School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia.
Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton, NSW, Australia.
Transl Psychiatry. 2022 Sep 8;12(1):373. doi: 10.1038/s41398-022-02141-3.
Psychiatric disorders such as schizophrenia are commonly associated with structural brain alterations affecting the cortex. Recent genetic evidence suggests circulating metabolites and other biochemical traits play a causal role in many psychiatric disorders which could be mediated by changes in the cerebral cortex. Here, we leveraged publicly available genome-wide association study data to explore shared genetic architecture and evidence for causal relationships between a panel of 50 biochemical traits and measures of cortical thickness and surface area. Linkage disequilibrium score regression identified 191 genetically correlated biochemical-cortical trait pairings, with consistent representation of blood cell counts and other biomarkers such as C-reactive protein (CRP), haemoglobin and calcium. Spatially organised patterns of genetic correlation were additionally uncovered upon clustering of region-specific correlation profiles. Interestingly, by employing latent causal variable models, we found strong evidence suggesting CRP and vitamin D exert causal effects on region-specific cortical thickness, with univariable and multivariable Mendelian randomization further supporting a negative causal relationship between serum CRP levels and thickness of the lingual region. Our findings suggest a subset of biochemical traits exhibit shared genetic architecture and potentially causal relationships with cortical structure in functionally distinct regions, which may contribute to alteration of cortical structure in psychiatric disorders.
精神疾病，如精神分裂症，通常与影响大脑皮层的结构性脑改变有关。最近的遗传证据表明，循环代谢物和其他生化特征在许多精神疾病中起因果作用，这些作用可能通过大脑皮层的变化来介导。在这里，我们利用公开的全基因组关联研究数据，探索了一组 50 种生化特征与皮质厚度和表面积测量值之间的共享遗传结构和因果关系的证据。连锁不平衡评分回归确定了 191 对遗传相关的生化-皮质特征对，其中血细胞计数和其他生物标志物（如 C 反应蛋白（CRP）、血红蛋白和钙）的一致性表现。通过对特定区域相关性图谱的聚类，还揭示了空间组织的遗传相关性模式。有趣的是，通过采用潜在因果变量模型，我们发现了强有力的证据表明 CRP 和维生素 D 对特定区域的皮质厚度有因果作用，单变量和多变量孟德尔随机化进一步支持血清 CRP 水平与舌状区域厚度之间存在负因果关系。我们的研究结果表明，一组生化特征表现出共享的遗传结构，并与功能不同的区域的皮质结构存在潜在的因果关系，这可能导致精神疾病中皮质结构的改变。
