Targeted Genome Sequencing Identifies Multiple Rare Variants in Caveolin-1 Associated with Obstructive Sleep Apnea

Obstructive sleep apnea (OSA) is a common disorder associated with increased risk for cardiovascular disease, diabetes, and premature mortality. There is strong clinical and epidemiologic evidence supporting the importance of genetic factors influencing OSA but limited data implicating specific genes. To search for rare variants contributing to OSA severity. Leveraging high-depth genomic sequencing data from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and imputed genotype data from multiple population-based studies, we performed linkage analysis in the CFS (Cleveland Family Study), followed by multistage gene-based association analyses in independent cohorts for apnea-hypopnea index (AHI) in a total of 7,708 individuals of European ancestry. Linkage analysis in the CFS identified a suggestive linkage peak on chromosome 7q31 (LOD = 2.31). Gene-based analysis identified 21 noncoding rare variants in (Caveolin-1) associated with lower AHI after accounting for multiple comparisons ( = 7.4 × 10). These noncoding variants together significantly contributed to the linkage evidence ( < 10). Follow-up analysis revealed significant associations between these variants and increased expression, and increased expression in peripheral monocytes was associated with lower AHI ( = 0.024) and higher minimum overnight oxygen saturation ( = 0.007). Rare variants in , a membrane-scaffolding protein essential in multiple cellular and metabolic functions, are associated with higher gene expression and lower OSA severity, suggesting a novel target for modulating OSA severity.