基于血浆蛋白质组的孟德尔随机化分析鉴定焦虑障碍的有效生物标志物

Identification of biological markers for anxiety disorder through Mendelian randomization analysis of the full plasma proteome

中文关键词:  焦虑障碍  血浆蛋白质组  孟德尔随机化；生物标志物

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

中文摘要:

      【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）数据和包含50 486例焦虑障碍患者及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5种方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<0.001）和PDE5A（OR=0.911，95% CI：0.864~0.961，P<0.001）是焦虑障碍的保护因素，CRYGD（OR=1.209，95% CI：1.095~1.334，P<0.001）、BTN3A3（OR=1.045，95% CI：1.018~1.073，P<0.001）、SERPINB13（OR=1.102，95% CI：1.040~1.168，P＜0.001）、ERBB4（OR=1.283，95% CI：1.109~1.484，P<0.001）、LSAMP（OR=1.096，95% CI：1.037~1.158，P＜0.005）、ICOSLG（OR=1.283，95% CI：1.104~1.490，P＜0.005）、DNAJB11（OR=1.172，95% CI：1.076~1.277，P<0.001）和TREML1（OR=1.115，95% CI：1.054~1.179，P<0.001）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:

      【Abstract】 Background Anxiety disorder represents a prevalent psychiatric condition with a persistently rising global prevalence, significantly compromising patients' quality of life and social functioning. Currently, there is a clinical scarcity of objective and reliable biomarkers for early diagnosis and treatment evaluation of anxiety disorders. Recent research suggests that plasma proteins may serve as potential biomarkers for psychiatric diseases; however, the causal relationship between specific plasma proteins and anxiety disorders remains unclear. Objective This study aims to identify plasma proteins causally associated with anxiety disorders and elucidate their underlying biological pathways, thereby providing insights for the discovery of biomarkers and potential therapeutic targets for this condition. Methods This study utilized protein quantitative trait locus (pQTL) data for 4,907 plasma proteins derived from the deCODE study comprising 35,559 Icelandic individuals, and genome-wide association study (GWAS) data encompassing 50,486 anxiety disorder cases and 330,460 healthy controls. Bidirectional Mendelian randomization analyses were conducted using inverse variance weighting (IVW) as the primary method, supplemented by MR-Egger, weighted median, simple mode, and weighted mode approaches.. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted for the identified proteins. Sensitivity analyses, including Cochran’s Q test, MR-Egger intercept test, MR-PRESSO global test, and leave-one-out analysis, were performed to assess the robustness of the findings. Results Ten plasma proteins were identified as significantly associated with anxiety disorders. Among these, SPATA9 (OR=0.856, 95% CI: 0.784~0.934, P<0.001) and PDE5A (OR=0.911, 95% CI: 0.864~0.961, P<0.001) were identified as protective factors, while CRYGD (OR=1.209, 95% CI: 1.095~1.334, P<0.001), BTN3A3 (OR=1.045, 95% CI: 1.018~1.073, P<0.001), SERPINB13 (OR=1.102, 95% CI: 1.040~1.168, P＜0.001), ERBB4 (OR=1.283, 95% CI: 1.109~1.484, P<0.001), LSAMP (OR=1.096, 95% CI: 1.037~1.158, P＜0.005), ICOSLG (OR=1.283, 95% CI: 1.104~1.490, P＜0.005), DNAJB11 (OR=1.172, 95% CI: 1.076~1.277, P<0.001), and TREML1 (OR=1.115, 95% CI: 1.054~1.179, P<0.001) were identified as risk factors. Sensitivity analyses confirmed the robustness of the results, with no evidence of heterogeneity (Cochran’s Q test, P>0.05) or pleiotropy (MR–Egger intercept test, P>0.05). Enrichment analysis indicated that these proteins were significantly enriched in biological processes such as T-cell signaling, lymphocyte proliferation, cell membrane structure, and synaptic function, as well as in the intestinal immune network for IgA production and the ErbB signaling pathway. Conclusion This study identified ten plasma proteins associated with the risk of anxiety disorders through MR analysis. These proteins are involved in multiple biological processes, including neurodevelopment and immune regulation, providing evidence for potential biomarkers and therapeutic targets for anxiety disorders.