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APOE4 纯合子的全基因组分析确定了阿尔茨海默病发病机制中的 DAB1-RELN 通路。

Whole genome analysis in APOE4 homozygotes identifies the DAB1-RELN pathway in Alzheimer's disease pathogenesis.

机构信息

Division of Psychological Medicine & Clinical Neurosciences, Cardiff University, Cardiff, UK; Dementia Research Institute, Cardiff University, Cardiff, UK.

Dementia Research Institute, Cardiff University, Cardiff, UK.

出版信息

Neurobiol Aging. 2022 Nov;119:67-76. doi: 10.1016/j.neurobiolaging.2022.07.009. Epub 2022 Jul 29.

DOI:10.1016/j.neurobiolaging.2022.07.009
PMID:35977442
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9548409/
Abstract

The APOE-ε4 allele is known to predispose to amyloid deposition and consequently is strongly associated with Alzheimer's disease (AD) risk. There is debate as to whether the APOE gene accounts for all genetic variation of the APOE locus. Another question which remains is whether APOE-ε4 carriers have other genetic factors influencing the progression of amyloid positive individuals to AD. We conducted a genome-wide association study in a sample of 5,390 APOE-ε4 homozygous (ε4ε4) individuals (288 cases and 5102 controls) aged 65 or over in the UK Biobank. We found no significant associations of SNPs in the APOE locus with AD in the sample of ε4ε4 individuals. However, we identified a novel genome-wide significant locus associated to AD, mapping to DAB1 (rs112437613, OR = 2.28, CI = 1.73-3.01, p = 5.4 × 10). This identification of DAB1 led us to investigate other components of the DAB1-RELN pathway for association. Analysis of the DAB1-RELN pathway indicated that the pathway itself was associated with AD, therefore suggesting an epistatic interaction between the APOE locus and the DAB1-RELN pathway.

摘要

载脂蛋白 E-ε4 等位基因易导致淀粉样蛋白沉积，因此与阿尔茨海默病 (AD) 的风险密切相关。目前仍存在争议的是，APOE 基因是否可以解释 APOE 基因座的所有遗传变异。另一个悬而未决的问题是，APOE-ε4 携带者是否存在其他遗传因素影响淀粉样蛋白阳性个体向 AD 的进展。我们在英国生物银行的一个由 5390 名 APOE-ε4 纯合子 (ε4ε4) 个体（288 例病例和 5102 例对照）组成的样本中进行了全基因组关联研究，这些个体年龄均在 65 岁及以上。我们在 ε4ε4 个体样本中未发现 APOE 基因座内的 SNPs 与 AD 有显著关联。然而，我们确定了一个与 AD 相关的新的全基因组显著基因座，该基因座映射到 DAB1（rs112437613，OR=2.28，CI=1.73-3.01，p=5.4×10）。DAB1 的鉴定促使我们对 DAB1-RELN 通路的其他成分进行关联分析。DAB1-RELN 通路的分析表明，该通路本身与 AD 相关，因此提示 APOE 基因座与 DAB1-RELN 通路之间存在上位性相互作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2adf/9548409/cb45c3653e52/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2adf/9548409/443c3d8c053d/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2adf/9548409/7d13847f1c3d/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2adf/9548409/a4792082de4a/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2adf/9548409/cb45c3653e52/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2adf/9548409/443c3d8c053d/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2adf/9548409/7d13847f1c3d/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2adf/9548409/a4792082de4a/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2adf/9548409/cb45c3653e52/gr4.jpg

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