Mutations

SORL1 A1584A (SNP 23)

Other Names: SNP 23

Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121605213 T>A
Position: (GRCh37/hg19):Chr11:121475922 T>A
dbSNP ID: rs3824968
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Silent
Codon Change: GCT to GCA
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 34

Findings

This synonymous variant (A1584A, “SNP 23”) is among those initially described by Rogaeva et al. in 2007 (Rogaeva et al., 2007), when the T allele was reported to be associated with an increased risk of AD in Caucasians. Subsequent studies failed to confirm this association (Bettens et al., 2008; Cellini et al., 2009; Cong et al., 2018; Elias-Sonnenschein et al., 2013; Kölsch et al., 2009; Laumet et al., 2010; Lee et al., 2007; Lee et al., 2008; Li et al., 2008; Liu et al., 2017; Minster et al., 2008; Reitz et al., 2011; Reynolds et al., 2010; Schjeide et al., 2009; Verheijen et al., 2016; Wang et al., 2016). Although one meta-analysis reported a nominal association of the T allele with an increased risk of AD, this relationship no longer reached statistical significance when the Rogaeva study was removed from the analysis (Liu et al., 2009).

It is not clear whether SNP 23 associates with AD in Asian populations. Four studies found no association—two in Han Chinese (Chou et al., 2016; Ning et al., 2010) and two in Japanese cohorts (Shibata et al., 2008; Wen et al., 2013). One study did report that the A allele nominally increased AD risk in Han Chinese, but the p value (0.042) was not adjusted for multiple comparisons (Tan et al., 2009). Another study found that the T allele increased AD risk in a Japanese cohort; when the subjects were stratified by APOE genotype, the association was maintained only in the subset who did not carry an E4 allele (Kimura et al., 2009). While three meta-analyses concluded that the SNP23 A allele is associated with an increased risk of AD in Asian populations (Ning et al., 2010; Reitz et al., 2011; Wang et al., 2016), a fourth did not find an association (Cong et al., 2018).

The variant did not associate with AD in a Mexican cohort of mixed Amerindian, Caucasian, and African ancestry (Toral-Rios et al., 2022) or in meta-analyses that pooled data from multiple ancestries (Jin et al., 2013; Wang et al., 2016).

This variant was not associated with incident AD in a majority Dutch sample (Liu et al., 2009), with age of onset of AD in a Swedish sample (Reynolds et al., 2010), MCI in a Han Chinese cohort (Chou et al., 2016), or cognitive impairment—MCI or dementia of unspecified etiology—in the Women’s Health Initiative Memory Study (Driscoll et al., 2019).

Heterozygous and homozygous carriers have been found among both AD cases and controls (Holstege et al., 2017).

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

Endophenotypes

Several studies have examined the relationship between SORL1 genotype and levels of CSF biomarkers, with inconsistent results. While two studies reported that the A allele of SNP23 was associated with lower concentrations of Aβ42 in Caucasian subjects with AD (Alexopoulos, et al., 2011; Guo et al., 2012), other studies found no association in AD patients (Elias-Sonnenschein et al., 2013; Kölsch et al., 2008; Louwersheimer et al., 2015) or in subjects across the spectrum from normal cognition through mild cognitive impairment to AD (Kauwe et al., 2010; Reynolds et al., 2010). The SNP23 variant was not associated with levels of Aβ40 (Kölsch et al., 2008) or tau (Elias-Sonnenschein et al., 2013; Louwersheimer et al., 2015; Reynolds et al., 2010).

Studies of the association of SNP23 with brain atrophy similarly have yielded varied results, which may be due to differences in the brain regions examined, stage of disease, or ancestry of the subjects. SNP23 did not associate with general cerebral atrophy or hippocampal atrophy in white and African-American participants in the MIRAGE study (Cuenco et al., 2008); with atrophy of the hippocampus, the parahippocampal gyrus, the entorhinal cortex, the middle temporal gyrus or the posterior cingulate in ADNI participants (Yin et al., 2016); or hippocampal atrophy in German AD patients (Louwersheimer et al., 2015). In a group of Chinese adults ranging in age from 21 to 92 years, the A allele was associated with smaller gray matter volumes in the right posterior cingulate, left middle occipital, medial frontal, and superior temporal gyri (Huang et al., 2016).

SNP23 did not associate with MRI of biomarkers of cerebrovascular disease in MIRAGE participants (Cuenco et al., 2008).

This variant did not associate with cognitive function in Dutch (Liu et al., 2009), German (Louwersheimer et al., 2015), Scottish (Houlihan et al., 2009), or Swedish (Reynolds et al., 2013) studies.

In a study investigating associations between neuropsychiatric symptoms and selected gene variants in Taiwanese Alzheimer’s patients, homozygous carriers of the T allele scored higher on measures of frontal syndrome symptoms—euphoria and disinhibition—in the Neuropsychiatric Inventory Questionnaire than individuals who carried the A allele (Huang et al., 2020).

