Formation of brain and spinal cord requires the successful closure of neural ectoderm into an embryonic neural tube. Defects in this process result in anencephaly or spina bifida, which together constitute a leading cause of mortality and morbidity in children, affecting all ethnic and socioeconomic groups. The subject of intensive research for decades, neural tube defects (NTDs), are understood to arise from complex interactions of genes and environmental conditions, though systems-level details are still elusive. Despite the variety of underlying causes, a single intervention, folic acid supplementation given in the first gestational month, can measurably reduce the occurrence of NTDs in a population. Evidence for and the scope of gene-environment interactions in the genesis of NTDs is discussed. A systems-based approach is now possible toward studies of genetic and environmental influences underlying NTDs that will enable the assessment of individual risk and personalized optimization of prevention. Copyright © 2009 John Wiley & Sons, Inc.

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