Genetic susceptibility to schizophrenia through neuroinflammatory pathways is associated with retinal thinning: Findings from the UK-Biobank.

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.

Retinal Neurodegeneration as a Potential Biomarker of Accelerated Aging in Schizophrenia Spectrum Disorders.

BACKGROUND AND HYPOTHESES: Several biological markers are believed to reflect accelerated aging in schizophrenia spectrum disorders; however, retinal neural changes have not yet been explored as potential CNS biomarkers of accelerated aging in this population. The aim of this study was to determine whether retinal neural layer thinning is more strongly related to age in schizophrenia and schizoaffective disorder patients (SZ) than in a psychiatrically healthy control group (CON). STUDY DESIGN: Schizophrenia (n = 60) and CON participants (n = 69) underwent spectral domain optical coherence tomography (OCT) scans to examine the following variables in both eyes: retinal nerve fiber layer (RNFL) thickness, macula central subfield (CSF) thickness, macula volume, ganglion cell layer-inner plexiform layer (GCL-IPL) thickness, optic cup volume, and cup-to-disc ratio. Eleven participants in each group had diabetes or hypertension. STUDY RESULTS: Significant negative relationships between age and RNFL thickness, macula volume, and GCL-IPL thickness were observed in the SZ group, while no significant relationships were observed in the CON group. However, many of the findings in the SZ group lost significance when participants with diabetes/hypertension were removed from analyses. A notable exception to this was that the age × SZ interaction accounted for a unique proportion of variance in GCL-IPL thinning over and above the effect of diabetes/hypertension. CONCLUSIONS: The results suggest that retinal atrophy occurs at an increased rate in schizophrenia spectrum disorders, potentially reflecting accelerated aging inherent to these conditions, with considerable contributions from systemic medical diseases closely linked to this population.

The Indirect Effect of Peritraumatic Dissociation on the Relationship Between Childhood Maltreatment and Schizotypy.

Schizotypy is a multidimensional personality construct that is understood as a vulnerability for schizophrenia, often manifesting as more subtle and attenuated symptoms, referred to as schizotypic psychopathology. It has many well-established environmental risk factors, including experiencing childhood maltreatment (CM), but the intermediary mechanisms that relate CM to schizotypic psychopathology are unclear. Prior studies have demonstrated that trait dissociation may indirectly affect the relationship between CM and schizotypic psychopathology. However, less is known about the importance of peritraumatic dissociative experiences during CM and how it relates to schizotypic symptom manifestations in young adulthood. Therefore, the present study explored the independent contributions of peritraumatic and trait dissociation in the relationship between CM and schizotypy. Participants (N = 346) were undergraduate students who completed online self-report measures on CM, trait dissociation, peritraumatic dissociation experienced during CM, and schizotypic symptoms. The indirect effect of peritraumatic dissociation and trait dissociation on the relationship between CM and schizotypy was examined using mediational analyses. Correlational analyses revealed significant associations between self-reported CM, schizotypy, trait dissociation, and peritraumatic dissociation. In addition, mediational analyses indicated a significant indirect effect of peritraumatic dissociation (ß = .06, 95% confidence interval (CI) [0.01, 0.12]), but not trait dissociation (ß = .05, 95% CI [-0.02, 0.12]), on CM and schizotypy. These results highlight peritraumatic dissociation as an important mechanism driving the expression of schizotypic symptoms among individuals with a history of CM. Understanding how trauma sequelae lead to schizotypic psychopathology may be crucial in assessing and treating individuals with maltreatment histories or those on the psychosis spectrum.

Theory of Mind and Alexithymia in Deaf and Hard-of-Hearing Young Adults.

The aim of the current study was to examine theory of mind (ToM), the ability to infer the mental states of others, in young adults who are deaf and hard-of-hearing (DHH), and to explore the influence of alexithymia, an inability to understand emotions of the self and others, on ToM performance in this group. Compared to participants with typical hearing, DHH participants displayed significantly lower affective ToM skills and greater alexithymia. After accounting for verbal intelligence quotient, hearing status and alexithymia significantly contributed to poorer ToM performance, accounting for over 14% of the variance. Having a parent who is deaf and being part of the Deaf community were associated with better emotion processing and appear to be important protective factors. Findings provide support that ToM difficulties may linger into young adulthood among DHH individuals and that alexithymia may be a contributing factor. Early intervention programs emphasizing emotional understanding, perspective-taking, and communication skills are warranted for DHH children as well as their caregivers.