Abstract

Importance As an accessible part of the central nervous system, the retina provides a unique window to study pathophysiological mechanisms of brain disorders in humans. Imaging and electrophysiological studies have revealed retinal alterations across several neuropsychiatric and neurological disorders, but it remains largely unclear which specific cell types and biological mechanisms are involved. Objective To determine whether specific retinal cell types are affected by genomic risk for neuropsychiatric and neurological disorders and to explore the mechanisms through which genomic risk converges in these cell types. Design, Setting, and Participants This genetic association study combined findings from genome-wide association studies in schizophrenia, bipolar disorder, major depressive disorder, multiple sclerosis, Parkinson disease, Alzheimer disease, and stroke with retinal single-cell transcriptomic datasets from humans, macaques, and mice. To identify susceptible cell types, Multi-Marker Analysis of Genomic Annotation (MAGMA) cell-type enrichment analyses were applied and subsequent pathway analyses performed. The cellular top hits were translated to the structural level using retinal optical coherence tomography (acquired between 2009 and 2010) and genotyping data in the large population-based UK Biobank cohort study. Data analysis was conducted between 2022 and 2024. Main Outcomes and Measures Cell type–specific enrichment of genetic risk loading for neuropsychiatric and neurological disorder traits in the gene expression profiles of retinal cells. Results Expression profiles of amacrine cells (interneurons within the retina) were robustly enriched in schizophrenia genetic risk across mammalian species and in different developmental stages. This enrichment was primarily driven by genes involved in synapse biology. Moreover, expression profiles of retinal immune cell populations were enriched in multiple sclerosis genetic risk. No consistent cell-type associations were found for bipolar disorder, major depressive disorder, Parkinson disease, Alzheimer disease, or stroke. On the structural level, higher polygenic risk for schizophrenia was associated with thinning of the ganglion cell inner plexiform layer, which contains dendrites and synaptic connections of amacrine cells (B, −0.09; 95% CI, −0.16 to −0.03; P = .007; n = 36 349; mean [SD] age, 57.50 [8.00] years; 19 859 female [54.63%]). Higher polygenic risk for multiple sclerosis was associated with increased thickness of the retinal nerve fiber layer (B, 0.06; 95% CI, 0.02 to 0.10; P = .007; n = 36 371; mean [SD] age, 57.51 [8.00] years; 19 843 female [54.56%]). Conclusions and Relevance This study provides novel insights into the cellular underpinnings of retinal alterations in neuropsychiatric and neurological disorders and highlights the retina as a potential proxy to study synaptic pathology in schizophrenia.