PROJECT SUMMARY Major birth defects (BDs) affect morbidity and mortality of tens of thousands of newborns annually in the US. Environmental (i.e. non-inherited) exposures or gene variants are estimated to explain about one-third of BDs that occur. Since 1996, the Iowa Center for Birth Defects Research and Prevention (CBDRP) has played a leadership role in surveillance and research of major BDs. Partnerships with the State of Iowa Department of Health and Human Services and Iowa Registry for Congenital and Inherited Disorders have allowed the Iowa CBDRP timely access to comprehensive surveillance data on deliveries to Iowa resident mothers for enrollment in the National Birth Defects Prevention Study and Birth Defects Study To Evaluate Pregnancy exposureS (BD-STEPS). Using exposure and genomic data collected, the Iowa CBDRP has made substantial contributions to understanding the etiopathogenesis of major BDs, ranging from prevalence estimates to gene- environmental interaction effects, with this work being disseminated in high-impact journals. Findings published support multifactorial inheritance patterns that vary among BDs across system groups and among BD subtypes within a system group. These findings of a heterogeneous etiopathogenesis reinforces the need to continue to investigate major BD phenotypes individually. With this application, the Iowa CBDRP proposes to continue its successful participation in BD-STEPS by timely ascertaining and classifying pregnancies with and without specific major BDs (Aim 1) and developing and evaluating novel modes of exposure data collection (Aim 2). Using data collected, the Iowa CBDRP proposes to expand the traditional epidemiology approach by integrating a multi-omics systems epidemiology approach to more fully investigate risk factors for specific major BDs (Aim 3). The traditional epidemiology approach will be used to examine associations between BD- STEPS exposure data and defects, with international datasets used to conduct confirmation analyses. The systems epidemiology approach will incorporate state-of-the-art genomic studies and machine learning analytics to improve characterization of child phenomes and exposomes and examine gene-environmental interaction effects. Concurrent with the proposed study activities will be training bachelor’s, predoctoral and postdoctoral research scholars to advance the next generation of birth defect researchers (Aim 4). The proposed research and training are not only consistent with BD-STEPS required activities (RFA-DD-23-001) but expands and innovates such activities by improved delineation of exposure pathways and genetic susceptibilities influencing development of specific major BDs. The interdisciplinary expertise of our key personnel and collaborators, along with access to rich exposure and biological data from independent populations, provides the Iowa CBDRP unique resources among all CBDRPs in disseminating novel findings in peer-reviewed publications. Findings...