TY - JOUR T1 - Multiethnic Meta-Analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea-related Quantitative Trait Locus in Men. JF - Am J Respir Cell Mol Biol Y1 - 2018 A1 - Chen, Han A1 - Cade, Brian E A1 - Gleason, Kevin J A1 - Bjonnes, Andrew C A1 - Stilp, Adrienne M A1 - Sofer, Tamar A1 - Conomos, Matthew P A1 - Ancoli-Israel, Sonia A1 - Arens, Raanan A1 - Azarbarzin, Ali A1 - Bell, Graeme I A1 - Below, Jennifer E A1 - Chun, Sung A1 - Evans, Daniel S A1 - Ewert, Ralf A1 - Frazier-Wood, Alexis C A1 - Gharib, Sina A A1 - Haba-Rubio, José A1 - Hagen, Erika W A1 - Heinzer, Raphael A1 - Hillman, David R A1 - Johnson, W Craig A1 - Kutalik, Zoltán A1 - Lane, Jacqueline M A1 - Larkin, Emma K A1 - Lee, Seung Ku A1 - Liang, Jingjing A1 - Loredo, Jose S A1 - Mukherjee, Sutapa A1 - Palmer, Lyle J A1 - Papanicolaou, George J A1 - Penzel, Thomas A1 - Peppard, Paul E A1 - Post, Wendy S A1 - Ramos, Alberto R A1 - Rice, Ken A1 - Rotter, Jerome I A1 - Sands, Scott A A1 - Shah, Neomi A A1 - Shin, Chol A1 - Stone, Katie L A1 - Stubbe, Beate A1 - Sul, Jae Hoon A1 - Tafti, Mehdi A1 - Taylor, Kent D A1 - Teumer, Alexander A1 - Thornton, Timothy A A1 - Tranah, Gregory J A1 - Wang, Chaolong A1 - Wang, Heming A1 - Warby, Simon C A1 - Wellman, D Andrew A1 - Zee, Phyllis C A1 - Hanis, Craig L A1 - Laurie, Cathy C A1 - Gottlieb, Daniel J A1 - Patel, Sanjay R A1 - Zhu, Xiaofeng A1 - Sunyaev, Shamil R A1 - Saxena, Richa A1 - Lin, Xihong A1 - Redline, Susan AB -

Obstructive sleep apnea (OSA) is a common heritable disorder displaying marked sexual dimorphism in disease prevalence and progression. Previous genetic association studies have identified a few genetic loci associated with OSA and related quantitative traits, but they have only focused on single ethnic groups, and a large proportion of the heritability remains unexplained. The apnea-hypopnea index (AHI) is a commonly used quantitative measure characterizing OSA severity. Because OSA differs by sex, and the pathophysiology of obstructive events differ in rapid eye movement (REM) and non-REM (NREM) sleep, we hypothesized that additional genetic association signals would be identified by analyzing the NREM/REM-specific AHI and by conducting sex-specific analyses in multiethnic samples. We performed genome-wide association tests for up to 19,733 participants of African, Asian, European, and Hispanic/Latino American ancestry in 7 studies. We identified rs12936587 on chromosome 17 as a possible quantitative trait locus for NREM AHI in men (N = 6,737; P = 1.7 × 10) but not in women (P = 0.77). The association with NREM AHI was replicated in a physiological research study (N = 67; P = 0.047). This locus overlapping the RAI1 gene and encompassing genes PEMT1, SREBF1, and RASD1 was previously reported to be associated with coronary artery disease, lipid metabolism, and implicated in Potocki-Lupski syndrome and Smith-Magenis syndrome, which are characterized by abnormal sleep phenotypes. We also identified gene-by-sex interactions in suggestive association regions, suggesting that genetic variants for AHI appear to vary by sex, consistent with the clinical observations of strong sexual dimorphism.

