Retinal thinning may serve as early biomarker of genetic risk for schizophrenia

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Regression analysis identified significant associations between the polygenic risk scores for schizophrenia, pathway-specific scores, and specific retinal layers,¹ according to coauthors Finn Rabe, PhD, from the Department of Adult Psychiatry and Psychotherapy, University of Zurich, and Lukasz Smigielski, PhD, Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry Zurich, University of Zurich, Zurich, Switzerland.

The researchers explained that while previous studies have identified retinal findings in patients with schizophrenia^2–11 that included inner retinal atrophy, thinner peripapillary retinal nerve fiber layers and macular ganglion cell and inner plexiform layers, and an enlarged cup-disc ratio, the schizophrenia diagnosis had already been established in those patient populations.

In this new study in Nature Mental Health, the researchers took the research a step further to determine if the retinal differences could be identified early—that is, before the symptoms of schizophrenia became apparent.

Considerations in this study, they pointed out, were that antipsychotic medication, smoking, lifestyle factors, and disease-related changes can impact retinal health and even obscure the interpretation of findings, making it difficult to determine whether observed differences in retinal thickness are related directly to the pathophysiology of schizophrenia or are secondary to these confounding factors, they explained.

A very interesting finding is that the thinner retinas observed in patients have also been seen in unaffected first-degree relatives, suggesting a link to genetic susceptibility to schizophrenia.³

The investigators opted to determine the polygenic risk scores because, they explained, the scores allow researchers to investigate the genetic underpinnings of the differences in retinal thickness in the context of schizophrenia risk, thus providing a potential understanding of the genetic contributions to retinal atrophy.¹²

“Polygenic risk scores aggregate the impact of numerous genetic variants throughout the genome and account for a considerable portion of the variance in disease risk.^13,14 The identification of shared genetic influences between retinal structures and schizophrenia^15,16 further supports the hypothesis that retinal atrophy observed in schizophrenia could reflect underlying genetic susceptibilities. This convergence from optical coherence tomography studies and genetic research may help in the exploration of the ways in which genetic predispositions contribute to the neurodevelopmental and neurodegenerative anomalies in schizophrenia,¹⁷ including retinal alterations,” they stated.

Investigation and results

The goal was to determine an association between polygenic risk scores for schizophrenia and retinal morphologies in individuals who did not have a schizophrenia diagnosis. The researchers used data from 34,939 Caucasian British and Irish individuals from the UKBiobank.

“Our robust regression results showed 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 neuroinflammatory gene sets were associated with thinner ganglion cell inner plexiform layers (b = −0.10, self-contained P = 0.014, competitive P = 0.02),” the authors reported.

“In this large observational study in healthy individuals, we found that an increased genetic risk for schizophrenia is associated with lower retinal thickness. This demonstrates that schizophrenia’s genetic risk factors affect not just the brain but also the retina. This result reaffirms the findings of a recent study on the genetic contribution to retinal thickness within the context of schizophrenia risk,¹⁸ in which it was found that, using inner retina-specific analyses, a higher genetic risk for schizophrenia is associated with thinner ganglion cell inner plexiform layers. Our results extend these findings by providing evidence that greater genetic risk for schizophrenia is also associated with thinner outer retinal thickness. This presents a more complete picture of the connection between genetic risk and retinal morphology,” Finn and Smigielski and colleagues commented.

They concluded, “These findings suggest that the retina may serve not only as a ‘window’ to the brain but also as a mirror reflecting the genetic complexities of schizophrenia. They allow us to better distinguish between the primary effects of genetic risk and secondary consequences of the disorder. While our results increase confidence that retinal thinning may be associated with core processes in schizophrenia, further research is crucial to establish the specificity and sensitivity of retinal thinning as a reliable indicator of core degenerative processes in the disorder. Future studies should focus on disentangling the complex interplay between genetic predisposition, environmental factors and comorbid conditions that can affect retinal health to determine the true potential of retinal changes as a biomarker for schizophrenia-related processes.”

References

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