Genetic susceptibility to schizophrenia through neuroinflammatory pathways associated with retinal thinness

Abstract

Schizophrenia is associated with structural and functional changes in the central nervous system, including the most distal part of it, the retina. However, the question of whether retinal atrophy is present before individuals develop schizophrenia or is a secondary consequence of the disorder remains unanswered. Here we address this question by examining the association between polygenic risk scores for schizophrenia and retinal morphologies in individuals without a schizophrenia diagnosis. We used population data for 34,939 white British and Irish individuals from the UK Biobank. Our robust regression results show that higher polygenic risk scores for schizophrenia were associated with thinner overall maculae, while controlling for confounding factors (b = -0.17, P = 0.018). Similarly, we found that greater polygenic risk scores for schizophrenia specific to neuroinflammation gene sets were associated with thinner ganglion cell inner plexiform layers (b = -0.10, self-contained P = 0.014, competitive P = 0.02). These results provide new evidence for genetic factors that could predispose individuals to heightened neuroinflammatory responses. Over time, these responses could contribute to neurodegenerative processes such as retinal thinning.

Keywords: Diagnostic markers; Genetics research; Schizophrenia.

Fig. 1. Association between genetic risk for schizophrenia and retinal thickness.

a, The anatomy of the eye and retina, displayed as a cross section of the eye, and a macular section of the retina. Optical coherence tomography measurements divide the macula into nine subfields, as indicated by the white crosshairs. The macular thickness is measured in micrometers. The structure of the different layers of the inner and outer retina is displayed on the right. b,c, The association between polygenic risk scores (z-scored) for schizophrenia and overall mean macular thickness (in micrometers) (b) and outer retinal thickness (c) averaged across both eyes. Solid lines represent the regression estimates, while complementary shaded areas correspond to the 95% confidence intervals. INLRPE, inner nuclear layer to the retinal pigment epithelium. Panel a was created with BioRender.com.

Fig. 2. Diagram of inclusion and exclusion of participants in this population.

F20–29 categorization includes individuals diagnosed with schizophrenia and schizotypal and delusional disorders. OCT, optical coherence tomography; QC, quality control.