Abstract
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 (NCs). NCs are moderately heritable although the genetic causes are largely unknown. Therefore, we investigated the impact of accumulated genetic variation (burden) on NCs 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 NCs, 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 NCs.
Results
Burden across the exome was associated with NCs in NHW (p = 0.05) preterm infants suggesting that multiple genes influence susceptibility. In a post hoc analysis, we find that PRS alone predicts NCs (AUC = 0.67) and that PRS is uncorrelated with GA (\(\widehat {\it{\rho }}\) = 0.05; p = 0.53). When PRS and GA at birth are combined, the AUC is 0.87.
Conclusions
Our results support the hypothesis that genetic burden influences NCs in NHW preterm infants.
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Acknowledgements
WES was performed by the Biomedical Genomics Core in The Research Institute at Nationwide Children’s Hospital. We thank the participants and their families for their involvement in this study, the Ohio Perinatal Research Network (OPRN) for recruiting preterm infants, and Dr. Will C. Ray for his help in editing the manuscript. We are also grateful to Andrew M Corris, Senior Licensing Associate, who provided professional advice concerning the patentability of various aspects of this research. This work was supported by the Abigail Wexner Research Institute at Nationwide Children’s Hospital and the Center for Clinical and Translational Science CTSA Grant UL1TR002733.
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All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data. W.C.L.S. and K.M.G. drafted the article, and P.W., B.K., M.K., I.A.B., and L.D.N. revised it critically for important intellectual content. All authors gave final approval of the version to be published.
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Stewart, W.C.L., Gnona, K.M., White, P. et al. Prediction of short-term neonatal complications in preterm infants using exome-wide genetic variation and gestational age: a pilot study. Pediatr Res 88, 653–660 (2020). https://doi.org/10.1038/s41390-020-0796-7
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DOI: https://doi.org/10.1038/s41390-020-0796-7