Linkage Disequilibrium

SNP 23 is in linkage disequilibrium with several other variants, including rs2070045 (SNP 19), rs1699102 (SNP 22), rs2282649 (SNP 24), rs1010159 (SNP 25) in cohorts of European ancestry (Jin et al., 2013; Rogaeva et al., 2007; Young et al., 2015); rs2070045 (SNP 19), rs1699102 (SNP 22), rs2282649 (SNP 24), and rs1010159 (SNP 25) in Asian cohorts (Jin et al., 2013; Ning et al., et al., 2010); rs2282649 (SNP 24) and rs1010159 (SNP 25) in an African American family dataset (Rogaeva et al., 2007); and rs2282649 (SNP 24) and rs1010159 (SNP 25) in a Hispanic family dataset (Rogaeva et al., 2007).

Functional Consequences

In neurons derived from human induced pluripotent stem cells, the SNP23 genotype did not influence SORL1 expression in response to BDNF (Young et al, 2015).

Levels of wild-type and A1584A SORL1 transcripts were similar in the prefrontal cortices in autopsy specimens from AD donors and controls (Alachkar et al., 2008).

Table

Risk Allele(s) N
Cases | Controls		 aAllele frequency
Cases | Controls		 Reported association measurements Ancestry
(Cohort)		 Reference(s)
Large-scale studies and meta-analyses
A b7009 | 9335   OR = 0.99
[CI: 0.90-1.08]
p = 0.80		 Caucasian and Asian

Cong et al., 2018
(meta-analysis)
b6035 | 7908   OR = 0.98
[CI: 0.89-1.09]
p = 0.77		 Caucasian
b974 | 1427   OR = 1.01
[CI: 0.78-1.31]
p = 0.94		 Asian
T 11837 | 20022   OR = 0.96
[CI: 0.90-1.03]
p = 0.22		 Caucasian, Asian, African American

Jin et al., 2013
(meta-analysis)
T 2032 | 5328   OR = 1.02
[0.94-1.10]
p = 0.85		 French Caucasian Laumet et al., 2010
(GWAS)
T 6222 | 14116   OR = 1.11
[CI: 1.01-1.23]
cp = 0.04		 Caucasian
(Rotterdam Study, Erasmus Rucphen Family Study)		 Liu et al., 2009
(meta-analysis)
A 17008 | 37154   p = 0.1638 European descent
(IGAP)

Liu et al., 2017
(GWAS)
A 984 | 1320   OR = 1.29
[CI: 1.14-1.46]
p < 10-4		 Chinese, Japanese

Ning et al., 2010
(meta-analysis)
T all = 20247   OR = 1.02
[CI: 0.95-1.09]
p = 0.62		 White

Reitz et al., 2011
(meta-analysis)

 
all = 16307   OR = 0.99
[CI: 0.95-1.03]
p = 0.62		 White
(Rogaeva, 2007 excluded)
all = 1753   OR = 0.79
[CI: 0.69-0.92]
p < 0.001		 Asian
T all = 5506   OR = 1.12
[CI: 1.02-1.22]
p not reported		 European Reynolds et al., 2010
(meta-analysis)
A 1255 | 1938 0.31 | 0.30 OR = 1.04
[CI: 0.92 – 1.18]
p = 0.5		 European
(European Early-Onset Dementia Consortium)

Verheijen et al., 2016
(meta-analysis)
A all = 16268   OR = 1.03
[CI: 0.95-1.12]
p = 0.447		 Asian and Caucasian

