Mutations

SORL1 S1187S (SNP 19)

Other Names: SNP 19

Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121577381 T>G
Position: (GRCh37/hg19):Chr11:121448090 T>G
dbSNP ID: rs2070045
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Silent
Codon Change: TCT to TCG
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 25

Findings

This synonymous variant (S1187S, “SNP 19”) is among those initially described by Rogaeva et al. in 2007 (Rogaeva et al., 2007), when it was reported to be associated with an increased risk of AD in Caucasians. The variant was subsequently reported in many other studies, sometimes associated with AD risk and sometimes not (see table).

Meta-analyses of these studies have also yielded a variety of results. Among cohorts described as Caucasian or of European ancestry, the G allele has been associated with both increased (Liu et al., 2017; Reitz et al., 2011; Wang et al., 2016) and decreased (Reynolds et al., 2010) risks of AD or has not been significantly associated with disease (Cong et al., 2018; Li et al., 2008). In one meta-analysis focused on Asian cohorts, the G allele was reported to increase AD risk (Reitz et al., 2011), while two others did not find a significant association between the variant and AD (Cong et al., 2018; Wang et al., 2016). The results of meta-analyses that combined Caucasian and Asian subjects were also inconsistent (Cong et al., 2018; Jin et al., 2013; Wang et al., 2016).

SNP 19 was not associated with MCI in a study of Han Chinese subjects (Chou et al., 2016) or with conversion from MCI to AD in a study of Italian and Italian-speaking Swiss subjects (Piscopo et al., 2015).

The variant did not associate with age-at-onset in Swedish dementia cases (~80 percent of whom were diagnosed with AD) (Reynolds, et al., 2010).

This variant is classified as likely pathogenic by the criteria of Holstege and colleagues (Holstege et al., 2017).

Linkage Disequilibrium

SNP 19 is in linkage disequilibrium with several other variants, including rs677078, rs17092943, rs4936636, rs4936637, rs3824966 (SNP 20), rs4936638, rs11218350, rs73595277 (SNP 21), rs1699102 (SNP 22), rs3824968 (SNP 23), rs2282649 (SNP 24), rs726601, rs1784931, and rs1010159 (SNP 25) in cohorts of European ancestry (Caglayan et al., 2012; Jin et al., 2013; Liu et al., 2017; Rogaeva et al., 2007); rs1699102 (SNP 22), rs3824968 (SNP 23), rs2282649 (SNP 24), and rs1010159 (SNP 25) in Asian cohorts (Jin et al., 2013; Ning et al., 2010); rs3824966 (SNP 20) and rs73595277 (SNP 21) in an African-American cohort (Rogaeva et al., 2007); and rs3824966 (SNP 20), rs1699102 (SNP 22), rs3824968 (SNP 23), rs2282649 (SNP 24), and rs1010159 (SNP 25) in a Mexican cohort (Toral-Rios et al., 2022).

In a large meta-analysis of data from the International Genomics of Alzheimer’s Project, seven SNPs in linkage disequilibrium with SNP 19 were all reported to be associated with late-onset AD (Liu et al., 2017).

Fluid Biomarkers

Generally, the S1187S variant was not found to associate with CSF biomarkers of AD—Aβ42 (Alexopoulos et al., 2011; Elias-Sonnenschein et al., 2013; Guo et al., 2012; Kauwe et al., 2010; Kölsch, et al., 2008; Reynolds, et al., 2010), total tau (Alexopoulos et al., 2011; Elias-Sonnenschein et al., 2013; Reynolds, et al., 2010), or phospho-tau (Alexopoulos et al., 2011; Elias-Sonnenschein et al., 2013). The SNP rs3824966, used as a proxy for the SNP 19 G allele, was reported to associate with increased levels of CSF total-tau in a set of AD subjects from ADNI and the German Dementia Competence Network (Louwersheimer et al., 2015).

Magnetic Resonance Imaging Markers

Several studies have investigated the relationships between SNP 19 and MRI markers.

SNP 19 did not associate with cerebral atrophy or white-matter hyperintensities in Caucasians or African Americans in the family-based Multi-Institutional Research in Alzheimer's Genetic Epidemiology (MIRAGE) Study (Cuenco et al., 2008). SNP rs3824966, a proxy for the SNP 19 G allele, was associated with greater hippocampal atrophy in AD patients from ADNI and the German Dementia Competence Network (Louwersheimer, et al., 2015).

