Variant-risk-exon interplay impacts circadian rhythm and dopamine signaling pathway in severe psychiatric disorders

Abstract

In psychiatric disorders, common and rare genetic variants cause widespread dysfunction of cells and their interactions, especially in the prefrontal cortex, giving rise to psychiatric symptoms. To better understand these processes, we traced the effects of common and rare genetics, and cumulative disease risk scores, to their molecular footprints in human cortical single-cell types. We demonstrated that examining gene expression at single-exon resolution is crucial for understanding the cortical dysregulation associated with diagnosis and genetic risk derived from common variants. We then used disease risk scores to identify a core set of genes that serve as a footprint of common and rare variants in the cortex. Pathways enriched in these genes indicated impaired cell-cell interactions and neuronal activity in psychopathology. With single-nuclei-RNA-sequencing, we pinpointed these effects to inhibitory cortical neurons and oligodendrocyte progenitors, two cell-types that closely interact. This constitutes a clear cellular target for new treatments for psychiatric disorders.

Contrasting genetic predisposition and diagnosis in psychiatric disorders: a multi-omic single-nucleus analysis of the human orbitofrontal cortex

“…Although previous research has identified numerous genes associated with disorders such as schizophrenia, the direction of effects and overlap with GWAS findings often vary, indicating a complex relationship between gene expression changes and genetic susceptibility 16,17 . Transcriptome-wide association studies (TWAS), expression quantitative trait loci (eQTL) and eQTScore (association analyses between PRS and gene expression) analyses have further bridged the gap between GWAS findings and gene expression data 9,16,18,19 . These integrative approaches provide insights into how the identified GWAS variants can influence gene expression, thereby contributing to the pathophysiology and a more nuanced understanding of psychiatric disorders 20 .…”

“…Genetic correlation analyses have unveiled distinct interconnected clusters among these disorders, indicating their interconnected nature and underscoring the genetic overlap between mood and psychotic disorders 5 . This shared genetic architecture has been the focus of extensive research [6][7][8][9][10] . Genome-wide association studies (GWAS) have significantly advanced our understanding of the genetic architecture of psychiatric disorders, uncovering numerous significant genetic variants 5,[11][12][13] .…”

“…Additionally, Hauberg et al observed considerable variability in chromatin accessibility across cell types in different cortical regions, revealing that such diversity may obscure cell type-specific effects in aggregate studies, thereby underscoring the intricate complexities of epigenetic regulation 22 . The etiology of psychiatric disorders is notably complex, involving diverse molecular, cellular, and structural alterations across various regions of the human brain, such as the prefrontal cortex, which plays a crucial role in higher cognitive functions and has been linked to various psychiatric conditions 9,[11][12][13]16,[23][24][25][26] . Structural and functional abnormalities in areas like the orbitofrontal cortex (OFC), a key component of the ventral prefrontal cortex, have been widely reported in many psychiatric disorders 27 .…”