Abstract: Background：Many previous studies have been conducted on risk genes for bronchopulmonary dysplasia (BPD), but the phenotypic variation among studies is large, making it difficult to be used as a genetic risk for BPD in respiratory distress syndrome (RDS). Objective：To identify genetic risk factors for RDS complicated by BPD and to clarify the impact of genetic factors on the prognosis of children with RDS. Design：A retrospective nested casecontrol study. Methods：Children with clinically confirmed RDS who were hospitalized at the Children's Hospital of Fudan University from January 1, 2016, to August 1, 2021, were included and divided into BPD and nonBPD groups based on whether they had concomitant BPD. A propensity scoring strategy was used to balance the gestational age of the two groups, and rarevariant association analysis and functional enrichment analysis were used to explore the biological process of rare variant gene enrichment and to screen for candidate risk genes with significantly more damaging variants in the BPD group. Gene expression data were retrieved from the GEO database, and time series analysis of gene expression patterns was performed to verify the expression characteristics of the high variant burden genes in this paper. Main outcome measures：Genetic risk factors for RDS complicated by BPD. Results：There were 111 cases in the BPD group and 157 cases in the nonBPD group, and the differences of gestational age in the two groups were not statistically significant. Based on 1,558 biological processes of 2 742 significantly enriched background genes (P<0.01), the most significantly enriched gene set for proteintruncating variants was associated with regulation of protein kinase activity (P=0.011), and the largest total number of genes carrying proteintruncating variants in the BPD group was for cation transmembrane transportrelated genes (P=0.027). The set of most significantly enriched genes for missense or nonsynonymous variants was associated with the developmental growth (P=0.001). Twenty-six genes in the BPD group had a significantly higher burden of missense or nonsynonymous variants than that of the nonBPD group (P<0.05), with three genes (ARSB, B9D2 and UVSSA) having high statistical significance (P<0.01). ARSB was significantly downexpressed in severe BPD as verified by GEO database data (P<0.001), and time series analysis revealed a significantly different expression pattern of ARSB genes in neonates with severe BPD compared to neonates without BPD or with mild BPD (P<0.01). Conclusion：ARSB is a risk genetic factor for RDS complicated by BPD.

Key words: Bronchopulmonary dysplasia, Respiratory distress syndrome, Rare-variant association analysis