Investigating the role of immune genes and inflammatory biomarkers in schizophrenia heterogeneity

项目摘要/摘要 精神分裂症是一种衰弱的神经精神疾病，具有很强的遗传成分，但不太好。 了解生物机制。来自全基因组关联研究(GWAS)的最强信号 精神分裂症位于主要组织相容性复合体基因座，部分由拷贝数驱动 补体组分4(C4)基因的变异是补体级联中的重要中介。 此外，交叉障碍研究表明精神分裂症和自身免疫疾病有共同的遗传风险。 疾病，提示在发病机制中潜在的免疫遗传作用。精神分裂症被认为与 外周炎症水平升高和免疫生物标记物预测患者预后更差 患上了这种疾病。然而，目前尚不清楚炎症是原因因素还是结果 疾病过程，以及免疫调节基因在多大程度上发挥作用。这项工作将调查 在与电子健康相关的大型生物库中，免疫生物标记物和遗传学在精神分裂症中的联合作用 记录(EHR)。首先，将使用具有纵向临床实验室数据的电子病历储存库来 检查免疫生物标记物水平和精神分裂症诊断之间的时间关系。在 精神分裂症谱系患者，这些生物标记物水平将被评估他们预测特定的能力 临床结果。第二，将建立与目标1中提议的纵向队列平行的纵向队列，但 整合了来自约90,000个个体的全基因组基因分型数据，这些个体是 BioVU，VUMC的生物库资源。免疫生物标记物的遗传预测将被包括在这些 模型，并评估它们对精神分裂症风险的相对贡献和预测临床的能力 结果。然后将进行中介分析，以调查连接C4CNV和 BioVU中精神分裂症患者免疫生物标志物的变化这些分析将被复制和元- 在百万退伍军人计划和我们所有人的其他功能强大的EHR链接生物库中进行分析 研究计划。拟议中的研究将阐明鲜为人知的 精神分裂症的免疫调节遗传危险因素、免疫生物标记物和临床异质性 谱系障碍。理解这些关系将产生机械性的见解并揭示 潜在的临床有用的精神分裂症病程的生物标志物。

PROJECT SUMMARY/ABSTRACT Schizophrenia is a debilitating neuropsychiatric condition with a strong genetic component but poorly understood biological mechanisms. The strongest signal from genome-wide association studies (GWAS) of schizophrenia lies in the major histocompatibility complex locus and is in part driven by copy number variation in the complement component 4 (C4) gene, an important mediator in the complement cascade. Furthermore, cross-disorder studies implicate shared genetic risk in schizophrenia and autoimmune disorders, suggesting a potential immunogenetic role in pathogenesis. Schizophrenia has been linked to increased levels of peripheral inflammation, and immune biomarkers predict worse outcomes in patients with the disorder. However, it is unclear whether inflammation is a causal factor or a consequence of the disease process, and to what extent immune-regulating genes play a role. This work will investigate the joint role of immune biomarkers and genetics in schizophrenia in a large biobank linked to electronic health records (EHRs). First, a repository of EHRs with longitudinal clinical laboratory data will be used to examine the temporal relationship between immune biomarker levels and schizophrenia diagnoses. Within schizophrenia spectrum patients, these biomarker levels will be assessed for their ability to predict specific clinical outcomes. Second, longitudinal cohorts paralleling those proposed in Aim 1 will be constructed but incorporating whole-genome genotyping data from a subset of ~90,000 individuals that are a part of the BioVU, VUMC’s biorepository resource. Genetic predictors of immune biomarkers will be included in these models and evaluated for their relative contributions to schizophrenia risk and their ability to predict clinical outcomes. Mediation analyses will then be conducted to investigate causal pathways linking C4 CNV and immune biomarker alterations in schizophrenia in BioVU. These analyses will be replicated and meta- analyzed in additional well-powered EHR-linked biobanks from the Million Veteran Program and All of Us research program. The proposed studies will elucidate the poorly understood relationships between immune-regulating genetic risk factors, immune biomarkers, and clinical heterogeneity in schizophrenia spectrum disorders. Understanding these relationships will yield mechanistic insights and uncover potentially clinically useful biomarkers of schizophrenia disease course.