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Genetic analysis of retinal cell types reveals synaptic pathology in schizophrenia
ImportanceAs 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. However, it remains largely unclear whether primary disease mechanisms within the retina contribute to the observed retinal alterations and which specific retinal cell types and biological mechanisms are involved.
ObjectiveTo 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 ParticipantsIn this study, we 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 data sets from humans, macaques, and mice. To identify susceptible cell types, we applied MAGMA cell type enrichment analyses and performed subsequent pathway analyses. Furthermore, we translated the cellular top hit to the structural level by using retinal optical coherence tomography and genotyping data in the large population-based UK Biobank cohort (n = 36,349).
Main Outcomes and MeasuresCell type-specific enrichment of genetic risk loading for neuropsychiatric and neurological disorder traits in the gene expression profiles of retinal cells.
ResultsAmacrine 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. 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. Moreover, 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 and Alzheimer disease, or stroke.
Conclusions and RelevanceThis 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. |
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A novel candidate neuromarker of central motor dysfunction in childhood apraxia of speech
Childhood apraxia of speech (CAS) is conceived as an impairment of the central motor systems ability to program multiple speech movements, resulting in inaccurate transitions between and relative timing across speech sounds. However, the extant neuroimaging evidence base is scant and inconclusive and the neurophysiological origins of these motor planning problems remain highly underspecified. In the first magnetoencephalography study of this disorder, we measured brain activity from typically developing children (N = 19) and children with CAS (N=7) during performance of a speech task designed to interrogate function of the speech areas of primary sensorimotor cortex. Relative to their typically developing peers, our sample of CAS children showed abnormal speech-related responses within the mu-band motor rhythm, and beamformer source reconstruction analyses specify a brain origin of this speech rhythm in the left cerebral hemisphere, within or near pre-Rolandic motor areas crucial for the planning and control of speech and oromotor movements. These results provide a new and specific candidate mechanism for the core praxic features of CAS; point to a novel and robust neurophysiological marker of typical and atypical expressive speech development; and support an emerging neuroscientific consensus which assigns a central role for programming and coordination of speech movements to the motor cortices of the precentral gyrus. |