Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121555246 A>T
Position: (GRCh37/hg19):Chr11:121425955 A>T
dbSNP ID: rs78274293
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Silent
Codon Change: ACA to ACT
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 18

Findings

This common, synonymous variant is among those initially described by Rogaeva et al. in 2007 (Rogaeva et al., 2007), when the A allele was reported to associate with increased risk for AD in a case-control dataset of individuals of Northern European ancestry. However, in this same publication, T was reported as the risk allele in Caucasian subjects from the family-based MIRAGE (Multi-Institutional Research in Alzheimer's Genetic Epidemiology) study, and the variant did not associate with AD in other cohorts included in this paper: a case-control dataset of individuals of Israeli-Arab ancestry, and African-American and Caribbean-Hispanic family datasets. Subsequently, the T833T variant has been found in both cases and controls in several cohorts and generally has not been found to associate with the risk of AD—including in the IGAP dataset with more than 17000 AD cases and more than 35000 controls of European descent (Liu et al., 2017). The T allele was associated with reduced risk of AD in a dataset from European Early Onset Dementia (EOD) consortium (Verheijen et al., 2016).

The T833T variant was reported to associate with cerebral atrophy, assessed using MRI, in Caucasian subjects from the MIRAGE study (Cuenco et al., 2008). However, this association was not seen for African American subjects. The variant did not associate with white matter hyperintensities—an imaging marker of cerebrovascular disease—in either white or black subjects in this study.

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

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”Putatively associated with AD” according to authors’ criterion (p <0.1).

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References

Paper Citations

1. Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F, Katayama T, Baldwin CT, Cheng R, Hasegawa H, Chen F, Shibata N, Lunetta KL, Pardossi-Piquard R, Bohm C, Wakutani Y, Cupples LA, Cuenco KT, Green RC, Pinessi L, Rainero I, Sorbi S, Bruni A, Duara R, Friedland RP, Inzelberg R, Hampe W, Bujo H, Song YQ, Andersen OM, Willnow TE, Graff-Radford N, Petersen RC, Dickson D, Der SD, Fraser PE, Schmitt-Ulms G, Younkin S, Mayeux R, Farrer LA, St George-Hyslop P. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet. 2007 Feb;39(2):168-77. PubMed.
2. Liu G, Sun JY, Xu M, Yang XY, Sun BL. SORL1 Variants Show Different Association with Early-Onset and Late-Onset Alzheimer's Disease Risk. J Alzheimers Dis. 2017;58(4):1121-1128. PubMed.
3. Verheijen J, Van den Bossche T, van der Zee J, Engelborghs S, Sanchez-Valle R, Lladó A, Graff C, Thonberg H, Pastor P, Ortega-Cubero S, Pastor MA, Benussi L, Ghidoni R, Binetti G, Clarimon J, Lleó A, Fortea J, de Mendonça A, Martins M, Grau-Rivera O, Gelpi E, Bettens K, Mateiu L, Dillen L, Cras P, De Deyn PP, Van Broeckhoven C, Sleegers K. A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer's disease. Acta Neuropathol. 2016 Aug;132(2):213-24. Epub 2016 Mar 30 PubMed.
4. T Cuenco K, Lunetta KL, Baldwin CT, McKee AC, Guo J, Cupples LA, Green RC, St George-Hyslop PH, Chui H, DeCarli C, Farrer LA, MIRAGE Study Group. Association of distinct variants in SORL1 with cerebrovascular and neurodegenerative changes related to Alzheimer disease. Arch Neurol. 2008 Dec;65(12):1640-8. PubMed.
5. Holstege H, van der Lee SJ, Hulsman M, Wong TH, van Rooij JG, Weiss M, Louwersheimer E, Wolters FJ, Amin N, Uitterlinden AG, Hofman A, Ikram MA, van Swieten JC, Meijers-Heijboer H, van der Flier WM, Reinders MJ, van Duijn CM, Scheltens P. Characterization of pathogenic SORL1 genetic variants for association with Alzheimer's disease: a clinical interpretation strategy. Eur J Hum Genet. 2017 Aug;25(8):973-981. Epub 2017 May 24 PubMed.
6. Bettens K, Brouwers N, Engelborghs S, De Deyn PP, Van Broeckhoven C, Sleegers K. SORL1 is genetically associated with increased risk for late-onset Alzheimer disease in the Belgian population. Hum Mutat. 2008 May;29(5):769-70. PubMed.
7. El Bitar F, Qadi N, Al Rajeh S, Majrashi A, Abdulaziz S, Majrashi N, Al Inizi M, Taher A, Al Tassan N. Genetic Study of Alzheimer's Disease in Saudi Population. J Alzheimers Dis. 2019;67(1):231-242. PubMed.
8. Lee JH, Cheng R, Schupf N, Manly J, Lantigua R, Stern Y, Rogaeva E, Wakutani Y, Farrer L, St George-Hyslop P, Mayeux R. The association between genetic variants in SORL1 and Alzheimer disease in an urban, multiethnic, community-based cohort. Arch Neurol. 2007 Apr;64(4):501-6. PubMed.
9. Meng Y, Lee JH, Cheng R, St George-Hyslop P, Mayeux R, Farrer LA. Association between SORL1 and Alzheimer's disease in a genome-wide study. Neuroreport. 2007 Nov 19;18(17):1761-4. PubMed.

Further Reading

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