In young adult Han Chinese subjects, the G allele was associated with lower functional connectivity density in the right inferior temporal gyrus (Shen, et al., 2016) and lower resting state functional connectivity between the hippocampus and the medial temporal gyrus (Shen et al., 2017). In the latter study, resting state functional connectivity between the hippocampus and the inferior frontal gyrus was influenced by an interaction between SORL1 and APOE genotypes, such that the presence of the SORL1 G allele had opposite effects in APOE E4 carriers and non-carriers.

In a study of healthy elderly Han Chinese living in Beijing, white-matter integrity in the cingulum bundle associated with the SNP 19 genotype in men but not women (Liang, et al., 2015).

Cognitive Function

SNP 19 did not associate with cognitive trajectory—verbal, spatial, memory and perceptual-speed performance—in a cohort of Swedes who were non-demented at baseline (Reynolds, et al., 2013). Nor did the variant associate with MMSE score in a cohort of Han Chinese over the age of 60 (Lin et al., 2017). However, in a study of healthy elderly Han Chinese, the SNP 19 genotype associated with executive function in men but not women (Liang, et al., 2015).

 

Functional Consequences

In a set of autopsy specimens from Caucasian donors with AD, the level of SORLA protein in the frontal cortex was lower in carriers of the SNP 19 G allele than in noncarriers, while the levels of SORL1 mRNA did not differ among the genotypes (Caglayan et al., 2012). An eQTL (expression quantitative trait locus) analysis found that the story might be more complicated, with pathology and brain region influencing the association between the allele and SORL1 expression: The G allele was associated with decreased levels of SORL1 mRNA in the temporal cortices of people with AD and in a dataset that combined specimens from subjects with AD, progressive supranuclear palsy, Lewy body dementia, corticobasal degeneration, frontotemporal lobar degeneration, multiple system atrophy, and vascular dementia. In the cerebellum, the G allele associated with increased SORL1 expression in the specimens with non-AD pathology, but it did not associate with SORL1 transcript levels in the AD specimens (Liu et al., 2017).

As noted above, SNP19 (G allele) is in linkage disequilibrium with SNP 22 (N1246N, C allele). The effect on SORL1 expression of a haplotype composed of these alleles was investigated in Chinese hamster ovary cells transfected with SORL1 mini-genes. Levels of SORLA protein were lower in cells carrying the SNP 19 and SNP 22 variants, compared with cells carrying the wild-type gene, while SORL1 mRNA levels did not differ between the genotypes. These findings suggest that the SNP19/SNP22 haplotype alters translation efficiency (Caglayan et al., 2012).

The SNP19 variant was predicted to be tolerated by SIFT and neutral by PROVEAN, and it was classified as a polymorphism by Mutation Taster (El Bitar et al., 2019).

