Genome-wide association study reveals CBX7 as a novel susceptibility gene associated with primary spontaneous pneumothorax in the Chinese Han population

Background Primary spontaneous pneumothorax is a rare disease commonly found in young adults, with unknown aetiology. We aimed to investigate the susceptibility genes and the downstream signalling involved in the development of primary spontaneous pneumothorax. Methods We conducted the first large-scale genome-wide association study (GWAS) composed of 2223 patients and 3838 controls. The functional role of the novel susceptibility loci was investigated by both in vivo and in vitro assays. Gene expression profiling in lung epithelial cell lines was performed, and conditional gene knockout mice were generated. Results We identified four novel susceptibility loci at 14q32.2 near C14orf177 , at 15q26.3 near CHSY1 , at 16q23.1 near CFDP1 and at 22q13.1 near CBX7 . The fine-mapping of 22q13.1 revealed a functional variant which regulated CBX7 expression by disrupting the binding activity of transcription factor CREB1. Conditional knockout of Cbx7 in mouse lung epithelial cells resulted in lung cyst formation. Meanwhile, downregulation of the CBX7 elevated the expression of MMP9 and MMP16 , which are part of extracellular matrix regulators and may lead to lung injury. Conclusions Our GWAS discovered four novel susceptibility loci of primary spontaneous pneumothorax and presented a mechanistic basis for the genetic association with primary spontaneous pneumothorax. The novel susceptibility gene CBX7 and downstream MMP signalling give a new clue to the pathogenesis of primary spontaneous pneumothorax.