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

Xiaoxiao Xu, Alan B. Wells, David R. O'Brien, Arye Nehorai, Joseph D. Dougherty

Research output: Contribution to journalArticle

90 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1420-1431
Number of pages12
JournalJournal of Neuroscience
Volume34
Issue number4
DOIs
StatePublished - Jan 27 2014

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