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Gene Expression Study of Brain Cell Layer Finds New Schizophrenia Risk Loci

NEW YORK – By focusing on specific types of cells found in the hippocampal area of the brain, researchers have uncovered additional genetic loci associated with risk of developing schizophrenia.

Many previous studies of gene expression in the human brain have relied on extracting RNA from bulk tissue, and single-cell approaches are increasingly used. However, for their study, researchers from Johns Hopkins School of Medicine and elsewhere instead paid particular attention to a cell type previously implicated in schizophrenia.

Using laser-capture microdissection followed by RNA sequencing, they profiled the transcriptomes of these cells, obtained from the brains of more than 250 individuals with schizophrenia, bipolar disorder, major depression, or neurotypical controls. As they reported Monday in Nature Neuroscience, the researchers uncovered schizophrenia-associated signals using this approach that were not found in bulk samples, including ones that may be druggable.

"This strategy of deeply sequencing target cell populations in postmortem human brain provides a powerful balance between unbiased single-nucleus and homogenate tissue sequencing that can identify cellular and spatial associations with common molecular and clinical traits," senior author Thomas Hyde, a researcher at Johns Hopkins, and his colleagues wrote in their paper.

For their study, they profiled the transcriptome of the granule cell layer of the dentate gyrus subfield (DG-GCL), which is involved in neurogenesis and has been tied to bipolar disorder and schizophrenia, from postmortem hippocampal tissue of 263 individuals.

For 112 individuals, the researchers had both DG-GCL and bulk hippocampal samples available. After confirming that the DG-GCL samples were indeed enriched for neuronal cells, they compared the DG-GCL and bulk hippocampal transcriptomes to find 1,899 genes that were differentially expressed between the two. Among the enriched genes were, for instance, KCNK1, CAMK1, and GABRD, while the depleted genes included MOBP and MBP.

As the hippocampus undergoes age-related changes, the researchers compared the expression of nearly 21,500 genes within their full cohort of 263 samples to age- and library-matched bulk hippocampal samples. In the DG-GCL samples, they noted 1,709 genes whose expression was linked with age, but only 1,428 such genes in the bulk samples, suggesting that there are cell-specific patterns.

They also searched for expression quantitative trait loci (eQTLs) among the DG-GCL samples, uncovering about 9 million eQTL SNP-feature pairs. Of those, about 15 percent were not found in the bulk hippocampal samples, indicating to the researchers that the regulation of gene expression can vary between cell populations and not be captured by bulk samples.

When they focused on eQTLs near schizophrenia risk variants that were reported by a recent genome-wide association study, the researchers found high overlap of significant loci between sample types. However, they still uncovered a number of associations in the DG-GCL samples that were not found in bulk samples, including at GRM3 and CACNA1C, an ion channel and a G-protein-coupled receptor, respectively, both classes of proteins that are classic drug targets.

Through a transcriptome-wide association study, they further identified more than 3,000 features associated with schizophrenia risk, including GRM3 and CACNA1C. Decreased expression of those genes was linked to increased risk of schizophrenia.

"GRM3 and CACNA1C have been especially alluring as schizophrenia gene targets given the druggability of the encoded G-protein-coupled receptor and ion channel, respectively," the researchers wrote.

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