Study of Neural Tube Defects Etiology: Genome and Exposome

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DESCRIPTION (provided by applicant): Gene-environment interactions (GEI) play a critical role in the etiology of neural tube defect (NTDs). Definitive conclusions regarding the association amongst environmental exposures, genetic factors and NTD risk have been hampered by the rarity of this outcome (e.g., <1/1000 births in the US), and differences in exposure assessment between studies, as well as adherence to overly simplistic etiological models. It is now appreciated that the toxic effects of environmental exposures are mediated by chemicals that alter critical molecules, cells, and physiological processes inside the human body. In the proposed research project, we intend to explore the maternal and embryonic exposomes, i.e., the internal chemical environment in NTD etiology by measuring relevant analytes and biomarkers using biological samples and data collected through an established infrastructure in an area known for its high NTD rate (~10/1000 live birth), extremely heavy pollution, and poor nutritional status in Shanxi Province, China. To identify the human gene(s) that predispose the embryo to a neural tube closure failure during embryonic development has been challenging. Hypothesis-driven candidate gene studies were not successful in identifying common variants that may be predictive for NTD risk. Re-sequencing of a limited number of candidate genes has yielded few genetic variants, although none of these variants alone is a robust predictor of human NTDs. This leads us to postulate that NTDs, like other complex diseases, may arise from combinatorial effects of rare variants. We propose to use next-generation sequencing technologies to screen the complete protein coding regions on the genome (the exome). We anticipate the yield of a spectrum of gene variants including single nucleotide variations (SNV), insertion/deletion (Indel) and structural variations (SV) that contribute to the expression of NTDs. The results of our studies will help defining the relationships among maternal exposure, maternal nutrition, immune responses, maternal/embryonic genetics, and NTD risk. Moreover, the biological sample and data bank will allow us to continuously explore the genome and exposome of NTDs as our toolkit of investigation continues to mature. Exposure and genetic markers will be identified through our effort. The information derived from these studies could provide the foundation for population-based or targeted, exposure-based and genotype-based risk-assessment strategies.