Haplotype analysis of APOE intragenic SNPsстатьяТезисы
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Дата последнего поиска статьи во внешних источниках: 6 декабря 2018 г.
Аннотация: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 fve SNPs across the gene using the ADNI
whole genome sequencing dataset. The compilation of ADNI data with 1000 Genomes identifed 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 profle 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 profles within APOE locus are highly skewed to population-specifc
haplotypes, suggesting that the ancestral background within diferent sites at APOE gene may shape the disease phenotype.
We propose that our results can be utilized for more specifc risk assessment based on population descent of
the individuals and on higher specifcity of fve site haplotypes associated with AD.