Background:Rare variants in PLCG2 (p.P522R), ABI3 (p.S209F), and TREM2 (p.R47H, p.R62H) have been associated with late onset Alzheimer’s disease (LOAD) risk in Caucasians. After the initial report, several studies have found positive results in cohorts of different ethnic background and with different phenotype. Objective:In this study, we aim to evaluate the association of rare coding variants in PLCG2, ABI3, and TREM2 with LOAD risk and their effect at different time points of the disease. Methods:We used a European American cohort to assess the association of the variants prior onset (using CSF Aβ42, tau, and pTau levels, and amyloid imaging as endophenotypes) and after onset (measured as rate of memory decline). Results:We confirm the association with LOAD risk of TREM2 p.R47H, p.R62H and ABI3 p.S209F variants, and the protective effect of PLCG2 p.P522R. In addition, ABI3 and TREM2 gene-sets showed significant association with LOAD risk. TREM2 p.R47H and PLCG2 p.P522R variants were also statistically associated with increase of amyloid imaging and AD progression, respectively. We did not observe any association of ABI3 p.S209F with any of the other AD endophenotypes. Conclusion:The results of this study highlight the importance of including biomarkers and alternative phenotypes to better understand the role of novel candidate genes with the disease.

中文翻译：

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通过多种表型检查 TREM2、ABI3 和 PLCG2 中稀有变异对 LOAD 的影响。

背景：PLCG2 (p.P522R)、ABI3 (p.S209F) 和 TREM2 (p.R47H、p.R62H) 的罕见变异与白种人迟发性阿尔茨海默病 (LOAD) 风险相关。在初次报告之后，多项研究在不同种族背景和不同表型的队列中发现了积极的结果。目的：在本研究中，我们旨在评估 PLCG2、ABI3 和 TREM2 中罕见编码变异与 LOAD 风险的关联及其在疾病不同时间点的影响。方法：我们使用欧洲裔美国人队列来评估发病前（使用 CSF Aβ42、tau 和 pTau 水平以及淀粉样蛋白成像作为内表型）和发病后（以记忆力下降率来衡量）变异的关联。结果：我们确认了 TREM2 p.R47H、p.R62H 和 ABI3 p.S209F 变体与 LOAD 风险的关联，以及 PLCG2 p.P522R 的保护作用。此外，ABI3 和 TREM2 基因组与 LOAD 风险显着相关。TREM2 p.R47H 和 PLCG2 p.P522R 变异也分别与淀粉样蛋白成像的增加和 AD 进展存在统计学相关性。我们没有观察到 ABI3 p.S209F 与任何其他 AD 内表型的任何关联。结论：这项研究的结果强调了纳入生物标志物和替代表型以更好地了解新候选基因与该疾病的作用的重要性。