Poster Presentation 47th Lorne Genome Conference 2026

Identifying novel targets for intervention through multi-omics studies in brain tissues of individuals with Prader-Willi syndrome (133454)

Shokouh Shahrokhi 1 2 , Michael See 1 3 , Mirana Ramialison 1 2 3 4 , Dinusha Gamage 1 , Rajvi Thakor 1 , Fernando Rossello 1 3 , Robert Nicholls 5 , Melissa Southey 6 7 , Olivia Veatch 1 8 , Waheeda Hossain 8 , Anthony Hannan 9 10 , David Amor 1 2 , Merlin Butler 8 , David Godler 1 2
  1. Murdoch Children's Research Institute, Parkville, VIC, Australia
  2. Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia
  3. reNEW Novo Nordisk Foundation Centre for Stem Cell Medicine & Stem Cell Biology, Murdoch Children's Research Institute , Parkville, VIC, Australia
  4. Monash Bioinformatics Platform, Monash University, Clayton, VIC, Australia
  5. Division of Genetic and Genomic Medicine, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
  6. Precision Medicine, School of Clinical Science at Monash Health, Monash University, Clayton, VIC, Australia
  7. Department of Anatomy and Physiology, School of Biomedical Sciences, University of Melbourne, Parkville, VIC, Australia
  8. Department of Psychiatry and Behavioural Sciences, Medical Centre, University of Kansas, Kansas, KS, USA
  9. Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
  10. Department of Anatomy and Physiology, School of Biomedical Sciences, University of Melbourne, Parkville, VIC, Australia

Introduction: Prader-Willi syndrome (PWS) is the leading cause of life-threatening obesity with learning difficulties, neuroendocrine deficits, and psychiatric problems. While it is known that the common genetic subtypes that lead to PWS are 15q11-q13 deletion (DEL) and maternal uniparental disomy (UPD), molecular mechanisms that underlie differences in clinical severity between them have not been established. To identify these mechanisms, this study performed multi-omics analyses in PWS on regions of the human cerebellum (CBL) and prefrontal cortex (PFC) that have been implicated in dysregulation of appetite control and behavioural issues in conditions other than PWS. Methods: NICHD Brain and Tissue Bank provided PFC and CBL tissues from the same eight deceased donors with PWS (four with DEL, four with UPD), and 11 deceased age- and sex-matched controls (aged 22 to 56 years). 17,705 long non-coding RNAs and 20,087 protein-coding genes were examined with bulk RNA-sequencing, and 8,146 proteins with spectrometry-based proteomics. Results: CBL showed more than 5,000 differentially expressed genes (DEGs) and 1,340 differentially expressed proteins (DEPs) for the UPD as compared to 13 DEGs and 281 DEPs for the DEL group. Moreover, the UPD group showed 5,696 DEGs and 1,934 DEPs in both brain regions as compared to only 24 DEGs and 809 DEPs for the DEL group. Top pathways dysregulated at RNA and protein levels in both brain regions of the UPD group included inflammation- and immune-related pathways. Conclusions: The UPD group showed greater dysregulation of transcriptome and proteome as compared to the DEL group in both brain regions. These differences may explain molecular mechanisms that underlie differences in clinical severity in PWS between these subtypes. These observations may lead to the identification of new targets related to inflammation for subtype-specific therapeutics based on multi-omics-driven medical care.