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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.
