Haplotype analysis of APOE intragenic SNPs

Babenko, V.; Afonnikov, D.; Ignatieva, E.; Klimov, A.; Gusev, F.; Rogaev, E.

Авторы: Babenko VN, Afonnikov DA, Ignatieva EV, Klimov AV, Gusev FE, Rogaev EI
Журнал: BMC Neuroscience
Том: 19
Номер: 1
Год издания: 2018
Издательство: BioMed Central
Местоположение издательства: London
Первая страница: 16
Последняя страница: 16
DOI: 10.1186/s12868-018-0413-4
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.
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