Table

Risk Allele(s) N
Cases | Controls
(families)		 aAllele frequency
Cases | Controls		 Reported association measurements Ancestry
(Cohort)		 Reference
Large-scale studies and meta-analyses
G b6095 | 8267   OR = 0.76
[CI: 0.54 - 1.06]
p = 0.11		 Caucasian and Asian Cong et al., 2018
(meta-analysis)
b5514 | 7340   OR = 1.14
[CI: 0.87 - 1.49]
p = 0.35		 Caucasian
b581 | 927   OR = 0.29
[CI: 0.07 - 1.22]
p = 0.09		 Asian
G     OR = 0.89
[CI: 0.83 - 0.96]
p = 2×10-3
(12 studies, allelic association, random effects model)		 Caucasian, Asian Jin et al., 2013
(meta-analysis)
    OR = 0.85
[CI: 0.76 - 0.96]
p not reported
(12 studies, generalized odds ratio)
G 2032 | 5328   OR = 1.09
[CI: 0.99 - 1.19]
p =  0.09		 French Caucasian Laumet et al., 2010
(GWAS)
G     OR = 1.20
[CI: 1.10 − 1.31]
reported not significant		 cCaucasian Li et al., 2008
(meta-analysis)
G 17008 | 37154   dp = 0.0116 European
(IGAP)		 Liu et al., 2017
(GWAS)
G 804 |  1190   OR = 1.33
[CI: 1.16 - 1.52]
p <10-4		 Chinese, Japanese Ning et al., 2010
(meta-analysis)
G AD + CTRL
19,206		   OR = 1.08
[CI: 1.01 - 1.14]
ep = 0.02		 Caucasian Reitz et al., 2011
(meta-analysis)
AD + CTRL
1443		   OR = 1.27
[CI: 1.10 - 1.41]
p = 1×10-3		 Asian
G 1270 Swedish AD cases, 2179 controls +
Alzgene cohorts (total 5331)		   OR = 0.89
[CI: 0.82 - 0.97]
reported significant		 European Reynolds et al., 2010
(meta-analysis)
G 1255 | 1938 0.23 | 0.22 OR = 1.1
[CI: 0.92  - 1.21]
p = 0.44		 European
(European Early-Onset Dementia Consortium)		 Verheijen et al., 2016
(meta-analysis)
G AD cases + controls
16,103		   OR = 1.13
[CI: 1.03 - 1.23]
p = 9×10-3		 Caucasian and Asian Wang et al., 2016
(meta-analysis)
    OR = 1.07
[CI: 1.02 - 1.13]
reported significant		 Caucasian
    OR = 1.26
[CI: 0.92 - 1.74]
reported not significant		 Asian
Other studies
G 550 | 634 N.A. | 0.21 reported not significant Belgian (Engelborghs et al., 2003) Bettens et al., 2008
G 251 | 358 0.225 | 0.215 p = 0.68 Italian
(Department of Neurological and Psychiatric Sciences, University of Florence)		 Cellini et al., 2009
T 793 | 394 0.372 | 0.3985 OR = 0.89
[CI: N.A.]
p = 0.204		 Han Chinese
(Taipei Veterans General Hospital and Taichung Veterans General Hospital, Taiwan)		 Chou et al., 2016
G 117 | 0 0.205 | N.A.   Saudi Arabian
(King Faisal Specialist Hospital & Research Center)		 El Bitar et al., 2019
G 883 | 695 0.25 | 0.27 p = 0.41 Finnish
(Finnish-AD)		 Elias-Sonnenschein et al., 2013
TT vs. TG+GG TT/TG/GG
AD: 0.57/0.37/0.06
CTRL: 0.54/0.39/0.07		 OR = 0.88
[CI: 0.72 - 1.07]
p = 0.20
G 640 | 1268 0 | 0   Dutch
(Rotterdam Study, Amsterdam Dementia Cohort, Alzheimer Centrum Zuidwest Nederland (ACZN), 100-plus Study)		 Holstege et al., 2017
G 437 | 450 0.490 | 0.437 OR = 1.53
[CI: 1.13 - 2.05]
p = 0.025		 Japanese
(Osaka University Graduate School of Medicine, Choju Medical Institute of Fukushimura Hospital)		 Kimura et al., 2009
APOE ε4+
214 | 72		 0.507 | 0.438 p = 0.149
APOE ε4-
223 | 378		 0.473 | 0.490 p = 0.218
G 349 | 483 0.25 | 0.23 p = 0.41 German
(German Competence Network Dementias)		 Kölsch et al., 2009
G 178 | 194 0.231 | 0.237 p = 0.8495 Caribbean Hispanic
(WHICAP)		 Lee et al., 2007
88 | 158 0.098 | 0.132 p = 0.2786 African-American
(WHICAP)
30 | 76 0.300 | 0.194 p = 0.1216 White, non-Hispanic European
(WHICAP)
G 991 | 1027 0.252 | 0.223 p = 0.035 Caucasian
(Washington University Knight ADRC, Cardiff University)		 Li et al., 2008
  859 | 549 0 | 0   not specified
(TGEN)		 Meng et al., 2007
G 994 | 1001 0.221 | 0.224 p = 0.823 Caucasian American
(University of Pittsburgh ADRC)		 Minster et al., 2008
G 144 | 476   OR = 1.73
[CI: 1.30- 2.31]
p = 1.59×10-3		 Chinese
(Shanghai Mental Health Center)		 Ning et al., 2010
G 338 | 215 all = 0.19 OR = 1.03
[CI: 0.74 - 1.41]
p = 0.86		 Italian, Swiss
