Regional heterogeneity in gene expression, regulation and coherence in hippocampus and dorsolateral prefrontal cortex across development and in schizophrenia

Abstract

Recent large-scale genomics efforts have better characterized the molecular correlates of schizophrenia in postmortem human neocortex, but not hippocampus which is a brain region prominently implicated in its pathogenesis. Here in the second phase of the BrainSeq Consortium (Phase II), we have generated RiboZero RNA-seq data for 900 samples across both the dorsolateral prefrontal cortex (DLPFC) and the hippocampus (HIPPO) for 551 individuals (286 affected by schizophrenia disorder: SCZD). We identify substantial regional differences in gene expression, in both pre-and post-natal life, and find widespread differences in how genes are regulated across development. By extending quality surrogate variable analysis (qSVA) to multiple brain regions, we identified 48 and 245 differentially expressed genes (DEG) by SCZD diagnosis (FDR<5%) in HIPPO and DLPFC, respectively, with surprisingly minimal overlap in DEG between the two brain regions. We further identified 205,618 brain region-dependent eQTLs (FDR<1%) and found that 124 GWAS risk loci contain eQTLs in at least one of the regions. We also identify potential molecular correlates of in vivo evidence of altered prefrontal-hippocampal functional coherence in schizophrenia. These results underscore the complexity and regional heterogeneity of the transcriptional correlates of schizophrenia, and suggest future schizophrenia therapeutics may need to target molecular pathologies localized to specific brain regions. Main text

Cell type-specific genetic regulation of expression in the granule cell layer of the human dentate gyrus

“…We lastly explored unique illness state-associated gene expression differences in the DG-GCL compared to the bulk hippocampus. Our previous work suggested that the hippocampus had fewer genes differentially expressed in samples from patients with schizophrenia compared to genes differentially expressed between patients and controls in the DLPFC (both using ribosomal-depletion sequencing methods) 9 . In the DG-GCL, we similarly found relatively small numbers of genes associated with diagnosis, particularly compared to aging and eQTL effects.…”

“…GRM3) are classic therapeutic drug targets and eQTLs for these genes in bulk tissue have been elusive. We explored the tissue specificity of these eQTLs using the BrainSeq DLPFC 8,9 , CommonMind Consortium DLPFC 3 and GTEx 5 bulk tissue projects. The GWAS index SNP that associated with GRM3 expression (rs12704290) was not significantly associated with any expression features in the BrainSeq or CommonMind Consortium DLPFC, or GTEx datasets across any brain region or body tissue.…”

“…We have previously identified extensive gene expression associations in human brain with schizophrenia and its genetic risk 7 , development/aging, and local genetic variation in the dorsolateral prefrontal cortex (DLPFC) 8 and more recently, the hippocampal formation (HIPPO) 9 . While eQTLs in these two brain regions were highly overlapping, consistent with previous work across many tissues in the body 6 , there were distinct region-specific expression profiles associated with brain development and subsequently dysregulated in schizophrenia.…”

“…We further identified stronger effects of schizophrenia diagnosis in the DLPFC compared to HIPPO, with an order of magnitude more genes differentially expressed. While these differences in signatures across brain regions likely related to the unique cell types underlying each region, particularly for changes across development 9 , the specific cell types in which these signals act within and across brain regions is largely unknown.…”

“…However, many of the previous findings linking this important cell type to these debilitating disorders have been based on animal models 21 , induced pluripotent stem cell (iPSC)-based approaches 22 , or low-resolution functional imaging [23][24][25] . We additionally selected this cell population to permit direct comparisons to bulk HIPPO RNA-seq data from a largely overlapping set of individuals 9 .…”