Overview

Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr19:45408475 A>G
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs439382
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Reference Isoform: APOE Isoform 1
Genomic Region: 2kb upstream

Findings

This variant was associated with Alzheimer’s disease (AD) in a genome-wide association study of African Americans from the AD Genetics Consortium (Reitz et al., 2013), as reported in the database of the National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS) (p=1.6x10^-16; Oct 2022). The underlying cause for the association is unknown and could be due to genetic linkage between c.-647A>G and another, harmful variant.

c.-647A>G was also reported in a small study in which the APOE genes of 257 Southern Chinese individuals—including 69 AD patients, 83 subjects with mild cognitive impairment (MCI), and 105 cognitively healthy controls—were sequenced (Yee et al., 2021). The variant was found in one AD patient (0.7%), two MCI patients (1.2%), and one control (0.5%). 

In the gnomAD variant database, the variant was reported at a frequency of 0.028 (gnomAD v2.1.1, Oct 2022). The frequency was higher (0.094) in individuals of African ancestry.

Biological Effect

The biological effect of this variant is unknown, but it is within the APOE promoter region (Paik et al., 1988) and, more specifically, in the HuD functional domain which spans nucleotides -651 to -366 (Maloney et al., 2007). In an in vitro reporter assay, HuD was shown to act as a negative regulatory element in multiple cell types, including neuronal-like rat chromaffin cells (PC12), SK-N-SH neuroblastoma cells, C6 glial cells, and U373 astroctyoma cells. However, the variant's 0.45 PHRED-scaled CADD score, which integrates diverse information in silico, was well below the commonly used threshold of 20 to predict deleteriousness (CADD v.1.6, Oct 2022).

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References

Paper Citations

1. Reitz C, Jun G, Naj A, Rajbhandary R, Vardarajan BN, Wang LS, Valladares O, Lin CF, Larson EB, Graff-Radford NR, Evans D, De Jager PL, Crane PK, Buxbaum JD, Murrell JR, Raj T, Ertekin-Taner N, Logue M, Baldwin CT, Green RC, Barnes LL, Cantwell LB, Fallin MD, Go RC, Griffith P, Obisesan TO, Manly JJ, Lunetta KL, Kamboh MI, Lopez OL, Bennett DA, Hendrie H, Hall KS, Goate AM, Byrd GS, Kukull WA, Foroud TM, Haines JL, Farrer LA, Pericak-Vance MA, Schellenberg GD, Mayeux R, . Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E ϵ4,and the risk of late-onset Alzheimer disease in African Americans. JAMA. 2013 Apr 10;309(14):1483-92. PubMed.
2. Yee A, Tsui NB, Kwan RY, Leung AY, Lai CK, Chung T, Lau JY, Fok M, Dai DL, Lau LT. Apolipoprotein E Gene Revisited: Contribution of Rare Variants to Alzheimer's Disease Susceptibility in Southern Chinese. Curr Alzheimer Res. 2021 Mar 24; PubMed.
3. Paik YK, Chang DJ, Reardon CA, Walker MD, Taxman E, Taylor JM. Identification and characterization of transcriptional regulatory regions associated with expression of the human apolipoprotein E gene. J Biol Chem. 1988 Sep 15;263(26):13340-9. PubMed.
4. Maloney B, Ge YW, Alley GM, Lahiri DK. Important differences between human and mouse APOE gene promoters: limitation of mouse APOE model in studying Alzheimer's disease. J Neurochem. 2007 Nov;103(3):1237-57. PubMed.

Further Reading

No Available Further Reading