Genome-wide Survival Study Identifies PARL as a Novel Locus for Clinical Progression and Neurodegeneration in Alzheimer’s Disease,Biological Psychiatry

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Genome-wide Survival Study Identifies PARL as a Novel Locus for Clinical Progression and Neurodegeneration in Alzheimer’s Disease
Biological Psychiatry ( IF 10.6 ) Pub Date : 2023-03-03 , DOI: 10.1016/j.biopsych.2023.02.992
Shi-Dong Chen ₁ , Wei Zhang ₂ , Yi-Wei Feng ₁ , Bang-Sheng Wu ₁ , Liu Yang ₁ , Ya-Ru Zhang ₁ , Hui-Fu Wang ₂ , Yu Guo ₁ , Yue-Ting Deng ₁ , Jian-Feng Feng ₃ , Wei Cheng ₄ , Qiang Dong ₁ , Jin-Tai Yu ₁

Affiliation

Department of Neurology and Institute of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, National Center for Neurological Disorders, Shanghai, China.
Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, Shanghai, China.
Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, Shanghai, China; Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Fudan University, Ministry of Education, Shanghai, China; Fudan ISTBI-ZJNU Algorithm Centre for Brain-Inspired Intelligence, Zhejiang Normal University, Jinhua, China; MOE Frontiers Center for Brain Science, Fudan University, Shanghai, Shanghai, China; Zhangjiang Fudan International Innovation Center, Shanghai, China.
Department of Neurology and Institute of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, National Center for Neurological Disorders, Shanghai, China; Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, Shanghai, China; Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Fudan University, Ministry of Education, Shanghai, China; Fudan ISTBI-ZJNU Algorithm Centre for Brain-Inspired Intelligence, Zhejiang Normal University, Jinhua, China.

Background

Variability exists in the trajectories of Alzheimer’s disease (AD). We aimed to identify genetic modulators of clinical progression in AD.

Methods

We conducted the first genome-wide survival study on AD using a two-stage approach. The discovery and replication stage separately included 1158 and 211,817 individuals without dementia from the Alzheimer’s Disease Neuroimaging Initiative and the UK Biobank, respectively (325 and 1103 progressed in average follow-up of 4.33 and 8.63 years, respectively). Cox proportional hazards models were applied with time to AD dementia as the phenotype of clinical progression. A series of bioinformatic analyses and functional experiments was performed to validate the novel findings.

Results

We found that APOE and PARL, a novel locus tagged by rs6795172 (hazard ratio = 1.66, p = 1.45 × 10⁻⁹), were significantly associated with AD clinical progression and were successfully replicated. The novel locus was linked to accelerated cognitive changes, higher tau levels, and faster atrophy of AD-specific brain structures, which were also verified in UK Biobank neuroimaging follow-up. Gene analysis and summary data–based Mendelian randomization indicated PARL as the most functionally relevant gene in the locus. Expression quantitative trait locus analyses and dual-luciferase reporter assays confirmed that PARL expression could be regulated by rs6795172. Three different AD mouse models consistently showed decreased PARL expression accompanied by elevated tau levels, and in vitro experiments revealed that knockdown/overexpression of PARL inversely changed tau levels.

Conclusions

Collectively, genetic, bioinformatic, and functional evidence suggests that PARL modulates clinical progression and neurodegeneration in AD. Targeting PARL may potentially modify AD progression and have implications for disease-modifying therapies.

中文翻译：

全基因组生存研究确定 PARL 是阿尔茨海默病临床进展和神经退行性疾病的新基因座

背景

阿尔茨海默病 (AD) 的发展轨迹存在变异性。我们的目的是确定 AD 临床进展的遗传调节因子。

方法

我们采用两阶段方法进行了第一个针对 AD 的全基因组生存研究。发现和复制阶段分别包括来自阿尔茨海默病神经影像计划和英国生物银行的 1158 名和 211,817 名无痴呆患者（平均随访 4.33 年和 8.63 年分别有 325 名和 1103 名患者取得进展）。Cox 比例风险模型随时间应用于 AD 痴呆作为临床进展的表型。进行了一系列生物信息学分析和功能实验来验证新发现。

结果

我们发现APOE和PARL是一个由 rs6795172 标记的新基因座（风险比 = 1.66，p = 1.45 × 10 ^-9），与 AD 临床进展显着相关，并且已成功复制。这个新的位点与加速的认知变化、更高的 tau 水平和 AD 特异性大脑结构更快的萎缩有关，这些在英国生物银行神经影像随访中也得到了验证。基因分析和基于汇总数据的孟德尔随机化表明PARL是该基因座中功能最相关的基因。表达数量性状基因座分析和双荧光素酶报告基因分析证实PARL表达可以受到 rs6795172 的调节。三种不同的 AD 小鼠模型一致显示 PARL 表达下降，同时 tau 水平升高，体外实验表明 PARL 的敲低/过度表达会反向改变 tau 水平。