Genetically determined alterations in inflammation and infection-associated genes are associated with hydrocephalus in patients of African Ancestry

Background and ObjectivesThe genetic mechanisms underlying hydrocephalus (HC) risk and pathogenesis are diverse and complex. While many human genetics studies of HC have been performed in largely European ancestry patients, the extent to which these genetic mechanisms are conserved in African ancestry populations is not known. Here we apply complementary and convergent human genetics and functional genomics approaches to identify genes and pathways implicated with HC risk in patients of African ancestry. MethodsWe perform a transcriptome-wide association study (TWAS) in pediatric patients of African ancestry with HC across 3,288 individuals (46 cases and 3,242 controls). Gene set enrichment analysis (GSEA) and functional genomics were performed to identify genetically determined pathways conferring HC risk and potential mechanisms of implicated genes, respectively. ResultsAfter multiple-testing correction (false discovery rate< 0.05) across all genes tested, we identify decreased expression of TMEM208 meeting experiment-wide statistical significance. TMEM208 met the highly stringent Bonferroni threshold for statistical-significance based on the total number of genes tested (OR= 2.07, p< 5.22x10-8) indicating that TMEM208 is a transcriptome-wide predictor of HC. STRING analysis identified co-expression and protein-protein interaction networks associated with TMEM208 enriched for infection and inflammation-associated genes, providing the basis for mechanistic, hypothesis-driven experiments to delineate the role of this gene in conferring HC risk. Finally, GSEA of all nominally associated genes (p< 0.05) revealed a marked association with genes regulating inflammatory and infection-related processes. ConclusionsWe perform the first systematic genetic study of HC in patients of African ancestry. We identify genetically determined alterations in inflammation and infection-associated genes underlying hydrocephalus in patients of African ancestry. Co-evolution of humans and pathogen-imposed selection pressures have differentially shaped the genetic etiology of HC across ancestral populations.