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

INTRODUCTION: Obstructive sleep apnea (OSA) is a common disorder associated with increased risk for cardiovascular disease, diabetes, and premature mortality. There is strong clinical and epi-demiologic evidence supporting the importance of genetic factors influencing OSA, but limited data implicating specific genes.

METHODS: Leveraging high depth genomic sequencing data from the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program and imputed genotype data from multiple population-based studies, we performed linkage analysis in the Cleve-land Family Study (CFS) followed by multi-stage gene-based association analyses in independent cohorts to search for rare variants contributing to OSA severity as assessed by the apnea-hypopnea index (AHI) in a total of 7,708 individuals of European ancestry.

RESULTS: Linkage analysis in CFS identified a suggestive linkage peak on chromosome 7q31 (LOD=2.31). Gene-based analysis identified 21 non-coding rare variants in Caveolin-1 (CAV1) associated with lower AHI after accounting for multiple comparisons (p=7.4×10-8). These non-coding variants together significantly contributed to the linkage evidence (p

CONCLUSION: Rare variants in CAV1, a membrane scaffolding protein essential in multiple cellular and metabolic functions, are associated with higher CAV1 gene expression and lower OSA severity, suggesting a novel target for modulating OSA severity.