Prediction of short-term neonatal complications in preterm infants using exome-wide genetic variation and gestational age: a pilot study

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 ([Formula: see text] = 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.

Figure 1:

Flow diagram of our whole-exome association study (WEAS) for NC. From a total sample of 287 preterm infants, only 182 were retained for the final analysis. Exclusion criteria included: DNA control check, multiple births and unknown race of the preterm infants.

Figure 2.

Manhattan plot of −log10 p-values obtained from the logistic regression of preterm infant status onto burden. After correcting for multiple tests , no single gene in Non-Hispanic White(left) and Non-Hispanic(right) preterm infants is statistically significant at the exome-wide level (dashed line).

Figure 3.

The exome-wide distribution of burden-based p-values by gene in Non-Hispanic White (NHW) preterm infants (left panel), and Non-Hispanic Black (NHB) preterm infants (right panel). The distribution of p-values in NHWs (n=75 SUS, n=56 RES) shows a statistically significant excess of low with p-values (p=0.05), suggesting that genetic burden influences neonatal complications in NHWs. By contrast, the distribution of p-values in NHBs (n=25 SUS, n=26 RES) is inconclusive (p=0.4).

Figure 4:

ROC curves are shown for three predictors of NC: Polygenic Risk Score(PRS) +Gestational Age (GA) (solid), GA alone(dashed), PRS alone(dotdashed), and Random (dotted), with their corresponding AUC’s 96%, 84%, 78%, and 50%, respectively. After correcting for over-fitting, the average AUC of PRS+GA dropped to 87%, and the average AUC of PRS alone dropped to 67%. The difference in predictive power between PRS+GA and PRS alone is significant (p=0.0012).