Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121595730 G>A
Position: (GRCh37/hg19):Chr11:121466439 G>A
dbSNP ID: rs774690115
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: GGC to AGC
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 32

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 six times—five times among the AD cases and once among the controls (Holstege et al., 2022). A mega-analysis of these data did not find an association between the variant and AD risk.

Previously, the G1493S variant was found in one of 332 Alzheimer’s cases and none of 676 controls in a set of Caucasian subjects from Britain and North America (Sassi et al., 2016).

This variant also was reported in two of 5198 AD cases and none of 4491 controls in a dataset from the Alzheimer’s Disease Sequencing Project (ADSP), consisting of subjects of non-Hispanic Caucasian ancestry from whom whole-exome sequencing data were available (Campion et al., 2019). The ADSP contributed data to the 2022 study cited above.

Functional Consequences

The SORL1 protein contains 11 complement-type repeats (CRs). A majority of known SORL1 ligands, including APP, bind to the CR cluster. Glycine-1493 is located at position 38 in CR10 and is one of a pair of glycines—located at positions 27 and 38—that is conserved in eight of the 11 CRs. Based on this degree of conservation, Andersen and colleagues predicted that substitutions of glycine at residue 1493 are moderately likely to increase AD risk (Andersen et al., 2023).

Substitutions of a conserved glycine at position 38 were found in 26 AD cases and 15 controls when the mega dataset cited above (Holstege et al., 2022) was expanded to 18,959 AD cases and 21,893 controls (Holstege et al., 2023). In aggregate, these variants associated with an increased risk of AD (odds ratio: 2.0; 95% confidence interval: 1.06 – 3.78; p = 0.040).

A pathogenic variant was identified in a homologous position in complement factor I (CFI), leading to CFI deficiency (Andersen et al., 2023).

This variant was predicted to be deleterious by SIFT, disease-causing by Mutation Taster, and probably damaging by PolyPhen-2 (Sassi et al., 2016).

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References

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. Sassi C, Ridge PG, Nalls MA, Gibbs R, Ding J, Lupton MK, Troakes C, Lunnon K, Al-Sarraj S, Brown KS, Medway C, Lord J, Turton J, ARUK Consortium, Morgan K, Powell JF, Kauwe JS, Cruchaga C, Bras J, Goate AM, Singleton AB, Guerreiro R, Hardy J. Influence of Coding Variability in APP-Aβ Metabolism Genes in Sporadic Alzheimer's Disease. PLoS One. 2016;11(6):e0150079. Epub 2016 Jun 1 PubMed.
3. Campion D, Charbonnier C, Nicolas G. SORL1 genetic variants and Alzheimer disease risk: a literature review and meta-analysis of sequencing data. Acta Neuropathol. 2019 Aug;138(2):173-186. Epub 2019 Mar 25 PubMed.
4. Andersen OM, Monti G, Jensen AM, deWaal M, Hulsman M, Olsen JG, Holstege H. Relying on the relationship with known disease-causing variants in homologous proteins to predict pathogenicity of SORL1 variants in Alzheimer's disease. 2023 Feb 27 10.1101/2023.02.27.524103 (version 1) bioRxiv.
5. Holstege H, deWaal MW, Tesi N, vanderLee SJ, ADESconsortium, ADSPconsortium, StEP-ADconsortium, Knight-ADRC, UCSF/NYGC/UAB, Vogel M, vanSpaendonk R, Hulsman M, Andersen OM. Effect of prioritized SORL1 missense variants supports clinical consideration for familial Alzheimer's Disease. 2023 Jul 16 10.1101/2023.07.13.23292622 (version 1) medRxiv.

Further Reading

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