Prediction of Short-Term Neonatal Complications in Preterm Infants Using Exome-Wide Genetic Variation and Gestational Age: A Pilot Study

BACKGROUND: Preterm birth is the leading cause of mortality and morbidity in young children with over a million deaths per year worldwide arising from neonatal complications (NC). NC are moderately heritable although the genetic causes are largely unknown. Therefore, we investigated the impact of accumulated genetic variation (burden) on NC in Non-Hispanic White (NHW) and Non-Hispanic Black (NHB) preterm infants. METHODS: We sequenced 182 exomes from infants with gestational ages from 26 to 31 weeks. These infants were cared for in the same time period and hospital environment. Eighty-one preterm infants did not develop NC, whereas 101 developed at least one severe complication. We measured the effect of burden at the single-gene and exome-wide levels, and derived a polygenic risk score (PRS) from the top 10 genes to predict NC. RESULTS: Burden across the exome was associated with NC in NHW (p=0.05) preterm infants suggesting that multiple genes influence susceptibility. In a post hoc analysis, we find that PRS alone predicts NC (AUC=0.67) and that PRS is uncorrelated with GA ([Formula: see text]; p=0.53). When PRS and GA at birth are combined, the AUC is 0.87. CONCLUSION: Our results support the hypothesis that genetic burden influences NC in NHW preterm infants.