Abstract
BackgroundPrevious studies have identified genetic variants associated with bronchopulmonary dysplasia (BPD) in extremely preterm infants. However, findings with genome-wide significance have been rare, and not replicated. We hypothesized that whole exome sequencing (WES) of premature subjects with extremely divergent phenotypic outcomes could facilitate the identification of genetic variants or gene networks contributing disease risk.ResultsThe Prematurity and Respiratory Outcomes Program (PROP) recruited a cohort of > 765 extremely preterm infants for the identification of markers of respiratory morbidity. We completed WES on 146 PROP subjects (85 affected, 61 unaffected) representing extreme phenotypes of early respiratory morbidity. We tested for association between disease status and individual common variants, screened for rare variants exclusive to either affected or unaffected subjects, and tested the combined association of variants across gene loci. Pathway analysis was performed and disease-related expression patterns were assessed. Marginal association with BPD was observed for numerous common and rare variants. We identified 345 genes with variants unique to BPD-affected preterm subjects, and 292 genes with variants unique to our unaffected preterm subjects. Of these unique variants, 28 (19 in the affected cohort and 9 in unaffected cohort) replicate a prior WES study of BPD-associated variants. Pathway analysis of sets of variants, informed by disease-related gene expression, implicated protein kinase A, MAPK and Neuregulin/epidermal growth factor receptor signaling.ConclusionsWe identified novel genes and associated pathways that may play an important role in susceptibility/resilience for the development of lung disease in preterm infants.
Highlights
Previous studies have identified genetic variants associated with bronchopulmonary dysplasia (BPD) in extremely preterm infants
We hypothesized that whole exome sequencing of subjects with extreme phenotypic outcomes would be more likely to enrich for common and rare deleterious and protective genetic variants that contribute to disease risk, and we utilized several analytic approaches with differing assumptions to identify signals that may contribute to the risk for Bronchopulmonary dysplasia (BPD)
Common variants We first assessed the association between common variants, as defined as a minor allele frequency (MAF) > 0.05, and BPD using Efficient Mixed-Model Association eXpedited (EMMAX) while adjusting for gestational age, sex, population stratification, and relatedness between siblings (Fig. 2a and Additional file 2: Table S2)
Summary
Previous studies have identified genetic variants associated with bronchopulmonary dysplasia (BPD) in extremely preterm infants. Reasoning that variants that would contribute to BPD would be under negative selection pressure, Li et al performed exome sequencing and identified extremely rare variants and associated networks of genes that were unique to the cohort with BPD [13]. As an initial step in identifying genes that might be contributing to adverse short-term outcomes in this population, and because we have access to high-resolution phenotype definition in this cohort, we performed exome sequencing on a subset of infants with BPD phenotypes at the extremes of disease severity. We hypothesized that whole exome sequencing of subjects with extreme phenotypic outcomes would be more likely to enrich for common and rare deleterious and protective genetic variants that contribute to disease risk, and we utilized several analytic approaches with differing assumptions to identify signals that may contribute to the risk for BPD
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