Novel susceptibility genes for sleep apnea revealed by a cross-tissue transcriptome-wide association study.

Sleep apnea (SA) is a sleep disorder characterized by frequent interruptions in breathing during sleep and is widely recognized as a significant global public health concern. Although genome-wide association studies (GWAS) have identified several loci associated with SA susceptibility, the underlying genes and biological mechanisms remain largely unknown. A cross-tissue transcriptome-wide association study (TWAS) was performed to integrate SA GWAS summary statistics from 410,385 individuals (43,901 cases and 366,484 controls) and gene expression data from 49 distinct tissues and obtained from 838 post-mortem donors. Functional Summary-based Imputation was employed to validate these findings in whole blood tissue. Additionally, candidate susceptibility genes were further verified using Gene Analysis combined with Multi-marker Analysis of Genomic Annotation. Subsequent Mendelian randomization and colocalization analyses were conducted. In the cross-tissue TWAS analysis, 60 susceptibility genes were identified. Two novel susceptibility genes, GPD2 and L3MBTL2, were validated through both single tissue TWAS and MAGMA analysis. Mitochondrial glycerophosphate dehydrogenase (GPD2) may reduce the SA risk by regulating energy metabolism, while Lethal (3) malignant brain tumor-like protein 2 (L3MBTL2) may increase the risk of SA by disturbing DNA damage repair pathway and by regulating the process of the cell cycle. In summary, two novel biological macromolecules were identified in our study whose expression was predicted to be associated with SA risk, providing new insight into the genetic basis of this condition.