Prematurity associated with singleton pregnancies remains high in the U.S., and well above rates in other developed countries. Moreover, there are significant racial/ethnic disparities in the incidence of premature birth, with African Americans experiencing a disproportionate number of preterm births compared to European Americans. The focus of the proposed research is on the genetics of preterm premature rupture of membranes (PPROM), the leading identifiable cause of preterm birth. We hypothesize that genetics plays into the prematurity in three different ways: 1) There are alleles that predispose to preterm birth in all populations, probably as a result of gene-environment interactions, and those environmental factors may be more prevalent in African American communities; 2) There are alleles of African ancestry that confer greater risk to African Americans, again probably interacting with environmental factors; and 3) Admixture of European ancestry risk alleles into the African ancestry genome confers risk that disproportionately affects African Americans, possibly again because of environmental interactions. Our past work identified examples of two of these mechanisms (1 & 2), and our preliminary described below provides strong support for the third (3). The three Specific Aims proposed in this application will test the above-noted hypothesis and provide a much-needed objective approach to identifying prematurity genes that contribute to ethnic/racial disparities. Specific Aim 1: To identify genetic variants by exome sequencing of chromosome 21 genes from PPROM cases (fetal/neonates) and controls. Specific Aim 2: To test variants identified in Specific Aim 1 for PPROM linkage in the presence of association using the transmission disequilibrium test (TDT). Specific Aim 3: To identify genetic variants on chromosomes 2 and 11 using exome sequencing of regions identified as carrying African ancestry risk alleles.