TY - JOUR

T1 - Haplotype analysis of APOE intragenic SNPs

AU - Babenko, Vladimir N.

AU - Afonnikov, Dmitry A.

AU - Ignatieva, Elena V.

AU - Klimov, Anton V.

AU - Gusev, Fedor E.

AU - Rogaev, Evgeny I.

PY - 2018/4/19

Y1 - 2018/4/19

N2 - 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.

AB - 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.

KW - ADNI dataset

KW - Alzheimer's disease

KW - APOE

KW - DNA methylation

KW - GWAS

KW - Haplotype analysis

KW - PCA

KW - SNPs

KW - Haplotypes

KW - Apolipoproteins E/genetics

KW - Genetic Predisposition to Disease

KW - African Continental Ancestry Group/ethnology

KW - Humans

KW - European Continental Ancestry Group/ethnology

KW - Whole Genome Sequencing

KW - DNA Methylation

KW - Alzheimer Disease/ethnology

KW - Asian Continental Ancestry Group/ethnology

KW - Polymorphism, Single Nucleotide

KW - Databases, Factual

KW - POPULATION

KW - EPSILON-4 CARRIERS

KW - ALZHEIMERS-DISEASE

KW - APOLIPOPROTEIN-E

KW - WHOLE-GENOME ASSOCIATION

KW - AGE

KW - RISK

KW - POLYMORPHISM

KW - GENE

KW - AFRICAN-AMERICANS

UR - http://www.scopus.com/inward/record.url?scp=85045552209&partnerID=8YFLogxK

U2 - 10.1186/s12868-018-0413-4

DO - 10.1186/s12868-018-0413-4

M3 - Article

C2 - 29745836

AN - SCOPUS:85045552209

VL - 19

SP - 16

JO - BMC Neuroscience

JF - BMC Neuroscience

SN - 1471-2202

IS - Suppl 1

M1 - 16

ER -