Transcription Factor Binding and Individual Genetic Risk of Valproate Teratogenicity

BACKGROUND AND OBJECTIVES: Valproate (VPA) use during pregnancy is associated with a wide range of structural birth defects, but not all exposed children are affected and there is evidence for a genetic predisposition. The development of a pharmacogenomic biomarker test that can be used for preconception counseling, allowing access to women unnecessarily denied VPA treatment because of concern about teratogenic risks if they were to become pregnant, is challenged by a poor understanding of how variation in maternal DNA could modify the risk. We hypothesized that genomic variants that affect the binding affinity of transcription factors (TFs), key regulators of gene expression, are integral to VPA-associated teratogenicity and a plausible explanation for both variance in interindividual risk and the wide range of birth defect types. METHODS: We interrogated genomic variants within maternal exomes from women recruited through international epilepsy pregnancy registries and genomics consortia. We applied a network-based approach that contextualized the variant spectra to genes associated with diverse birth defect types, gene burden tests, and evidence from multiple modalities to identify variant-sensitive TFs. RESULTS: -TF interactions. DISCUSSION: related gene regulation is a teratogenic mechanism that is common to heterogeneous birth defect types and sensitive to genetic variation. This has implications for the development of pharmacogenomic risk biomarkers and safer drugs for women of childbearing potential.