Project Summary Infants born before 28 weeks of gestation are at high risk for morbidity that often persists through childhood in the form of asthma, alveolar disease, or pulmonary vascular disease. Bronchopulmonary dysplasia (BPD) is the clinical description of chronic respiratory disease that is typically defined by the need for respiratory support at 36 weeks post-menstrual age (PMA, termed “typical BPD”). This description, though, may be discordant with later outcomes, that is, approximately 60% of babies with BPD have long-term cardiorespiratory morbidity, but conversely, approximately 40% of infants without BPD have some long-term cardiorespiratory morbidity. Thus, there is an unmet need to anticipate these outcomes early in the newborn period to develop precise, mechanism- based interventions for prevention or treatment. We hypothesize that these later cardiorespiratory outcomes represent endotypes of BPD that can be defined by key mechanistically linked gene pathways (“BPD endotypes”). We have a unique opportunity to address the limitations of preceding genetic studies by leveraging several cohorts of approximately 2000 former premature children who were enrolled in prospective studies in the newborn intensive care unit (NICU), who have existing genome-wide data or DNA samples, and who are being followed at school-age and above. Through leveraging extant data obtained through the Environmental Influences on Child Health Outcomes (ECHO) program (n=~1500) and deeper phenotyping of a prospective cohort of children with echocardiography and spirometry (n=~500), we will perform what we believe will be the largest cross-cohort genetic meta-analysis that will integrate genetic networks and longitudinal data and will have the statistical power to characterize these longer-term BPD endotypes. Our overall goals are to include genetic variation and longitudinal clinical data in directed and agnostic fashions to address a critical gap by providing physiologic and genetic criteria for early diagnosis of subtypes of respiratory disease. We will use a combination of traditional genetic association approaches that focus on gene pathways rather than individual variants or genes, as well as novel gene-forward approaches that incorporate genetic pathways to inform mechanism-based BPD endotypes. As we try to move away from the concept of “typical BPD,” understanding the physiologic processes resulting in these “BPD endotypes” will permit developing personalized, mechanism-specific interventions to prevent or treat these respiratory consequences of prematurity.