Multiomic investigation of shared genetic pathways in paediatric congenital heart disease and neurodevelopmental disorders

Overview

This repository contains the computational analysis code for our multiomic 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 (15 trios)
• Key findings:
  • 57% P/LP detection rate from genetic variants
  • Epigenetic age acceleration in CHD patients
  • 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

• mae_analysis.sh - Monoallelic expression 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, J. M., Gao, Y., Iwasawa, E., Das, D., Rath, E., Troup, M., Humphreys, D. T., Heydarian, H., Anixt, J., Kasparian, N. A., Froehlich, T. E., Tchieu, J., Weaver, K. N., Congenital Heart Disease Synergy Study Group, Kirk, E. P., Dale, R., Dunwoodie, S. L., Winlaw, D. S., & Giannoulatou, E. (2026). Multiomic investigation of shared genetic pathways in paediatric congenital heart disease and neurodevelopmental disorders. Human Mutation, 2026, 7869246. https://doi.org/10.1155/humu/7869246

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: j.thompson@victorchang.edu.au

For questions about the study or data access:

• David Winlaw: david.winlaw@northwestern.edu
• Eleni Giannoulatou: e.giannoulatou@victorchang.edu.au

Acknowledgments

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