Haplotype analysis of APOE intragenic SNPs.
Haplotype analysis of APOE intragenic SNPs.
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DOI：
10.1186/s12868-018-0413-4
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发表时间：
2018-04-19
期刊：
影响因子：
2.4
通讯作者：
Rogaev EI
中科院分区：
文献类型：
--
作者：
Babenko VN;Afonnikov DA;Ignatieva EV;Klimov AV;Gusev FE;Rogaev EI
APOE ε4等位基因是阿尔茨海默病（AD）和认知功能减退最常见的遗传危险因子。然而，为什么只有一些APOE ε4携带者发展为AD以及APOE基因座的种族差异如何导致AD风险仍然知之甚少。在这里，为了解决APOE单倍型的作用，我们重新评估了APOE基因座在主要种族群体和阿尔茨海默病神经影像学倡议（ADNI）数据集中的AD患者，轻度认知障碍（MCI）和对照非痴呆个体的多样性。我们使用ADNI全基因组测序数据集对APOE基因的5个SNP进行了短块单倍型分析。ADNI数据与1000个基因组的汇编确定了APOE ε4连锁单倍型，这似乎是亚洲，非洲和欧洲人群的遥远。常见的欧洲ε4单倍型与AD相关，但与MCI无关，非洲人缺乏这种单倍型。单倍型推断揭示等位基因，可能赋予对AD的保护。通过评估APOE单倍型的DNA甲基化谱，我们发现AD相关单倍型的特征是APOE CpG含量升高，这意味着该位点也可以通过遗传-表观遗传相互作用进行调节。我们发现，在APOE基因座内的SNP频率分布高度偏于群体特异性单倍型，这表明在APOE基因的不同位点内的祖先背景可能塑造疾病表型。我们建议，我们的研究结果可以用于更具体的风险评估的基础上人口下降的个人和更高的特异性与AD相关的5个位点单倍型。本文的在线版本（10.1186/s12868-018-0413-4）包含补充材料，可供授权用户使用。
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. 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. 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. The online version of this article (10.1186/s12868-018-0413-4) contains supplementary material, which is available to authorized users.
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影响因子：
15.8
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Mooijaart, Simon P.;Berbee, Jimmy F. P.;van Heemst, Diana;Havekes, Louis M.;de Craen, Anton J. M.;Slagboom, P. Eline;Rensen, Patrick C. N.;Westendorp, Rudi G. J.
通讯作者：
Westendorp, Rudi G. J.
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通讯作者：
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影响因子：
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通讯作者：
Saykin, Andrew J.