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. 2018 Apr 19;19(Suppl 1):16.
doi: 10.1186/s12868-018-0413-4.

Haplotype analysis of APOE intragenic SNPs

Vladimir N Babenko  1   2 , Dmitry A Afonnikov  3   4 , Elena V Ignatieva  3   4 , Anton V Klimov  3   4 , Fedor E Gusev  5 , Evgeny I Rogaev  3   5   6   7
Affiliations

Haplotype analysis of APOE intragenic SNPs

Vladimir N Babenko et al. BMC Neurosci. .

Abstract

Background: APOE ε4 allele is most common genetic risk factor for Alzheimer's disease (AD) and cognitive decline. However, it remains poorly understood why only some carriers of APOE ε4 develop AD and how ethnic variabilities in APOE locus contribute to AD risk. Here, to address the role of APOE haplotypes, we reassessed the diversity of APOE locus in major ethnic groups and in Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset on patients with AD, and subjects with mild cognitive impairment (MCI), and control non-demented individuals.

Results: We performed APOE gene haplotype analysis for a short block of five SNPs across the gene using the ADNI whole genome sequencing dataset. The compilation of ADNI data with 1000 Genomes identified the APOE ε4 linked haplotypes, which appeared to be distant for the Asian, African and European populations. The common European ε4-bearing haplotype is associated with AD but not with MCI, and the Africans lack this haplotype. Haplotypic inference revealed alleles that may confer protection against AD. By assessing the DNA methylation profile of the APOE haplotypes, we found that the AD-associated haplotype features elevated APOE CpG content, implying that this locus can also be regulated by genetic-epigenetic interactions.

Conclusions: We showed that SNP frequency profiles within APOE locus are highly skewed to population-specific haplotypes, suggesting that the ancestral background within different sites at APOE gene may shape the disease phenotype. We propose that our results can be utilized for more specific risk assessment based on population descent of the individuals and on higher specificity of five site haplotypes associated with AD.

Keywords: ADNI dataset; APOE; Alzheimer’s disease; DNA methylation; GWAS; Haplotype analysis; PCA; SNPs.

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Figures

Fig. 1
Fig. 1
Minor allele frequencies of five SNPs included in analysis. Intronic rs769449 and APOE ε4 rs429358 SNPs with significant association to AD are encircled
Fig. 2
Fig. 2
Haplotype frequencies in human populations and ADNI cohort. X-axis labels represent allelic status of 5 SNPs (rs440446, rs769449, rs769450, rs429358,rs7412; Table 2) in APOE locus. Haplotype associated with APOE ε4 are in bold italic
Fig. 3
Fig. 3
Principal Components analysis based on the haplotype frequencies distribution across 6 populations (Afr, Ori, Eur, AD, MCI, CT). Haplotype encoding corresponds to Table 2. AD—associated haplotypes are marked by the bold italic type
Fig. 4
Fig. 4
Phylogenetic tree of APOE haplotypes. GAGCC is the disease haplotype specific to Europeans (Table 3). The AD-associated haplotype subset is encircled
Fig. 5
Fig. 5
Methylation profile of the APOE locus. a Genomic location of Illumina Methyl 450 bead array probes; b methylation profile of APOE gene based on two methylome projects. 63 HAIB cell lines (HAIB ENCODE methylation data), and 179 fetal brain samples [27] were used. Vertical dotted bars correspond to standard deviation of methylation score. Arrows indicate age related methylation drive [18]
Fig. 6
Fig. 6
UCSC genome browser screenshot depicting active H3K4me3 spot in the vicinity of rs769449 (encircled) along with previously associated with APOE ε4 cg06750524 methylation status [18]
See this image and copyright information in PMC

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