Retinal Alterations Reveal Insights Into Schizophrenia, Sclerosis Risk

A recent study showed that specific retinal alterations provided insight into the risk of schizophrenia and sclerosis.1

“Most notably, we found robust associations between schizophrenia risk and amacrine cells and between multiple sclerosis risk and retinal immune cells, which were conserved across different mammalian species,” wrote investigators, led by Emanuel Boudriot, MD, from Max Planck Institute of Psychiatry and the department of psychiatry and psychotherapy at Ludwig Maximilian University Hospital, in Germany.

The retina, an extension of the central nervous system (CNS), allows people to study the pathophysiological mechanisms of brain disorders. Imaging and electrophysiological studies have shown retinal alterations across many neuropsychiatric and neurological disorders. For instance, meta-analyses have demonstrated individuals with schizophrenia have reduced thickness of the retinal nerve fiber layer and the ganglion cell inner plexiform layer compared with healthy controls.2,3

Despite studies showing how retinal alterations can indicate a neuropsychiatric disorder, research has not yet identified what specific cell types and biological mechanisms are involved.1 Therefore, investigators conducted a genetic association study between 2022 and 2024 to determine whether the genomic risk for neuropsychiatric and neurological disorders impacts specific retinal cell types. The analysis assumed that the polygenic risk burden for complex brain disorder accumulates in both brain cells for clinical phenotype and tissues and cell types affected by the same genetic architecture.

The team leveraged genome-wide association studies in schizophrenia, bipolar disorder, major depressive disorder (MDD), multiple sclerosis, Parkinson Disease, Alzheimer Disease, and stroke with retinal single-cell transcriptomic datasets from humans, macaques, and mice.

Multi-Marker Analysis of Genomic Annotation (MAGMA) cell-type enrichment analyses were applied to identify susceptible cell types. Investigators translated cellular hits to the structural level using retinal optical coherence tomography and genotyping data from a large population-based UK Biobank study.

The study revealed expression profiles of amacrine cells, the interneurons within the retina, were enriched in schizophrenia genetic risk factors in different developmental stages. Genes involved in the synapses drove the enrichment of these schizophrenia risk factors. The genes with the strongest association with schizophrenia were CACNA1I (encodes the calcium voltage-gated channel subunit alpha1 I), DOC2A (important for Ca2+ - dependent neurotransmitter release), the dopamine receptor D2 (common target of antipsychotics), and SLC32AI (codes for a protein involved in the GABA and glycine update into synaptic vesicles).

“Interestingly, the enrichment of genetic associations with schizophrenia in amacrine cells was also detectable in fetal retinal tissue, suggesting that the retina reflects the neurodevelopmental component in schizophrenia pathogenesis,” investigators wrote.

Furthermore, expression profiles of retinal immune cell populations were enriched in multiple sclerosis genetic risk. Interleukin 2-receptor subunit alpha was the gene with the strongest association with sclerosis.

The study found no consistent cell-type associations for bipolar disorder, MDD, Parkinson Disease, Alzheimer Disease, or stroke.

On the structural level, a greater polygenic risk for schizophrenia was linked to the thinning of the ganglion cell inner plexiform layer, containing dendrites and synaptic connections of amacrine cells (95% confidence interval [CI], -0.16 to -0.03; P = .007). This was observed among 36,349 participants, with a mean age of 57.50 years and half female (54.63%).

A greater polygenic risk for multiple sclerosis was linked to an increased thickness of the retinal nerve fiber layer (95% CI, 0.002 to 0.10; P = .007). The finding was found among 36,371 individuals, with a mean age of 57.51 years and 54.56% females.

“Our findings highlight the retina as a unique opportunity to image microstructures that could reflect synaptic pathology in the CNS, which is challenging to investigate in the brain itself in vivo in humans,” investigators wrote. “While amacrine cells remain difficult to study directly, future advancements in retinal imaging may enable visualization of individual cells.”

References

1. Boudriot, E, Stephan, M, Rabe, F, et al. Genetic Analysis of Retinal Cell Types in Neuropsychiatric Disorders. 2025. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2024.4230
2. Komatsu H, Onoguchi G, Silverstein SM, et al. Retina as a potential biomarker in schizophrenia spectrum disorders: a systematic review and meta-analysis of optical coherence tomography and electroretinography. Mol Psychiatry. 2023;29(2):464-482. doi:10.1038/s41380-023-01983-7
3. Sheehan N, Bannai D, Silverstein SM, Lizano P. Neuroretinal alterations in schizophrenia and bipolar disorder: an updated meta-analysis. Schizophr Bull. 2024;50(5):1067-1082. doi:10.1093/schbul/sbae102