03348nas a2200541 4500008004100000022001400041245012000055210006900175260001600244520177900260100002002039700001702059700001902076700002502095700001702120700001502137700002002152700002002172700001402192700002402206700002102230700001702251700002002268700001702288700002202305700002202327700002202349700002802371700002002399700001902419700001802438700002102456700002002477700002302497700002102520700001602541700001702557700002002574700002702594700002102621700002102642700002202663700001702685700001902702700001802721710003102739856003602770 2022 eng d a1535-497000aTargeted Genome Sequencing Identifies Multiple Rare Variants in Caveolin-1 Associated with Obstructive Sleep Apnea.0 aTargeted Genome Sequencing Identifies Multiple Rare Variants in c2022 Jul 133 a
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<10-3). Follow-up anal-ysis 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).
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.
1 aLiang, Jingjing1 aWang, Heming1 aCade, Brian, E1 aKurniansyah, Nuzulul1 aHe, Karen, Y1 aLee, Jiwon1 aSands, Scott, A1 aBrody, Jennifer1 aChen, Han1 aGottlieb, Daniel, J1 aEvans, Daniel, S1 aGuo, Xiuqing1 aGharib, Sina, A1 aHale, Lauren1 aHillman, David, R1 aLutsey, Pamela, L1 aMukherjee, Sutapa1 aOchs-Balcom, Heather, M1 aPalmer, Lyle, J1 aPurcell, Shaun1 aSaxena, Richa1 aPatel, Sanjay, R1 aStone, Katie, L1 aTranah, Gregory, J1 aBoerwinkle, Eric1 aLin, Xihong1 aLiu, Yongmei1 aPsaty, Bruce, M1 aVasan, Ramachandran, S1 aManichaikul, Ani1 aRich, Stephen, S1 aRotter, Jerome, I1 aSofer, Tamar1 aRedline, Susan1 aZhu, Xiaofeng1 aTOPMed Sleep Working Group uhttps://chs-nhlbi.org/node/9101