Rabe Finn, Smigielski Lukasz, Georgiadis Foivos, Kallen Nils, Omlor Wolfgang, Kirschner Matthias, Cathomas Flurin, Grünblatt Edna, Silverstein Steven, Blose Brittany, Barthelmes Daniel, Schaal Karen, Rubio Jose, Lencz Todd, Homan Philipp
Department of Adult Psychiatry and Psychotherapy, University of Zurich, Zurich, Switzerland.
Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry Zurich, University of Zurich, Zurich, Switzerland.
medRxiv. 2024 Apr 17:2024.04.05.24305387. doi: 10.1101/2024.04.05.24305387.
The human retina is part of the central nervous system and can be easily and non-invasively imaged with optical coherence tomography. While imaging the retina may provide insights on central nervous system-related disorders such as schizophrenia, a typical challenge are confounders often present in schizophrenia which may negatively impact retinal health. Here, we therefore aimed to investigate retinal changes in the context of common genetic variations conveying a risk of schizophrenia as measured by polygenic risk scores. We used population data from the UK Biobank, including White British and Irish individuals without diagnosed schizophrenia, and estimated a polygenic risk score for schizophrenia based on the newest genome-wide association study (PGC release 2022). We hypothesized that greater genetic susceptibility to schizophrenia is associated with retinal thinning, especially within the macula. To gain additional mechanistic insights, we conducted pathway-specific polygenic risk score associations analyses, focusing on gene pathways that are related to schizophrenia. Of 65484 individuals recruited, 48208 participants with available matching imaging-genetic data were included in the analysis of whom 22427 (53.48%) were female and 25781 (46.52%) were male. Our robust principal component regression results showed that polygenic risk scores for schizophrenia were associated with retinal thinning while controlling for confounding factors (b = -0.03, p = 0.007, pFWER = 0.01). Similarly, we found that polygenic risk for schizophrenia specific to neuroinflammation gene sets revealed significant associations with retinal thinning (b = -0.03, self-contained p = 0.041 (reflecting the level of association), competitive p = 0.05 (reflecting the level of enrichment)). These results go beyond previous studies suggesting a relationship between manifested schizophrenia and retinal phenotypes. They indicate that the retina is a mirror reflecting the genetic complexities of schizophrenia and that alterations observed in the retina of individuals with schizophrenia may be connected to an inherent genetic predisposition to neurodegenerative aspects of the condition. These associations also suggest the potential involvement of the neuroinflammatory pathway, with indications of genetic overlap with specific retinal phenotypes. The findings further indicate that this gene pathway in individuals with a high polygenic risk for schizophrenia could contribute through acute-phase proteins to structural changes in the retina.
人类视网膜是中枢神经系统的一部分，可通过光学相干断层扫描轻松且无创地成像。虽然对视网膜成像可能有助于了解精神分裂症等中枢神经系统相关疾病，但精神分裂症中经常存在的混杂因素可能会对视网膜健康产生负面影响，这是一个典型的挑战。因此，在这里，我们旨在研究在通过多基因风险评分衡量的、传达精神分裂症风险的常见基因变异背景下的视网膜变化。我们使用了英国生物银行的人群数据，包括未被诊断患有精神分裂症的英国白人和爱尔兰人，并根据最新的全基因组关联研究（PGC 2022年发布）估计了精神分裂症的多基因风险评分。我们假设对精神分裂症的遗传易感性越高，与视网膜变薄有关，尤其是在黄斑区内。为了获得更多的机制性见解，我们进行了特定通路的多基因风险评分关联分析，重点关注与精神分裂症相关的基因通路。在招募的65484名个体中，48208名有可用匹配成像-遗传数据的参与者被纳入分析，其中22427名（53.48%）为女性，25781名（46.52%）为男性。我们稳健的主成分回归结果表明，在控制混杂因素的情况下，精神分裂症的多基因风险评分与视网膜变薄有关（b = -0.03，p = 0.007，pFWER = 0.01）。同样，我们发现特定于神经炎症基因集的精神分裂症多基因风险与视网膜变薄有显著关联（b = -0.03，自包含p = 0.041（反映关联程度），竞争p = 0.05（反映富集程度））。这些结果超越了先前表明已确诊的精神分裂症与视网膜表型之间关系的研究。它们表明视网膜是反映精神分裂症遗传复杂性的一面镜子，并且在精神分裂症患者视网膜中观察到的改变可能与该疾病神经退行性方面的内在遗传易感性有关。这些关联还表明神经炎症通路可能参与其中，表明与特定视网膜表型存在遗传重叠。研究结果进一步表明，在精神分裂症多基因风险高的个体中，这条基因通路可能通过急性期蛋白导致视网膜结构变化。
