1Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education of China, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
2Department of Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Eur Psychiatry. 2023 Apr 14;66(1):e33. doi: 10.1192/j.eurpsy.2023.20.
Genetic approaches are increasingly advantageous in characterizing treatment-resistant schizophrenia (TRS). We aimed to identify TRS-associated functional brain proteins, providing a potential pathway for improving psychiatric classification and developing better-tailored therapeutic targets.
TRS-related proteome-wide association studies (PWAS) were conducted on genome-wide association studies (GWAS) from CLOZUK and the Psychiatric Genomics Consortium (PGC), which provided TRS individuals ( = 10,501) and non-TRS individuals ( = 20,325), respectively. The reference datasets for the human brain proteome were obtained from ROS/MAP and Banner, with 8,356 and 11,518 proteins collected, respectively. We then performed colocalization analysis and functional enrichment analysis to further explore the biological functions of the proteins identified by PWAS.
In PWAS, two statistically significant proteins were identified using the ROS/MAP and then replicated using the Banner reference dataset, including CPT2 ( = 4.15 × 10 and = 3.38 × 10) and APOL2 ( = 4.49 × 10 and = 8.26 × 10). Colocalization analysis identified three variants that were causally related to protein expression in the human brain, including (PP4 = 0.981), (PP4 = 0.894), and (PP4 = 0.757). We extended PWAS results from gene-based analysis to pathway-based analysis, identifying 14 gene ontology (GO) terms and the only candidate pathway for TRS, metabolic pathways ( 0.05).
Our results identified two protein biomarkers, and cautiously support that the pathological mechanism of TRS is linked to lipid oxidation and inflammation, where mitochondria-related functions may play a role.
遗传方法在鉴定治疗抵抗性精神分裂症（TRS）方面具有越来越大的优势。我们旨在鉴定与 TRS 相关的功能性大脑蛋白，为改善精神科分类和开发更有针对性的治疗靶点提供潜在途径。
对 CLOZUK 和精神疾病基因组学联盟（PGC）的全基因组关联研究（GWAS）进行了与 TRS 相关的蛋白质组全关联研究（PWAS），分别为 TRS 个体（n=10501）和非 TRS 个体（n=20325）提供了参考数据集。人类大脑蛋白质组的参考数据集分别从 ROS/MAP 和 Banner 获得，分别收集了 8356 种和 11518 种蛋白质。然后，我们进行了共定位分析和功能富集分析，以进一步探索 PWAS 鉴定的蛋白质的生物学功能。
在 PWAS 中，使用 ROS/MAP 鉴定了两个具有统计学意义的蛋白质，并使用 Banner 参考数据集进行了复制，包括 CPT2（ = 4.15×10 和 = 3.38×10）和 APOL2（ = 4.49×10 和 = 8.26×10）。共定位分析鉴定了三个与人类大脑中蛋白质表达因果相关的变体，包括 （PP4 = 0.981）、 （PP4 = 0.894）和 （PP4 = 0.757）。我们将 PWAS 结果从基于基因的分析扩展到基于途径的分析，确定了 14 个基因本体（GO）术语和唯一的候选途径，即代谢途径（0.05）。
我们的研究结果鉴定了两个蛋白质生物标志物，并谨慎地支持 TRS 的病理机制与脂质氧化和炎症有关，其中与线粒体相关的功能可能起作用。
