Language
English
Publication Date
11-15-2022
Journal
American Journal of Respiratory and Critical Care Medicine
DOI
10.1164/rccm.202203-0618OC
PMID
35822943
PMCID
PMC9746833
PubMedCentral® Posted Date
7-13-2022
PubMedCentral® Full Text Version
Post-print
Abstract
Rationale: 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.
Objectives: To search for rare variants contributing to OSA severity.
Methods: 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.
Measurements and Main Results: 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 CAV1 (Caveolin-1) associated with lower AHI after accounting for multiple comparisons (P = 7.4 × 10-8). These noncoding variants together significantly contributed to the linkage evidence (P < 10-3). Follow-up analysis revealed significant associations between these variants and increased CAV1 expression, and increased CAV1 expression in peripheral monocytes was associated with lower AHI (P = 0.024) and higher minimum overnight oxygen saturation (P = 0.007).
Conclusions: 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.
Keywords
Humans, Caveolin 1, Sleep Apnea, Obstructive, Sequence Analysis, DNA, High-Throughput Nucleotide Sequencing, obstructive sleep apnea, caveolin-1, apnea–hypopnea index, genetic association analysis, rare variants
Published Open-Access
yes
Recommended Citation
Liang, Jingjing; Wang, Heming; Cade, Brian E; et al., "Targeted Genome Sequencing Identifies Multiple Rare Variants in Caveolin-1 Associated with Obstructive Sleep Apnea" (2022). Faculty and Staff Publications. 4257.
https://digitalcommons.library.tmc.edu/baylor_docs/4257