Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121590884 G>C
Position: (GRCh37/hg19):Chr11:121461593 G>C
dbSNP ID: rs2282647
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Intron 30

Findings

In a study that included 15,808 Alzheimer’s cases and 16,097 control subjects from multiple European and American cohorts, this allele was observed 1336 times—616 time among the AD cases and 720 times among the controls (Holstege et al., 2022). A mega-analysis of these data found that the variant was associated with a slight reduction in AD risk (odd ratio 0.86, 95% confidence interval: 0.75-0.98, p=0.02).

A GWAS including 1893 Alzheimer’s cases and 2001 controls from the Japanese Genetic Consortium for Alzheimer Disease did not detect an association of the variant with disease (odd ratio 1.00, 95% confidence interval: 0.88-1.12, p=0.937) (Miyashita et al., 2013). Nor did a study of neuropathologically characterized subjects from Japanese ADNI, including 213 late-onset AD cases and 370 controls (odds ratio 0.66, 95% confidence interval: 0.49-0.89, p=4.88x10^-3, Bonferroni-corrected threshold for significance : 2.63x10^-3) (Wen et al., 2013).

Most recently, this variant was identified within a haplotype found to confer strong protection against AD in people of East Asian ancestry (Zhou et al., 2024). This study further explored potential biological effects of the variant. Data mining showed that the variant is located in a candidate cis-regulatory element. While rs2282647 is intronic in the canonical 2214-amino acid SORL1 isoform, it is a coding variant in a truncated isoform (“SORL1-206” or “sorLA-30B,” ENST00000527934.1, Uniprot E9PKB0). This isoform has 829-amino acids, and its N-terminal is formed by a fragment of intron 30 spliced in-frame to exon 31 (numbered according to full-length SORL1) (Blechingberg et al., 2018). SORL1-206 contains only three of the complement-type repeat domains found in full-length SORL1, but all six fibronectin-type III domains and the transmembrane and intracellular domains, and is expressed in human brain, most prominently in the hippocampus and temporal lobe (Blechingberg et al., 2018). Variant rs2282647 introduces a tryptophan-to-cysteine substitution at residue 15 (numbered according to the SORL1-206 sequence) in this truncated isoform. In silico analyses predicted that the Trp15Cys mutation might affect the stability or localization of the protein, and the mutation resulted in a 17 percent reduction in the level of SORLA protein in HEK cells transfected with a vector encoding Trp15Cys SORL1-206, compared with cells transfected with wild-type SORL1-206 (Zhou et al., 2024).

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References

Mutations Citations

1. SORL1 Haplotype A

Paper Citations

1. Holstege H, Hulsman M, Charbonnier C, Grenier-Boley B, Quenez O, Grozeva D, van Rooij JG, Sims R, Ahmad S, Amin N, Norsworthy PJ, Dols-Icardo O, Hummerich H, Kawalia A, Amouyel P, Beecham GW, Berr C, Bis JC, Boland A, Bossù P, Bouwman F, Bras J, Campion D, Cochran JN, Daniele A, Dartigues JF, Debette S, Deleuze JF, Denning N, DeStefano AL, Farrer LA, Fernández MV, Fox NC, Galimberti D, Genin E, Gille JJ, Le Guen Y, Guerreiro R, Haines JL, Holmes C, Ikram MA, Ikram MK, Jansen IE, Kraaij R, Lathrop M, Lemstra AW, Lleó A, Luckcuck L, Mannens MM, Marshall R, Martin ER, Masullo C, Mayeux R, Mecocci P, Meggy A, Mol MO, Morgan K, Myers RM, Nacmias B, Naj AC, Napolioni V, Pasquier F, Pastor P, Pericak-Vance MA, Raybould R, Redon R, Reinders MJ, Richard AC, Riedel-Heller SG, Rivadeneira F, Rousseau S, Ryan NS, Saad S, Sanchez-Juan P, Schellenberg GD, Scheltens P, Schott JM, Seripa D, Seshadri S, Sie D, Sistermans EA, Sorbi S, van Spaendonk R, Spalletta G, Tesi N, Tijms B, Uitterlinden AG, van der Lee SJ, Visser PJ, Wagner M, Wallon D, Wang LS, Zarea A, Clarimon J, van Swieten JC, Greicius MD, Yokoyama JS, Cruchaga C, Hardy J, Ramirez A, Mead S, van der Flier WM, van Duijn CM, Williams J, Nicolas G, Bellenguez C, Lambert JC. Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease. Nat Genet. 2022 Dec;54(12):1786-1794. Epub 2022 Nov 21 PubMed.
2. Miyashita A, Koike A, Jun G, Wang LS, Takahashi S, Matsubara E, Kawarabayashi T, Shoji M, Tomita N, Arai H, Asada T, Harigaya Y, Ikeda M, Amari M, Hanyu H, Higuchi S, Ikeuchi T, Nishizawa M, Suga M, Kawase Y, Akatsu H, Kosaka K, Yamamoto T, Imagawa M, Hamaguchi T, Yamada M, Morihara T, Moriaha T, Takeda M, Takao T, Nakata K, Fujisawa Y, Sasaki K, Watanabe K, Nakashima K, Urakami K, Ooya T, Takahashi M, Yuzuriha T, Serikawa K, Yoshimoto S, Nakagawa R, Kim JW, Ki CS, Won HH, Na DL, Seo SW, Mook-Jung I, Alzheimer Disease Genetics Consortium, St George-Hyslop P, Mayeux R, Haines JL, Pericak-Vance MA, Yoshida M, Nishida N, Tokunaga K, Yamamoto K, Tsuji S, Kanazawa I, Ihara Y, Schellenberg GD, Farrer LA, Kuwano R. SORL1 is genetically associated with late-onset Alzheimer's disease in Japanese, Koreans and Caucasians. PLoS One. 2013;8(4):e58618. Epub 2013 Apr 2 PubMed.
3. Wen Y, Miyashita A, Kitamura N, Tsukie T, Saito Y, Hatsuta H, Murayama S, Kakita A, Takahashi H, Akatsu H, Yamamoto T, Kosaka K, Yamaguchi H, Akazawa K, Ihara Y, Kuwano R. SORL1 is genetically associated with neuropathologically characterized late-onset Alzheimer's disease. J Alzheimers Dis. 2013;35(2):387-94. PubMed.
4. Zhou X, Cao H, Jiang Y, Chen Y, Zhong H, Fu WY, Lo RM, Wong BW, Cheng EY, Mok KY, Kwok TC, Mok VC, Ip FC, Alzheimer's Disease Neuroimaging Initiative, Miyashita A, Hara N, Ikeuchi T, Hardy J, Chen Y, Fu AK, Ip NY. Transethnic analysis identifies SORL1 variants and haplotypes protective against Alzheimer's disease. Alzheimers Dement. 2025 Jan;21(1):e14214. Epub 2024 Dec 10 PubMed.
5. Blechingberg J, Poulsen AS, Kjølby M, Monti G, Allen M, Ivarsen AK, Lincoln SJ, Thotakura G, Vægter CB, Ertekin-Taner N, Nykjær A, Andersen OM. An alternative transcript of the Alzheimer's disease risk gene SORL1 encodes a truncated receptor. Neurobiol Aging. 2018 Nov;71:266.e11-266.e24. Epub 2018 Jun 28 PubMed.

Further Reading

No Available Further Reading