Gene Ontology Enrichment Analysis
None of the nominally significant genes among MA myelomeningocele subjects overlapped with the genes from the EA subjects (Table 1). However, gene ontologies from each gene set did overlap between ethnicities. GO enrichment analysis revealed that the three GO terms titled “cell-cell signaling by wnt”, “Wnt signaling pathway”, and “Signaling by Wnt” were enriched in disrupted genes from both populations. Enrichment of these broad terms were expected because the original 523 genes were retrieved using the overarching “cell-cell signaling by wnt” term. In other words, any subset of the original gene list is likely to be enriched for terms that describe the general WNT signaling pathway.
More interesting are the lower level, more specific GO terms that were enriched in both populations’ signaling pathways. These shared ontologies suggest a shared mechanism behind myelomeningocele in these two ethnicities. The clearest example is negative regulation of the canonical WNT/β-catenin component of WNT signaling. Also, myoblasts are mentioned in two different GO terms, one from each population. “WNT/β-catenin plays a crucial role in myoblast fusion” is enriched among MA genes and “myoblast differentiation” is enriched in the EA population. While these are technically two different terms, together they suggest that disrupted genes in both ethnicities may be important for myoblast function.
That said, many GO terms were only enriched in one or the other population’s disrupted gene lists. So, while some mechanisms may be shared, others may be unique to each ethnicity. The ontology terms enriched in only the MA gene list largely pertain to PCP, whereas the story is less clear for the EA ontology terms.
Another difference between populations can be seen in Fig 2B, where MA subjects tended to have more disrupted genes than EA subjects. More research is needed, but the discrepancy could help explain why the prevalence of myelomeningocele among Mexicans is higher than in non-Hispanic whites (Canfield et al., 2014).