基于血浆蛋白质组的孟德尔随机化分析鉴定焦虑障碍的生物标志物

Proteome-wide Mendelian randomization analysis of plasma proteins identifies biomarkers for anxiety disorders

中文关键词:  焦虑障碍  血浆蛋白  孟德尔随机化  生物标志物

英文关键词:Anxiety disorders  Plasma proteins  Mendelian randomization  Biomarkers

中文摘要:

      背景 焦虑障碍是一种常见的精神障碍，其患病率呈持续上升趋势，严重影响患者的生活质量和社会功能。由于临床上缺乏客观、可靠的生物标志物，一定程度上限制了焦虑障碍的早期识别与诊治。血浆蛋白具有作为精神疾病生物标志物的潜力，然而其与焦虑障碍的因果关系尚不明确。目的 识别与焦虑障碍存在因果关联的血浆蛋白，并阐释其参与的生物学通路，为寻找焦虑障碍的生物标志物及探索潜在治疗靶点提供参考。方法 基于deCODE数据库涵盖35 559名冰岛人的4 907种血浆蛋白的蛋白质数量性状位点（pQTL）数据以及包含50 486例焦虑障碍患者和330 460名健康对照者的全基因组关联研究（GWAS）数据，以逆方差加权（IVW）法为主要分析方法，辅以MR-Egger法、加权中位数法、简单模式法及加权模式法进行双向孟德尔随机化分析。对相关蛋白进行基因本体（GO）和京都基因与基因组百科全书（KEGG）通路富集分析。采用Cochran’s Q检验、MR-Egger截距检验、MR-PRESSO检验和留一法分析等进行敏感性分析，以评估结果的稳健性。结果 共鉴定出10种与焦虑障碍相关的血浆蛋白。其中，SPATA9（OR=0.856，95% CI：0.784~0.934，P<0.01）和PDE5A（OR=0.911，95% CI：0.864~0.961，P<0.01）是焦虑障碍的保护因素，CRYGD（OR=1.209，95% CI：1.095~1.334，P<0.01）、BTN3A3（OR=1.045，95% CI：1.018~1.073，P<0.01）、SERPINB13（OR=1.102，95% CI：1.040~1.168，P<0.01）、ERBB4（OR=1.283，95% CI：1.109~1.484，P<0.01）、LSAMP（OR=1.096，95% CI：1.037~1.158，P<0.01）、ICOSLG（OR=1.283，95% CI：1.104~1.490，P<0.01）、DNAJB11（OR=1.172，95% CI：1.076~1.277，P<0.01）和TREML1（OR=1.115，95% CI：1.054~1.179，P<0.01）是焦虑障碍的危险因素。敏感性分析显示结果稳健，无异质性（Cochran’s Q检验P>0.05）和多效性（MR-Egger截距检验P>0.05）证据。富集分析表明，这些血浆蛋白富集于T细胞信号传导、淋巴细胞增殖、细胞膜结构和突触功能等生物学过程，以及产生IgA的肠道免疫网络和ErbB信号通路。结论 本研究鉴定出10种与焦虑障碍存在因果关联的血浆蛋白，这些血浆蛋白的功能涉及神经发育、免疫调节等多个生物学过程。

英文摘要:

      Background Anxiety disorder is a common mental disorder， with its prevalence showing a continuous upward trend， significantly affecting the quality of life and social function of patients. Due to the lack of objective and reliable biomarkers in clinical practice， the early identification and treatment of anxiety disorder have been somewhat limited. Plasma proteins have the potential to serve as biomarkers for mental diseases， however， the causal relationship between them and anxiety disorder remains unclear.Objective To identify the plasma proteins that have a causal relationship with anxiety disorders， and to elucidate the associated biological pathways， in order to provide references for the search for biomarkers of anxiety disorders and the exploration of potential therapeutic targets.Methods Based on the protein quantitative trait locus （pQTL） data of 4 907 plasma proteins covering 35 559 Icelandic individuals from the deCODE database， and the genome-wide association studies （GWAS） data of 50 486 patients with anxiety disorders and 330 460 healthy controls， the inverse-variance weighted （IVW） method was used as the main analysis method， supplemented by MR-Egger method， weighted median method， simple model method， and weighted model method for bidirectional Mendelian randomization analysis. Enrichment analysis of gene ontology （GO） and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathways was conducted for the related proteins. Sensitivity analysis was performed using Cochran's Q test， MR-Egger intercept test， MR-PRESSO test， and leave-one-out analysis to evaluate the robustness of the results.Results A total of 10 plasma proteins were identified as significantly associated with anxiety disorders. Among these， SPATA9 （OR=0.856， 95% CI： 0.784–0.934， P<0.01） and PDE5A （OR=0.911， 95% CI： 0.864–0.961， P<0.01） were identified as protective factors， while CRYGD （OR=1.209， 95% CI： 1.095–1.334， P<0.01）， BTN3A3 （OR=1.045， 95% CI： 1.018–1.073， P<0.01）， SERPINB13 （OR=1.102， 95% CI： 1.040–1.168， P<0.01）， ERBB4 （OR=1.283， 95% CI： 1.109–1.484， P<0.01）， LSAMP （OR=1.096， 95% CI： 1.037–1.158， P<0.01）， ICOSLG （OR=1.283， 95% CI： 1.104–1.490， P<0.01）， DNAJB11 （OR=1.172， 95% CI： 1.076–1.277， P<0.01）， and TREML1 （OR=1.115， 95% CI： 1.054–1.179， P<0.01） were identified as risk factors. The sensitivity analysis showed that the results were robust， with no heterogeneity （Cochran's Q test P>0.05） or pleiotropy （MR-Egger intercept test P>0.05）. Enrichment analysis indicated that these plasma proteins were enriched in biological processes such as T-cell signal transduction， lymphocyte proliferation， cell membrane structure and synaptic function， as well as the intestinal immune network that produces IgA and the ErbB signaling pathway.Conclusion This study identified 10 plasma proteins associated with anxiety disorders. The functions of these plasma proteins involve multiple biological processes such as neural development and immune regulation.