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Cell type-specific expression analysis to identify putative cellular mechanisms for neurogenetic disorders

Recent advances have substantially increased the number of genes that are statistically associated with complex genetic disorders of the CNS such as autism and schizophrenia. It is now clear that there will likely be hundreds of distinct loci contributing to these disorders, underscoring a remarkabl...

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Published in:The Journal of neuroscience 2014-01, Vol.34 (4), p.1420-1431
Main Authors: Xu, Xiaoxiao, Wells, Alan B, O'Brien, David R, Nehorai, Arye, Dougherty, Joseph D
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container_title The Journal of neuroscience
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creator Xu, Xiaoxiao
Wells, Alan B
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description Recent advances have substantially increased the number of genes that are statistically associated with complex genetic disorders of the CNS such as autism and schizophrenia. It is now clear that there will likely be hundreds of distinct loci contributing to these disorders, underscoring a remarkable genetic heterogeneity. It is unclear whether this genetic heterogeneity indicates an equal heterogeneity of cellular mechanisms for these diseases. The commonality of symptoms across patients suggests there could be a functional convergence downstream of these loci upon a limited number of cell types or circuits that mediate the affected behaviors. One possible mechanism for this convergence would be the selective expression of at least a subset of these genes in the cell types that comprise these circuits. Using profiling data from mice and humans, we have developed and validated an approach, cell type-specific expression analysis, for identifying candidate cell populations likely to be disrupted across sets of patients with distinct genetic lesions. Using human genetics data and postmortem gene expression data, our approach can correctly identify the cell types for disorders of known cellular etiology, including narcolepsy and retinopathies. Applying this approach to autism, a disease where the cellular mechanism is unclear, indicates there may be multiple cellular routes to this disorder. Our approach may be useful for identifying common cellular mechanisms arising from distinct genetic lesions.
doi_str_mv 10.1523/JNEUROSCI.4488-13.2014
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subjects Animals
Brain
Gene Expression Profiling - methods
Genetic Predisposition to Disease
Humans
Mice
Nervous System Diseases - genetics
Nervous System Diseases - physiopathology
Transcriptome - genetics
title Cell type-specific expression analysis to identify putative cellular mechanisms for neurogenetic disorders
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