Cell Type-Specific Expression Analysis to Identify Putative Cellular Mechanisms for Neurogenetic Disorders

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.

Early pridopidine treatment improves behavioral and transcriptional deficits in YAC128 Huntington disease mice

“…P < 0.05) using cell type-specific expression analysis (34). Whereas DEGs common to both the 10 mg/kg and 30 mg/kg groups were enriched in genes expressed in striatal medium spiny and cortical project neurons ( Figure 7A), DEGs specific to the 30 mg/kg group were additionally enriched in transcripts expressed in cholinergic neurons ( Figure 7B).…”

FoxP1 orchestration of ASD-relevant signaling pathways in the striatum

“…6B). Finally, we used a recently developed tool-cellspecific expression analysis (Xu et al 2014)-to examine within which brain regions and cellular populations the conserved FoxP1 targets are enriched. We found that DEGs down-regulated with loss of Foxp1 and up-regulated with overexpression of FOXP1 are enriched for striatal genes (Fig.…”

“…While there is a strong genetic component to ASD, this is divided among several hundred genes, each with only a small contribution to the prevalence of the disorder (Geschwind and State 2015). Furthermore, many autismrisk genes are thought to exert their effects during early brain development (State and Sestan 2012;Xu et al 2014;Parikshak et al 2015). Transcription factors play a key role in orchestrating the spatial and temporal gene expression patterns important for this process.…”

Transcriptome sequencing implicates dorsal striatum-specific gene network, immune response and energy metabolism pathways in bipolar disorder

“…Regional markers were originally determined using existing gene expression data from the Atlas of the Developing Human Brain (www.brainspan.org); cell-type markers were originally derived via translational profiling of genetically tagged cell lines isolated from mouse brain. 36 Marker enrichment was tested through the Fisher's Exact test.…”

“…In order to determine whether the modules detected in our data set are part of regionally restricted network, we tested their enrichment in gene expression markers of distinct brain regions and cell types. 36 Figure 3 presents the results from this analysis at pSI 0.001 (see Materials and Methods). Of the two modules (M5 and M7) that previously showed a trend for association with BD based on eigengene expression, M7 was found to be enriched in markers for immune cells, whereas M5 showed no cell-type or regional marker enrichment.…”