Abstract
Despite compelling epidemiological evidence that folic acid supplements reduce the frequency of neural tube defects (NTDs) in newborns, common variant association studies with folate metabolism genes have failed to explain the majority of NTD risk. The contribution of rare alleles as well as genetic interactions within the folate pathway have not been extensively studied in the context of NTDs. Thus, we sequenced the exons in 31 folate-related genes in a 480-member NTD case-control population to identify the full spectrum of allelic variation and determine whether rare alleles or obvious genetic interactions within this pathway affect NTD risk. We constructed a pathway model, predetermined independent of the data, which grouped genes into coherent sets reflecting the distinct metabolic compartments in the folate/one-carbon pathway (purine synthesis, pyrimidine synthesis, and homocysteine recycling to methionine). By integrating multiple variants based on these groupings, we uncovered two provocative, complex genetic risk signatures. Interestingly, these signatures differed by race/ethnicity: a Hispanic risk profile pointed to alterations in purine biosynthesis, whereas that in non-Hispanic whites implicated homocysteine metabolism. In contrast, parallel analyses that focused on individual alleles, or individual genes, as the units by which to assign risk revealed no compelling associations. These results suggest that the ability to layer pathway relationships onto clinical variant data can be uniquely informative for identifying genetic risk as well as for generating mechanistic hypotheses. Furthermore, the identification of ethnic-specific risk signatures for spina bifida resonated with epidemiological data suggesting that the underlying pathogenesis may differ between Hispanic and non-Hispanic groups.
Highlights
Neural tube defects (NTDs) are common, costly, and deadly human congenital anomalies whose causes remain largely unknown
Our goal was to identify the full spectrum of allelic variation in folate pathway genes and determine whether rare alleles, combinations of alleles, or obvious genetic interactions within this pathway conferred NTD risk, spina bifida
Folate Pathway Sequencing in NTD Cases and Controls We sequenced the coding regions of 31 genes in the folatehomocysteine metabolic pathway, comprising 430 coding exons, in 239 newborns with spina bifida and 241 non-malformed controls
Summary
Neural tube defects (NTDs) are common, costly, and deadly human congenital anomalies whose causes remain largely unknown. And spina bifida are the most common forms of NTDs and result from failure of the neural tube to close properly in the developing brain or lower spine, respectively. Maternal use of anticonvulsants or other folic acid antagonist medications increases the occurrence of NTDs in offspring [6]. Taken together, these observations suggest that folic acid supplementation prevents NTDs by compensating for susceptibilities in folate transport, metabolism, or utilization.
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