PROJECT SUMMARY Anotia/microtia is a birth defect characterized by an absent or hypoplastic external ear; it is estimated that >80,000 Americans are living with this condition, which causes significant hearing loss in >75% of affected individuals. This study will identify social/environmental and genetic drivers of anotia/microtia, with an emphasis on addressing health disparities for Hispanic/Latinx populations. Notably, the birth prevalence of anotia/microtia is increased in Hispanic relative to non-Hispanic white populations, but Hispanic infants are less likely to be diagnosed with an anotia/microtia syndrome than their non-Hispanic white peers. This study will use a three-part approach. First, by leveraging data on >10 million live births and >3,500 cases with anotia/microtia from population-based birth defects registries in California and Texas, it will evaluate the extent to which sociodemographic factors explain differences in the birth prevalence of anotia/microtia syndromes between Hispanic and non-Hispanic populations. Second, using an ancestry-aware genome-wide association method (Tractor), archived biospecimens from the California Biobank Program and National Birth Defects Prevention Study, and publicly available whole-genome sequencing data from the Gabriella Miller Kids First Pediatric Research Initiative, it will identify genetic variants associated with anotia/microtia in Hispanic and non-Hispanic individuals. Next, it will apply a rigorous machine learning technique to data from the National Birth Defects Prevention Study (N=699 cases with anotia/microtia and >10,000 controls without birth defects) to identify maternal exposures associated with anotia/microtia in Hispanic and non-Hispanic populations. Finally, it will perform an integrative assessment of the role of sociodemographic, genetic, and maternal factors in determining risk for anotia/microtia. In accomplishing these objectives, the study will: identify drivers of disparities in anotia/microtia among Hispanic populations; shed light on the etiology of anotia/microtia in diverse populations by characterizing genetic variants associated with this disease, which will be targets for future investigation; and identify potentially modifiable maternal exposures that could be used to facilitate prevention.