Transcriptomic signatures in brain and blood related to cognitive and psychiatric phenotypes of Prader–Willi syndrome

TL;DR

This study identifies gene expression patterns in the brain and blood of individuals with Prader-Willi syndrome that are linked to cognitive and behavioral symptoms.

Contribution

The study reveals consistent gene dysregulation in PWS brains and links RPS18 expression in blood to cognitive and behavioral traits.

Findings

PWS brains show increased interneuron proportions and dysregulated genes across all cell types.

RPS18 is the only protein-coding gene upregulated in PWS prefrontal cortex across all comparisons.

Higher RPS18 levels in blood correlate with intellectual functioning and challenging behaviors in young PWS patients.

Abstract

This study defined gene expression changes across different cell types in prefrontal cortex (PFC) of donors with Prader-Willi syndrome (PWS) compared to controls and examined relationships between these changes in blood and PWS symptoms. 8,338 long non-coding RNAs and 17,079 protein-coding genes were examined using single-nucleus RNA-sequencing (snRNA-seq) in the PFC of 8 donors with PWS (4 deletion, 4 non-deletion), and 4 age- and sex-matched neurotypical controls. snRNA-seq analyses showed an increased proportion of interneurons in both PWS groups compared to controls. Fifty-four genes and related pathways were consistently dysregulated across all cell types in the PFC of the PWS group compared to controls, with RPS18 being the only protein-coding gene upregulated in PWS PFC across all comparisons. Increase in RPS18 mRNA levels in peripheral blood mononuclear cells (PBMCs) of another cohort (16 deletion, 20 non-deletion, ages 1–45 years) assessed using droplet digital PCR was found to be associated with intellectual functioning and challenging behaviors, but not autistic traits in children with PWS due to non-deletion (< 13 years old; N = 19). If confirmed in future studies, these findings may lead to development of prognostic biomarkers and therapeutics targeting consistently dysregulated genes and related pathways between brain and periphery.

The online version contains supplementary material available at 10.1038/s41598-025-33041-3.

Figures