Rare-variant collapsing analyses identified risk genes for neonatal acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) could account for a considerable proportion of neonatal death, while the genetic etiology and pathophysiology of neonatal ARDS remain elusive. In this case-control study, 515 neonates were enrolled in the China Neonatal Genomes Project (CNGP, NCT03931707) from August 2016 to June 2021, including 196 ARDS and 319 non-ARDS matched by sex, gestational age, birth weight, perinatal asphyxia, pneumonia, sepsis, and necrotizing enterocolitis. Clinical exome sequencing was used to detect genetic variants. Collapsing analyses together with permutation tests were used to identify ARDS risk genes enriched for rare variants in ARDS samples. In silico functional interaction analysis and expression pattern studies at different stages of lung development were used to investigate the biological functions of the risk genes.

Collapsing analyses identified that rare variants were significantly abundant in the genes associated with the precursor of the lamellar body and there were eight predicted risk genes with strong confidence (P < 0.01). Among them, the expression of EDNRB increased significantly in lung development and was up-regulated in ARDS (P < 0.05). In addition, 151 predicted transcriptional target proteins of EDNRB were highly enriched in the lamellar body responsible for pulmonary surfactant storage and secretion.

In our study, the genes associated with pulmonary surfactant storage and release were highly enriched with rare variants. A novel neonatal ARDS risk gene EDNRB may be a key gene for neonatal lung development and pulmonary surfactant homeostasis. Additional validation in independent patient populations and further exploration of underlying molecular mechanisms are warranted.