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多基因风险评分在尸检诊断的散发性早发性阿尔茨海默病中的应用。

Polygenic risk score in postmortem diagnosed sporadic early-onset Alzheimer's disease.

机构信息

Human Genetics Group, University of Nottingham, Nottingham, UK.

Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK; Department of Medical Sciences, Institute of Biomedicine-iBiMED, University of Aveiro, Aveiro, Portugal; UK Dementia Research Institute at UCL (UK DRI), London, UK.

出版信息

Neurobiol Aging. 2018 Feb;62:244.e1-244.e8. doi: 10.1016/j.neurobiolaging.2017.09.035. Epub 2017 Oct 10.


DOI:10.1016/j.neurobiolaging.2017.09.035
PMID:29103623
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5995122/
Abstract

Sporadic early-onset Alzheimer's disease (sEOAD) exhibits the symptoms of late-onset Alzheimer's disease but lacks the familial aspect of the early-onset familial form. The genetics of Alzheimer's disease (AD) identifies APOEε4 to be the greatest risk factor; however, it is a complex disease involving both environmental risk factors and multiple genetic loci. Polygenic risk scores (PRSs) accumulate the total risk of a phenotype in an individual based on variants present in their genome. We determined whether sEOAD cases had a higher PRS compared to controls. A cohort of sEOAD cases was genotyped on the NeuroX array, and PRSs were generated using PRSice. The target data set consisted of 408 sEOAD cases and 436 controls. The base data set was collated by the International Genomics of Alzheimer's Project consortium, with association data from 17,008 late-onset Alzheimer's disease cases and 37,154 controls, which can be used for identifying sEOAD cases due to having shared phenotype. PRSs were generated using all common single nucleotide polymorphisms between the base and target data set, PRS were also generated using only single nucleotide polymorphisms within a 500 kb region surrounding the APOE gene. Sex and number of APOE ε2 or ε4 alleles were used as variables for logistic regression and combined with PRS. The results show that PRS is higher on average in sEOAD cases than controls, although there is still overlap among the whole cohort. Predictive ability of identifying cases and controls using PRSice was calculated with 72.9% accuracy, greater than the APOE locus alone (65.2%). Predictive ability was further improved with logistic regression, identifying cases and controls with 75.5% accuracy.

摘要

散发性早发性阿尔茨海默病(sEOAD)表现出晚发性阿尔茨海默病的症状,但缺乏早发性家族性形式的家族性方面。阿尔茨海默病(AD)的遗传学确定 APOEε4 是最大的风险因素;然而,这是一种复杂的疾病,涉及环境风险因素和多个遗传位点。多基因风险评分(PRS)根据个体基因组中存在的变体累积个体表型的总风险。我们确定 sEOAD 病例的 PRS 是否高于对照组。对 sEOAD 病例进行了神经 X 阵列基因分型,并使用 PRSice 生成了 PRS。目标数据集由 408 名 sEOAD 病例和 436 名对照组成。基础数据集由国际阿尔茨海默病基因组学项目联盟整理,关联数据来自 17008 例晚发性阿尔茨海默病病例和 37154 名对照,可以用于识别由于具有共同表型而导致的 sEOAD 病例。使用基础和目标数据集之间所有常见的单核苷酸多态性生成 PRS,还使用 APOE 基因周围 500 kb 区域内的单核苷酸多态性生成 PRS。性别和 APOE ε2 或 ε4 等位基因的数量用作逻辑回归的变量,并与 PRS 结合使用。结果表明,sEOAD 病例的 PRS 平均值高于对照组,尽管整个队列之间仍存在重叠。使用 PRSice 识别病例和对照的预测能力为 72.9%,高于单独的 APOE 基因座(65.2%)。通过逻辑回归进一步提高了预测能力,识别病例和对照的准确率为 75.5%。

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本文引用的文献

[1]
Polygenic risk score analysis of pathologically confirmed Alzheimer disease.

Ann Neurol. 2017-8

[2]
Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.

Nat Genet. 2017-9

[3]
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Neurobiol Aging. 2017-9

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PLoS Med. 2017-3-21

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Am J Med Genet B Neuropsychiatr Genet. 2017-1

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The Correlation between Inflammatory Biomarkers and Polygenic Risk Score in Alzheimer's Disease.

J Alzheimers Dis. 2017

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Mutation analysis of sporadic early-onset Alzheimer's disease using the NeuroX array.

Neurobiol Aging. 2017-1

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Polygenic score prediction captures nearly all common genetic risk for Alzheimer's disease.

Neurobiol Aging. 2017-1

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An Alzheimer's Disease Genetic Risk Score Predicts Longitudinal Thinning of Hippocampal Complex Subregions in Healthy Older Adults.

eNeuro. 2016-7-15

[10]
A loss of function variant in CASP7 protects against Alzheimer's disease in homozygous APOE ε4 allele carriers.

BMC Genomics. 2016-6-23

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