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Assessing Genetic Overlap and Causality Between Blood Plasma Proteins and Alzheimer’s Disease
Journal of Alzheimer’s Disease ( IF 4 ) Pub Date : 2021-08-25 , DOI: 10.3233/jad-210462
Alex Handy 1, 2 , Jodie Lord 2 , Rebecca Green 2, 3 , Jin Xu 2, 4 , Dag Aarsland 2, 5 , Latha Velayudhan 2 , Abdul Hye 2 , Richard Dobson 1, 2, 3, 6, 7 , Petroula Proitsi 2 , ,
Affiliation  

Background:Blood plasma proteins have been associated with Alzheimer’s disease (AD), but understanding which proteins are on the causal pathway remains challenging. Objective:Investigate the genetic overlap between candidate proteins and AD using polygenic risk scores (PRS) and interrogate their causal relationship using bi-directional Mendelian randomization (MR). Methods:Following a literature review, 31 proteins were selected for PRS analysis. PRS were constructed for prioritized proteins with and without the apolipoprotein E region (APOE+/–PRS) and tested for association with AD status across three cohorts (n = 6,244). An AD PRS was also tested for association with protein levels in one cohort (n = 410). Proteins showing association with AD were taken forward for MR. Results:For APOE ɛ3, apolipoprotein B-100, and C-reactive protein (CRP), protein APOE+ PRS were associated with AD below Bonferroni significance (pBonf, p < 0.00017). No protein APOE- PRS or AD PRS (APOE+/–) passed pBonf. However, vitamin D-binding protein (protein PRS APOE-, p = 0.009) and insulin-like growth factor-binding protein 2 (AD APOE- PRS p = 0.025, protein APOE- PRS p = 0.045) displayed suggestive signals and were selected for MR. In bi-directional MR, none of the five proteins demonstrated a causal association (p < 0.05) in either direction. Conclusion:Apolipoproteins and CRP PRS are associated with AD and provide a genetic signal linked to a specific, accessible risk factor. While evidence of causality was limited, this study was conducted in a moderate sample size and provides a framework for larger samples with greater statistical power.

中文翻译:

评估血浆蛋白与阿尔茨海默病之间的遗传重叠和因果关系

背景:血浆蛋白与阿尔茨海默病 (AD) 相关,但了解哪些蛋白处于因果通路中仍然具有挑战性。目的:使用多基因风险评分 (PRS) 研究候选蛋白与 AD 之间的遗传重叠,并使用双向孟德尔随机化 (MR) 探讨它们的因果关系。方法:通过文献回顾,选择31个蛋白进行PRS分析。PRS 是针对具有和不具有载脂蛋白 E 区 (APOE+/–PRS) 的优先蛋白质构建的,并测试了三个队列 (n = 6,244) 与 AD 状态的关联。还对一组 (n = 410) 中的 AD PRS 与蛋白质水平的关联进行了测试。显示与 AD 相关的蛋白质被用于 MR。结果:对于 APOE ɛ3、载脂蛋白 B-100 和 C 反应蛋白 (CRP),蛋白 APOE+ PRS 与 AD 的相关性低于 Bonferroni 显着性 (pBonf,p < 0.00017)。没有蛋白质 APOE- PRS 或 AD PRS (APOE+/–) 通过 pBonf。然而,维生素 D 结合蛋白(蛋白 PRS APOE-,p = 0.009)和胰岛素样生长因子结合蛋白 2(AD APOE- PRS p = 0.025,蛋白 APOE- PRS p = 0.045)显示出提示性信号并被选择对于先生。在双向 MR 中,这五种蛋白质均未在任一方向上表现出因果关系 (p < 0.05)。结论:载脂蛋白和 CRP PRS 与 AD 相关,并提供与特定的、可接近的危险因素相关的遗传信号。虽然因果关系的证据有限,但这项研究是在中等规模的样本中进行的,并为具有更大统计能力的更大样本提供了一个框架。
更新日期:2021-08-29
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