A Genetic Signature of Spina Bifida Risk from Pathway-Informed Comprehensive Gene-Variant Analysis

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.

Nutritional Control of Epigenetic Processes in Yeast and Human Cells

“…If histone methylation perturbation were the cause of NTDs, the common A222V allele of MTHFR might cause altered histone methylation. A more comprehensive evaluation of genetic variants of all genes affecting folate metabolism has provided a stronger link to NTDs than previously reported and is also consistent with a mechanism rooted in chromatin modification (Marini et al 2011).…”

Association between MTHFR polymorphisms and orofacial clefts risk: A meta‐analysis

“…Last, but not least, between‐study heterogeneity, which must be considered with attention, existed in both overall and subgroup analyses. The heterogeneity among individual studies, as we mentioned above, had various origins, among which the ethnic variations might play a crucial role as differences in folic acid pathway risk profiles have recently been reported between Hispanics and non‐Hispanic whites (Marini et al,2011), but we could not separate Hispanics out for most of the included studies that barely distinguished between these two ethnic groups.…”

Association between MTHFD1 polymorphisms and neural tube defect susceptibility

“…In our meta-analysis, we extracted data from 9 relevant articles [1,[8][9][10][15][16][17][18][19]; they were all selected through a pre-specified search strategy. Quality assessment for the overall studies was shown with a bar graph according to the Newcastle-Ottawa Scale tool in Fig.…”

“…Neural tube defect (NTD) is among the most common and deadly human congenital malformations at birth and manifested as a wide range of phenotypes, primarily including anencephaly, spina bifida and encephalocele which result from failure of the neural tube to close properly in the developing brain or lower spine [1,2]. The incidence rate of NTD is about 0.2% worldwide, but this rate varies in different races and sections with a conspicuous diversity which may be a result of genetic diversity [3].…”