Project Summary/Abstract Non-syndromic orofacial clefts are one of the most common birth defects worldwide. Genetic variation is thought to play a major role in risk of non-syndromic clefts; indeed, several genetic risk loci have been identified, to date. However, these loci cumulatively explain only part of the heritability, and for most of these loci, the specific causal variants have not yet been determined. Moreover, recent work has suggested that cleft subtypes (i.e., cleft lip alone, cleft lip with cleft palate, cleft palate alone, and subtypes defined by laterality and completeness) may have partially overlapping and partially distinct etiologies, although the shared and unshared genetic architectures of cleft subtypes are not well understood. Furthermore, maternal environmental exposures (i.e., smoking, alcohol consumption, and folate) during pregnancy are known to influence cleft risk and may interact with genetic factors as part of the underlying cleft liability. This proposal will seek to fill the gap in knowledge regarding the genetic variants and their interactions with maternal exposures leading to overt forms of clefts. This project will include analyses of existing data on our previously collected cohort comprising cases with orofacial clefts, their immediate family members, and controls with no history of clefts. We will use these data to perform genome-wide association studies and targeted gene-by-environmental interaction analyses for orofacial clefts and subtypes. Understanding the genetic architecture of orofacial clefts may ultimately lead to improved prediction of risk and recurrence, and may inform new preventive or therapeutic interventions.