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基于孟德尔随机化分析的大脑、脑脊液和血浆蛋白质组学研究为注意缺陷多动障碍的潜在药物靶点提供了依据。

Mendelian randomization analysis of the brain, cerebrospinal fluid, and plasma proteome identifies potential drug targets for attention deficit hyperactivity disorder.

机构信息

Mental Health Center and Psychiatric Laboratory, The State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, China.

Affiliated Mental Health Center & Hangzhou Seventh People's Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China; Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou, 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou, 310058, China.

出版信息

EBioMedicine. 2024 Jul;105:105197. doi: 10.1016/j.ebiom.2024.105197. Epub 2024 Jun 13.

DOI:10.1016/j.ebiom.2024.105197

PMID:38876042

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11225168/

Abstract

BACKGROUND

The need for new therapeutics for attention deficit hyperactivity disorder (ADHD) is evident. Brain, cerebrospinal fluid (CSF), and plasma protein biomarkers with causal genetic evidence could represent potential drug targets. However, a comprehensive screen of the proteome has not yet been conducted.

METHODS

We employed a three-pronged approach using Mendelian Randomization (MR) and Bayesian colocalization analysis. Firstly, we studied 608 brains, 214 CSF, and 612 plasma proteins as potential causal mediators of ADHD using MR analysis. Secondly, we analysed the consistency of the discovered biomarkers across three distinct subtypes of ADHD: childhood, persistent, and late-diagnosed ADHD. Finally, we extended our analysis to examine the correlation between identified biomarkers and Tourette syndrome and pervasive autism spectrum disorder (ASD), conditions often linked with ADHD. To validate the MR findings, we conducted sensitivity analysis. Additionally, we performed cell type analysis on the human brain to identify risk genes that are notably enriched in various brain cell types.

FINDINGS

After applying Bonferroni correction, we found that the risk of ADHD was increased by brain proteins GMPPB, NAA80, HYI, CISD2, and HYI, TIE1 in CSF and plasma. Proteins GMPPB, NAA80, ICA1L, CISD2, TIE1, and RMDN1 showed overlapped loci with ADHD risk through Bayesian colocalization. Overexpression of GMPPB protein was linked to an increase in the risk for all three ADHD subtypes. While ICA1L provided protection against both ASD and ADHD, CISD2 increased the probability of both disorders. Cell-specific studies revealed that GMPPB, NAA80, ICA1L, and CISD2 were predominantly present on the surface of excitatory-inhibitory neurons.

INTERPRETATION

Our comprehensive MR investigation of the brain, CSF, and plasma proteomes revealed seven proteins with causal connections to ADHD. Particularly, GMPPB and TIE1 emerged as intriguing targets for potential ADHD therapy.

FUNDING

This work was partly funded by the Key R & D Program of Zhejiang (T.L. 2022C03096); the National Natural Science Foundation of China Project (C.Z. 82001413); Postdoctoral Foundation of West China Hospital (C.Z. 2020HXBH163).

摘要

背景

对于注意力缺陷多动障碍（ADHD），新的治疗方法迫在眉睫。具有因果遗传证据的大脑、脑脊液（CSF）和血浆蛋白生物标志物可能代表潜在的药物靶点。然而，蛋白质组的全面筛查尚未进行。

方法

我们采用孟德尔随机化（MR）和贝叶斯共定位分析的三管齐下的方法。首先，我们使用 MR 分析研究了 608 个大脑、214 个 CSF 和 612 个血浆蛋白，以确定它们是否为 ADHD 的潜在因果介导物。其次，我们分析了在三种不同亚型的 ADHD（儿童期、持续性和后期诊断的 ADHD）中发现的生物标志物的一致性。最后，我们扩展了分析范围，以检查已确定的生物标志物与抽动秽语综合征和广泛自闭症谱系障碍（ASD）之间的相关性，这两种疾病通常与 ADHD 有关。为了验证 MR 的发现，我们进行了敏感性分析。此外，我们对人类大脑进行了细胞类型分析，以鉴定在各种脑细胞类型中显著富集的风险基因。

发现

经过 Bonferroni 校正后，我们发现大脑蛋白 GMPPB、NAA80、HYI、CISD2 和 HYI、TIE1 在 CSF 和血浆中增加了 ADHD 的风险。通过贝叶斯共定位发现，蛋白 GMPPB、NAA80、ICA1L、CISD2、TIE1 和 RMDN1 与 ADHD 风险存在重叠的基因座。GMPPB 蛋白的过表达与所有三种 ADHD 亚型的风险增加有关。虽然 ICA1L 对 ASD 和 ADHD 都有保护作用，但 CISD2 增加了这两种疾病的发生概率。细胞特异性研究表明，GMPPB、NAA80、ICA1L 和 CISD2 主要存在于兴奋性抑制神经元的表面。