TY - JOUR T1 - Systems Biology Analysis of Human Genomes Points to Key Pathways Conferring Spina Bifida Risk JF - bioRxiv DO - 10.1101/2021.07.02.450913 SP - 2021.07.02.450913 AU - Vanessa Aguiar-Pulido AU - Paul Wolujewicz AU - Alexander Martinez-Fundichely AU - Eran Elhaik AU - Gaurav Thareja AU - Alice AbdelAleem AU - Nader Chalhoub AU - Tawny Cuykendall AU - Jamel Al-Zamer AU - Yunping Lei AU - Haitham El-Bashir AU - James M. Musser AU - Abdulla Al-Kaabi AU - Gary M. Shaw AU - Ekta Khurana AU - Karsten Suhre AU - Christopher E. Mason AU - Olivier Elemento AU - Richard H. Finnell AU - M. Elizabeth Ross Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/07/04/2021.07.02.450913.abstract N2 - 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 GWAS 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 vs. 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, indicating their impact on the pathogenesis of human SB. Additionally, interrogation of conserved non-coding 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 interrogation of coding and non-coding sequence variant contributions to rare complex genetic disorders.Competing Interest StatementDr. Finnell formerly held a leadership position with the now dissolved TeratOmic Consulting LLC. He also receives travel funds to attend editorial board meetings of the Journal of Reproductive and Developmental Medicine published out of the Red Hospital of Fudan University. Dr. Elhaik consults for the DNA Diagnostics Center (DDC). The remaining authors have no competing interests. ER -