Systems biology analysis of human genomes points to key pathways conferring spina bifida risk

Vanessa Aguiar-Pulido, Paul Wolujewicz, Alexander Martinez-Fundichely, Eran Elhaik, Gaurav Thareja, Alice Abdel Aleem, Nader Chalhoub, Tawny Cuykendall, Jamel Al-Zamer, Yunping Lei, Haitham El-Bashir, James M. Musser, Abdulla Al-Kaabi, Gary M. Shaw, Ekta Khurana, Karsten Suhre, Christopher E. Mason, Olivier Elemento, Richard H. Finnell, M. Elizabeth Ross

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Spina bifida (SB) is a debilitating birth defect caused by multiple gene and environment interactions. Though SB shows non-Mendelian inheritance, genetic factors contribute to an estimated 70% of cases. Nevertheless, identifying human mutations conferring SB risk is challenging due to its relative rarity, genetic heterogeneity, incomplete penetrance, and environmental influences that hamper genome-wide association studies approaches to untargeted discovery. Thus, SB genetic studies may suffer from population substructure and/or selection bias introduced by typical candidate gene searches. We report a population based, ancestry-matched whole-genome sequence analysis of SB genetic predisposition using a systems biology strategy to interrogate 298 case-control subject genomes (149 pairs). Genes that were enriched in likely gene disrupting (LGD), rare protein-coding variants were subjected to machine learning analysis to identify genes in which LGD variants occur with a different frequency in cases versus controls and so discriminate between these groups. Those genes with high discriminatory potential for SB significantly enriched pathways pertaining to carbon metabolism, inflammation, innate immunity, cytoskeletal regulation, and essential transcriptional regulation consistent with their having impact on the pathogenesis of human SB. Additionally, an interrogation of conserved noncoding sequences identified robust variant enrichment in regulatory regions of several transcription factors critical to embryonic development. This genome-wide perspective offers an effective approach to the interrogation of coding and noncoding sequence variant contributions to rare complex genetic disorders.

Original languageEnglish (US)
Article numbere2106844118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number51
StatePublished - Dec 21 2021


  • Myelomeningocele
  • Neural tube defects
  • Pathway analysis
  • Rare variant enrichment
  • Whole-genome sequence

ASJC Scopus subject areas

  • General


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