower in carriers of the SNP 22 C allele, in a gene-dose-dependent manner (Caglayan et al., 2012).

In neurons derived from human induced pluripotent stem cells, SORL1 expression increased in response to BDNF, but the size of this response did not depend upon the SNP22 genotype (Young et al, 2015).

This variant is predicted to be tolerated by SIFT and neutral by PROVEAN, and is classified as a polymorphism by Mutation Taster (El Bitar et al., 2019).

Table

^aAllele frequencies as reported by study authors or calculated by Alzforum curators from data provided in the study, assuming heterozygosity if not explicitly stated in the paper.
^b”Borderline statistical significance,” per authors, which became non-significant when data from Rogaeva et al. are excluded.

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References

Paper Citations

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