Genetically Determined Alterations in Inflammation and Infection-Associated Genes are Associated With Hydrocephalus...

The genetic mechanisms underlying hydrocephalus (HC) risk and pathogenesis are diverse and complex. Although many human genetics studies of HC have been performed in European ancestry cohorts, the extent to which these genetic mechanisms are conserved in African ancestral populations is not known. In this study, we apply integrative human genetics and functional genomics approaches to identify genes and pathways implicated with HC risk in patients of mixed African ancestry in the US.

We performed a transcriptome-wide association study, which estimated the genetic component of gene expression, in pediatric patients of African ancestry with HC across 3288 individuals (46 cases and 3242 controls). Gene set enrichment analysis and functional genomics were performed to identify genetically determined pathways conferring HC risk and potential mechanisms of implicated genes, respectively.

After multiple-testing correction (false-discovery rate< 0.05) across all genes tested, we identified decreased TMEM208 genetic component of gene expression meeting experiment-wide statistical significance. TMEM208 met the highly stringent Bonferroni threshold for statistical-significance based on the total number of genes tested (odds ratio = 2.07, P < 5.22 × 10 -8 ) indicating that TMEM208 is a transcriptome-wide predictor of HC. Search Tool of the Retrieval of Interacting Genes/Proteins (STRING) analysis identified coexpression and protein-protein interaction networks associated with TMEM208 enriched for inflammation and infection-associated genes. Gene set enrichment analysis of all nominally associated genes ( P < .05) revealed significant associations with pathways regulating inflammatory and infection-related processes. Finally, TMEM208 was the most statistically significant gene associated with cerebrospinal fluid shunt failure and other HC-related phenotypes in our cohort.

We identified genetically determined alterations in inflammation and infection-associated genes underlying HC in patients of mixed African ancestry in the US. Coevolution of humans and pathogen-imposed selection pressures have likely differentially shaped the genetic etiology of HC across populations, but large-scale human genetics studies, experimental validation, and replication in African ancestry cohorts are needed.