Wang et al., 2016
(meta-analysis)
  OR = 1.20
[CI: 1.06-1.35]
p < 0.05		 Asian
  OR = 0.98
[CI: 0.93-1.03]
reported not significant		 Caucasian
Other studies
A 550 | 634 N.A. | 0.28 reported not significant Belgian
(Engelborghs et al., 2003)		 Bettens et al., 2008
A 251 | 358 0.306 | 0.283 p = 0.38 Italian
(Department of Neurological and Psychiatric Sciences, University of Florence)		 Cellini et al., 2009
T 791 | 395 0.358 | 0.375 OR = 0.93
[CI: N.A.]
p = 0.409		 Han Chinese
(Taipei Veterans General Hospital and Taichung Veterans General Hospital, Taiwan)		 Chou et al., 2016
A 117 | 0 0.2051 | N.A.   Saudi Arabian
(King Faisal Specialist Hospital & Research Center)		 El Bitar et al., 2019
A 673 | 568 0.36 | 0.36 p = 0.42 Finnish
(Finnish-AD)		 Elias-Sonnenschein et al., 2013
TT vs. TA+AA TT/TA/AA
AD: 0.44/0.39/0.17
CTRL: 0.42/0.43/0.15		 OR = 0.93
[CI: 0.74–1.12]
p = 0.51
A 640 | 1268 0.298 | 0.295   Dutch
(Rotterdam Study, Amsterdam Dementia Cohort, Alzheimer Centrum Zuidwest Nederland (ACZN), 100-plus Study)		 Holstege et al., 2017
T 436 | 451 0.503 | 0.449 OR = 1.57
[CI: 1.16-2.12]
p = 0.022		 Japanese
(Osaka University Graduate School of Medicine, Choju Medical Institute of Fukushimura Hospital)		 Kimura et al., 2009
APOE E4+
213 | 72		 0.495 | 0.451 p = 0.362
APOE E4-
223 | 379		 0.511 | 0.449 OR = 1.57
[CI: 1.06-2.32]
p = 0.035
T 349 | 483 0.31 | 0.30 p = 0.80 German
(German Competence Network Dementias)		 Kölsch et al., 2009
T 178 | 194 0.283 | 0.303 p = 0.5616 Caribbean Hispanic
(WHICAP)		 Lee et al., 2007
88 | 158 0.140 | 0.155 p = 0.6429 African-American
(WHICAP)
30 | 76 0.385 | 0.264 p = 0.1049 White, non-Hispanic European
(WHICAP)
A 103 | 93 0.316 | 0.259 p = 0.2736 White, non-Hispanic
(autopsy-confirmed)		 Lee et al., 2008
T 998 | 1033 0.311 | 0.299 p = 0.416 Caucasian
(Washington University Knight ADRC, Cardiff University)		 Li et al., 2008
A 1001 | 1007 0.293 | 0.305 p = 0.420 Caucasian American
(University of Pittsburgh ADRC)		 Minster et al., 2008
A 144 | 476   OR = 1.49
[CI: 1.12-1.98]
p = 0.058		 Chinese
(Shanghai Mental Health Center)		 Ning et al., 2010
  1231 | 2184   OR = 1.08
[CI: 0.97-1.19]
p = 0.16		 Swedish
(Swedish Twin Registry, Mölndal Prospective Dementia Study, longitudinal geriatric study from Piteå, Sweden)		 Reynolds et al., 2010
T 1554 | 2333 all = 0.292 OR = 1.15
[CI: 1.04–1.27]
p 0.0075		 Combined Caucasian case-control datasets
(North European, Mayo Jacksonville, Mayo Rochester, Mayo autopsy)		 Rogaeva et al., 2007
1400 | 2113 all = 0.309 OR = 1.12
[CI: 1.01–1.24]
p = 0.031		 Combined Mayo series
178 | 242 all = 0.125 OR = 2.16
[CI: 1.37 - 3.40]
p = 0.00073		 North European
(case-control)
549 | 477 all = 0.296 OR = 1.31
[CI: 1.08–1.59]
p = 0.006		 Mayo Jacksonville
433 | 1217 all = 0.321 OR = 1.09
[CI: 0.93–1.29]
p = 0.287		 Mayo Rochester
423 | 430 all = 0.302 OR = 1.12
[CI: 0.91–1.37]
p = 0. 0.294		 Mayo autopsy
111 | 114 all = 0.345 OR = 1.09
[CI: 0.74 - 1.61]
p = 0.672		 Israeli-Arab
[case-control]
(Wadi Area population study)
321 | 342
(53)		 all = 0.264 p = 0.0031 North European
[family]
605 | 517
(78)		 all = 0.288 p = 0.513 Caribbean Hispanic
[family]
279 | 252
(81)		 all = 0.333 p = 0.680 Caucasian [family]
(MIRAGE)
244 | 127
(26)		 all = 0.193 p = 0.818 African-American [family]
(MIRAGE)
T 407 families   OR = 1.03
[CI: N.A.]
p = 0.33		 Mixed
(NIMH, NIA, NCRAD, CAG)		 Schjeide et al., 2009
Caucasian subset
399 families		   OR = 1.02
[CI: N.A.]
p = 0.37		 Caucasian
(NIMH, NIA, NCRAD, CAG)
T 180 | 130 0.525 | 0.565 p = 0.59 Japanese Shibata et al., 2008
>= 65, APOE E4+
46 | 9		 0.489 | 0.444 p = 0.80
>= 65, APOE E4-
58 | 25		 0.517 | 0.64 p = 0.39
< 65, APOE E4+
29 | 24		 0.586 | 0.563 p = 0.99
< 65, APOE E4-
47 | 72		 0.532 | 0.556 p = 0.68
A 223 | 263 0.331 | 0.394 OR = 1.31
[CI: 1.01-1.71]
p = 0.042		 Han Chinese Tan et al., 2009
T 156 | 221 0.39 | 0.33 reported not 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+AT vs. AA TT/TA/AA
AD: 0.24/0.49/0.26
CTRL: 0.21/0.49/0.29		 OR = 1.123
[CI: 0.704–1.791]
p = 0.626
T 213 |370 0.497 | 0.493 OR = 0.98
[CI: 0.77-1.25]
p = 0.883		 Japanese
[autopsy confirmed]
(Japanese ADNI)		 Wen 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.
cLiu (19584446). No longer significant if Rogaeva removed from 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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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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