Haplotype analysis of APOE intragenic SNPs

Abstract

BackgroundAPOE 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.ResultsWe 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.ConclusionsWe 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.Electronic supplementary materialThe online version of this article (10.1186/s12868-018-0413-4) contains supplementary material, which is available to authorized users.

Investigation of base excision repair gene variants in late-onset Alzheimer’s disease

“…Rs769449 is in strong linkage disequilibrium with rs429358 of APOE ε2/ε3/ε4 polymorphism [69]. It has been suggested that the statistically significant effect of rs769449 on LOAD is probably related to that effect of APOE ε4 [69,70]. In the present study, APOE rs769449 increased the risk of LOAD in APOE ε4 carriers (OR = 6.09, 95% CI = 1.42–26.17, p = 0.0131), but not in non- APOE ε4 carriers.…”

“…In the present study, APOE rs769449 increased the risk of LOAD in APOE ε4 carriers (OR = 6.09, 95% CI = 1.42–26.17, p = 0.0131), but not in non- APOE ε4 carriers. Rs769449 may have a regulatory effect on APOE by modifying the epigenetic state in the APOE gene region, influencing transcription levels and protein concentration without changing protein structure, and thus may contribute to LOAD [69,70]. APOE rs769449 and rs429358 were also found among common variants in Turkish population with MAF 0.10 and 0.15, respectively (S10 Table).…”

Association of Uncommon, Noncoding Variants in the APOE Region With Risk of Alzheimer Disease in Adults of European Ancestry

“… 55 , 56 , 57 Haplotypes derived from rs429358, rs7412, and neighboring noncoding SNVs that vary in frequency across populations are associated with increased risk of AD. 55 Admixture analyses in Puerto Rican, African American, and Caribbean Hispanic data sets have shown that ε4 alleles inherited on an African background are associated with reduced risk of AD compared with those inherited on a European background, again suggesting that haplotype structures correlated with ε4 vary between populations and are associated with AD risk. 56 , 57 All SNVs with significant associations with AD were located within a 186-kb region immediately 5′ of APOE .…”

Evolutionary Pattern of Interferon Alpha Genes in Bovidae and Genetic Diversity of IFNAA in the Bovine Genome

“…Our study revealed the first evidence of IFNAA haplotype-base framework in cattle, which could be used in association studies of different disease phenotypes. Several reports have shown that association studies with haplotype analysis are a powerful tool to elucidate genetic mechanism of variations underlying complex disease traits ( 36 , 45 – 47 ).…”