Pathway-Specific Polygenic Risk Scores as Predictors of Amyloid-β Deposition and Cognitive Function in a Sample at Increased Risk for Alzheimer's Disease.
Pathway-Specific Polygenic Risk Scores as Predictors of Amyloid-β Deposition and Cognitive Function in a Sample at Increased Risk for Alzheimer's Disease.
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DOI：
10.3233/jad-160195
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发表时间：
2017
期刊：
影响因子：
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通讯作者：
Engelman CD
中科院分区：
文献类型：
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作者：
Darst BF;Koscik RL;Racine AM;Oh JM;Krause RA;Carlsson CM;Zetterberg H;Blennow K;Christian BT;Bendlin BB;Okonkwo OC;Hogan KJ;Hermann BP;Sager MA;Asthana S;Johnson SC;Engelman CD
多基因风险评分（PRSs）已被用于整合全基因组关联研究中所确定的具有微小效应的变异的影响。我们探讨了使用特定通路的多基因风险评分作为阿尔茨海默病（AD）相关生物标志物和认知功能早期变化的预测因子的潜力。参与者来自威斯康星州阿尔茨海默病预防登记处，这是一项对入组时认知无症状且有阿尔茨海默病家族史富集的成年人进行的纵向研究。利用国际阿尔茨海默病基因组项目的荟萃分析中与阿尔茨海默病相关的基因，我们确定了基因簇，这些基因簇可归类为涉及β - 淀粉样蛋白（Aβ）沉积和神经退行性变的通路：Aβ清除、胆固醇代谢和免疫反应。我们开发了加权的特定通路和总体多基因风险评分，并与仅APOE进行了比较。使用混合模型评估每种多基因风险评分是否与1200名个体的认知、168名个体中使用淀粉样蛋白配体（匹兹堡化合物B）正电子发射断层成像（PET）测量的脑Aβ沉积以及111名个体的脑脊液（CSF）Aβ沉积、神经退行性变和tau病理相关，并在一个独立样本中进行了重复验证。我们发现包括APOE的多基因风险评分似乎是由APOE的纳入所驱动的，这表明此处使用的特定通路的多基因风险评分并不比总体多基因风险评分或仅APOE更具预测性。然而，随着对阿尔茨海默病特定生物学通路中所涉及的基因变异有更多了解，特定通路的多基因风险评分可能会被证明是有用的。
Polygenic risk scores (PRSs) have been used to combine the effects of variants with small effects identified by genome-wide association studies. We explore the potential for using pathway-specific PRSs as predictors of early changes in Alzheimer’s disease (AD)-related biomarkers and cognitive function. Participants were from the Wisconsin Registry for Alzheimer’s Prevention, a longitudinal study of adults who were cognitively asymptomatic at enrollment and enriched for a parental history of AD. Using genes associated with AD in the International Genomics of Alzheimer’s Project’s meta-analysis, we identified clusters of genes that grouped into pathways involved in β-amyloid (Aβ) deposition and neurodegeneration: Aβ clearance, cholesterol metabolism, and immune response. Weighted pathway-specific and overall PRSs were developed and compared to APOE alone. Mixed models were used to assess whether each PRS was associated with cognition in 1,200 individuals, cerebral Aβ deposition measured using amyloid ligand (Pittsburgh compound B) positron emission imaging (PET) in 168 individuals, and cerebrospinal fluid (CSF) Aβ deposition, neurodegeneration, and tau pathology in 111 individuals, with replication performed in an independent sample. We found that PRSs including APOE appeared to be driven by the inclusion of APOE, suggesting that the pathway-specific PRSs used here were not more predictive than an overall PRS or APOE alone. However, pathway-specific PRSs could prove to be useful as more knowledge is gained on the genetic variants involved in specific biological pathways of AD.