VL - 58 IS - 3 ER - TY - JOUR T1 - Admixture mapping identifies novel loci for obstructive sleep apnea in Hispanic/Latino Americans. JF - Hum Mol Genet Y1 - 2019 A1 - Wang, Heming A1 - Cade, Brian E A1 - Sofer, Tamar A1 - Sands, Scott A A1 - Chen, Han A1 - Browning, Sharon R A1 - Stilp, Adrienne M A1 - Louie, Tin L A1 - Thornton, Timothy A A1 - Johnson, W Craig A1 - Below, Jennifer E A1 - Conomos, Matthew P A1 - Evans, Daniel S A1 - Gharib, Sina A A1 - Guo, Xiuqing A1 - Wood, Alexis C A1 - Mei, Hao A1 - Yaffe, Kristine A1 - Loredo, Jose S A1 - Ramos, Alberto R A1 - Barrett-Connor, Elizabeth A1 - Ancoli-Israel, Sonia A1 - Zee, Phyllis C A1 - Arens, Raanan A1 - Shah, Neomi A A1 - Taylor, Kent D A1 - Tranah, Gregory J A1 - Stone, Katie L A1 - Hanis, Craig L A1 - Wilson, James G A1 - Gottlieb, Daniel J A1 - Patel, Sanjay R A1 - Rice, Ken A1 - Post, Wendy S A1 - Rotter, Jerome I A1 - Sunyaev, Shamil R A1 - Cai, Jianwen A1 - Lin, Xihong A1 - Purcell, Shaun M A1 - Laurie, Cathy C A1 - Saxena, Richa A1 - Redline, Susan A1 - Zhu, Xiaofeng AB -

Obstructive sleep apnea (OSA) is a common disorder associated with increased risk of cardiovascular disease and mortality. Its prevalence and severity vary across ancestral background. Although OSA traits are heritable, few genetic associations have been identified. To identify genetic regions associated with OSA and improve statistical power, we applied admixture mapping on three primary OSA traits [the apnea hypopnea index (AHI), overnight average oxyhemoglobin saturation (SaO2) and percentage time SaO2 < 90%] and a secondary trait (respiratory event duration) in a Hispanic/Latino American population study of 11 575 individuals with significant variation in ancestral background. Linear mixed models were performed using previously inferred African, European and Amerindian local genetic ancestry markers. Global African ancestry was associated with a lower AHI, higher SaO2 and shorter event duration. Admixture mapping analysis of the primary OSA traits identified local African ancestry at the chromosomal region 2q37 as genome-wide significantly associated with AHI (P < 5.7 × 10-5), and European and Amerindian ancestries at 18q21 suggestively associated with both AHI and percentage time SaO2 < 90% (P < 10-3). Follow-up joint ancestry-SNP association analyses identified novel variants in ferrochelatase (FECH), significantly associated with AHI and percentage time SaO2 < 90% after adjusting for multiple tests (P < 8 × 10-6). These signals contributed to the admixture mapping associations and were replicated in independent cohorts. In this first admixture mapping study of OSA, novel associations with variants in the iron/heme metabolism pathway suggest a role for iron in influencing respiratory traits underlying OSA.

VL - 28 IS - 4 ER - TY - JOUR T1 - Targeted Genome Sequencing Identifies Multiple Rare Variants in Caveolin-1 Associated with Obstructive Sleep Apnea. JF - Am J Respir Crit Care Med Y1 - 2022 A1 - Liang, Jingjing A1 - Wang, Heming A1 - Cade, Brian E A1 - Kurniansyah, Nuzulul A1 - He, Karen Y A1 - Lee, Jiwon A1 - Sands, Scott A A1 - Brody, Jennifer A1 - Chen, Han A1 - Gottlieb, Daniel J A1 - Evans, Daniel S A1 - Guo, Xiuqing A1 - Gharib, Sina A A1 - Hale, Lauren A1 - Hillman, David R A1 - Lutsey, Pamela L A1 - Mukherjee, Sutapa A1 - Ochs-Balcom, Heather M A1 - Palmer, Lyle J A1 - Purcell, Shaun A1 - Saxena, Richa A1 - Patel, Sanjay R A1 - Stone, Katie L A1 - Tranah, Gregory J A1 - Boerwinkle, Eric A1 - Lin, Xihong A1 - Liu, Yongmei A1 - Psaty, Bruce M A1 - Vasan, Ramachandran S A1 - Manichaikul, Ani A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Sofer, Tamar A1 - Redline, Susan A1 - Zhu, Xiaofeng AB -

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.

ER -