Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Nov;18(11):2067-2078.
doi: 10.1002/alz.12540. Epub 2022 Jan 3.

Genome-wide analysis identified abundant genetic modulators of contributions of the apolipoprotein E alleles to Alzheimer's disease risk

Alireza Nazarian  1 , Yury Loika  1 , Liang He  1 , Irina Culminskaya  1 , Alexander M Kulminski  1
Affiliations

Genome-wide analysis identified abundant genetic modulators of contributions of the apolipoprotein E alleles to Alzheimer's disease risk

Alireza Nazarian et al. Alzheimers Dement. 2022 Nov.

Abstract

Introduction: The apolipoprotein E (APOE) ε2 and ε4 alleles have beneficial and adverse impacts on Alzheimer's disease (AD), respectively, with incomplete penetrance, which may be modulated by other genetic variants.

Methods: We examined whether the associations of the APOE alleles with other polymorphisms in the genome can be sensitive to AD-affection status.

Results: We identified associations of the ε2 and ε4 alleles with 314 and 232 polymorphisms, respectively. Of them, 35 and 31 polymorphisms had significantly different effects in AD-affected and -unaffected groups, suggesting their potential involvement in the AD pathogenesis by modulating the effects of the ε2 and ε4 alleles, respectively. Our survival-type analysis of the AD risk supported modulating roles of multiple group-specific polymorphisms. Our functional analysis identified gene enrichment in multiple immune-related biological processes, for example, B cell function.

Discussion: These findings suggest involvement of local and inter-chromosomal modulators of the effects of the APOE alleles on the AD risk.

Keywords: APOE; Cox regression; age at onset; aging; dementia; genetic modulators; genetic polymorphisms; genome-wide association studies; neurodegenerative diseases; sex-specific associations.

PubMed Disclaimer

Conflict of interest statement

CONFLICTS OF INTEREST

The authors declare no conflicts of interest.

Figures

Figure 1.
Figure 1.
The effect sizes of the ε2-associated group-specific SNPs in Alzheimer’s disease-affected (AD) and unaffected (NAD) groups. (A) SNPs outside of the APOE 19q13.3 locus and (B) SNPs within the APOE 19q13.3 locus. The x-axis shows SNPs and genes identifiers; the y-axis shows the effect sizes (i.e., beta coefficients), red bars indicate the AD group; blue bars indicate the NAD group. Vertical lines show 95% confidence intervals.
Figure 2.
Figure 2.
The effect sizes of the ε4-associated group-specific SNPs in Alzheimer’s disease-affected (AD) and unaffected (NAD) groups. (A) SNPs outside of the APOE 19q13.3 locus and (B) SNPs within the APOE 19q13.3 locus. The x-axis shows SNPs and genes identifiers; the y-axis shows the effect sizes (i.e., beta coefficients), red bars indicate the AD group; blue bars indicate the NAD group. Vertical lines show 95% confidence intervals.
Figure 3.
Figure 3.
Enrichment of bio-functions. (A) Top-10 bio-functions enriched for genes harboring the ɛ2-associated SNPs. (B) Enrichment of bio-functions for genes harboring the ɛ4-associated SNPs. All bio-functions are significantly enriched at a false discovery rate-adjusted P<0.05.
See this image and copyright information in PMC

References

    1. Stelzer G, Rosen N, Plaschkes I, et al. The GeneCards suite: from gene data mining to disease genome sequence analyses. Current Protocols in Bioinformatics. 2016;54(1):1.30.1–1.30.33. doi:10.1002/cpbi.5 - DOI - PubMed
    1. Belloy ME, Napolioni V, Greicius MD. A quarter century of APOE and Alzheimer’s disease: progress to date and the path Forward. Neuron. 2019;101(5):820–838. doi:10.1016/j.neuron.2019.01.056 - DOI - PMC - PubMed
    1. Pericak-Vance MA, Bebout JL, Gaskell PC, et al. Linkage studies in familial Alzheimer disease: evidence for chromosome 19 linkage. Am J Hum Genet. 1991;48(6):1034–1050. - PMC - PubMed
    1. Farrer LA, Cupples LA, Haines JL, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. JAMA. 1997;278(16):1349–1356. - PubMed
    1. Liu C-C, Liu C-C, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013;9(2):106–118. doi:10.1038/nrneurol.2012.263 - DOI - PMC - PubMed

Publication types