(Memory Clinic of University “Sapienza” (Rome), Alzheimer’s Units of Ospedale Maggiore Policlinico (Milan), Geriatric Division of the Ospedali Riuniti of Lugano and Mendrisio (Canton Ticino, Switzerland))		 Piscopo et al., 2015
G 1270 | 2179   OR = 0.96
[CI: 0.86 - 1.08]
p = 0.52		 Swedish
(Swedish Twin Registry, Mölndal Prospective Dementia Study, longitudinal geriatric study from Piteå, Sweden)		 Reynolds et al., 2010
G 1554 | 2333 all = 0.238 OR = 1.18
[CI: 1.06–1.31]
p = 2.3×10-3		 Combined Caucasian case-control datasets
(North European, Mayo Jacksonville, Mayo Rochester, Mayo autopsy)		 Rogaeva et al., 2007
1400 | 2113 all = 0.234 OR = 1.13
[CI: 1.01–1.26]
p = 0.038		 Combined Mayo series
178 | 242 all = 0.287 OR = 1.79
[CI: 1.27 - 2.53]
p = 8.2×10-4		 North European
(case-control)
549 | 477 all = 0.224 OR = 1.14
[CI: 0.93 – 1.41]
p = 0.210		 Mayo Jacksonville
433 | 1217 all = 0.242 OR = 1.19
[CI: 1.00 – 1.42]
p = 0.055		 Mayo Rochester
423 | 430 all = 0.230 OR = 1.15
[CI: 0.92 – 1.44]
p = 0.225		 Mayo autopsy
111 | 114 all = 0.236 OR = 1.16
[CI: 0.75 - 1.80]
p = 0.499		 Israeli-Arab
(case-control)
(Wadi Area population study)
321 | 342
(42)		 all = 0.207 p = 0.031 North European
[family]
605 | 517
(84)		 all = 0.245 p = 0.617 Caribbean Hispanic
[family]
279 | 252
(58)		 all = 0.277 p = 0.765 Caucasian [family]
(MIRAGE)
244 | 127
(22)		 all = 0.175 p = 0.352 African-American [family]
(MIRAGE)
G 223 | 263 0.380 | 0.427 OR = 1.22
[CI: 0.94 - 1.57]
p = 0.140		 Han Chinese Tan et al., 2009
T 156 | 221 0.49 | 0.46 reported significant Mexican
(Geriatric Clinic, “Mocel” General Hospital, Mexico City; Instituto Nacional de Neurología y Neurocirugía, Hospital de Alta Especialidad de Ixtapaluca; Geriatric Center, Querétaro)		 Toral-Rios et al., 2022
TT+TG vs. GG TT/TG/GG
AD: 0.24/0.49/0.27
CTRL: 0.23/0.47/0.31		 OR = 1.186
[CI: 0.75 – 1.88]
p = 0.469
T 77 | 100 0.558 | 0.44 OR = 1.6
[CI: N.A.]
p = 0.027		 Han Chinese Xue et al., 2013

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.
bCalculated by Alzforum curator from data supplied in paper; numbers of subjects are total for entire study and may not equal the number successfully genotyped for this particular variant.
cLi et al. and Rogaeva et al. Caucasian samples.
dMet criteria for “nominal” significance (p <0.05), according to authors.
eNo longer significant if Rogaeva omitted from the meta-analysis.

This table is meant to convey the range of results reported in the literature. As specific analyses, including co-variates, differ among studies, this information is not intended to be used for quantitative comparisons, and readers are encouraged to refer to the original papers. Thresholds for statistical significance were defined by the authors of each study. (Significant results are in bold.) Note that data from some cohorts may have contributed to multiple studies, so each row does not necessarily represent an independent dataset. While every effort was made to be accurate, readers should confirm any values that are critical for their applications.

Last Updated: 18 Jul 2024

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References

Paper Citations

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  35. 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.
  36. 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.
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  39. Xue X, Zhang M, Lin Y, Xu E, Jia J. Association between the SORL1 rs2070045 polymorphism and late-onset Alzheimer's disease: interaction with the ApoE genotype in the Chinese Han population. Neurosci Lett. 2014 Jan 24;559:94-8. Epub 2013 Dec 3 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  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.

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