Multi-omic analysis achieves high diagnostic yield and identifies accelerated biological aging in paediatric congenital heart disease and neurodevelopmental disorders

Overview

This repository contains the computational analysis code for our multi-omic study investigating the genetic and epigenetic factors contributing to the co-occurrence of neurodevelopmental disorders (NDD) and congenital heart disease (CHD).

Study Design

• Cohort: 14 trios and 1 duo (probands with NDD and/or CHD plus biological parents)
• Data types:
  • Whole genome sequencing (WGS)
  • RNA sequencing (subset of 10 trios)
  • DNA methylation arrays (all 15 families)
• Key findings:
  • 64% diagnostic yield from genetic variants
  • Dramatic epigenetic age acceleration in CHD patients (~17 years)
  • Methylation dysregulation in specific patients

Analysis Scripts

DNA Methylation Analysis

• dmr_analysis.r - Identifies differentially methylated probes in study probands compared to control samples from GEO
• epigenetic_age_analysis.r - Calculates epigenetic age using Hannum clock and identifies age acceleration
• methylation_pathway_analysis.r - Collapses CpG sites into differentially methylated regions (DMRs) and performs GO enrichment analysis

Genetic Variant Analysis

• splicing_validation.py - Validates splice-affecting variants using RNA-seq junction analysis with inheritance awareness
• mae_analysis.sh - Monoallelic expression (MAE) analysis pipeline for identifying parent-of-origin expression bias
• prs_pipeline_pgs-calc.sh - Calculates polygenic risk scores for neurodevelopmental and psychiatric traits using pgsc_calc

Citation

If you use this code, please cite:

Thompson JM, Gao Y, Iwasawa E, et al. Multi-omic analysis achieves high diagnostic yield and identifies accelerated biological aging in paediatric congenital heart disease and neurodevelopmental disorders. [Journal] 2025; [details to be added upon publication]

License

This project is licensed under the CC License - see the LICENSE file for details.

Contact

For questions about the code or analysis:

• Jamie-Lee Thompson: [email protected]

For questions about the study or data access:

• David Winlaw: [email protected]
• Eleni Giannoulatou: [email protected]

Acknowledgments

• Victor Chang Cardiac Research Institute
• Cincinnati Children's Hospital Medical Center
• The families who participated in this study