Rationale: Obstructive sleep apnea is a common disorder associated with increased risk for cardiovascular disease, diabetes, and premature mortality. Although there is strong clinical and epidemiologic evidence supporting the importance of genetic factors in influencing obstructive sleep apnea, its genetic basis is still largely unknown. Prior genetic studies focused on traits defined using the apnea-hypopnea index, which contains limited information on potentially important genetically determined physiologic factors, such as propensity for hypoxemia and respiratory arousability.Objectives: To define novel obstructive sleep apnea genetic risk loci for obstructive sleep apnea, we conducted genome-wide association studies of quantitative traits in Hispanic/Latino Americans from three cohorts.Methods: Genome-wide data from as many as 12,558 participants in the Hispanic Community Health Study/Study of Latinos, MultiEthnic Study of Atherosclerosis, and Starr County Health Studies population-based cohorts were metaanalyzed for association with the apnea-hypopnea index, average oxygen saturation during sleep, and average respiratory event duration.Measurements and Main Results: Two novel loci were identified at genome-level significance (rs11691765, GPR83, P = 1.90 3 10 28 for the apnea-hypopnea index, and rs35424364; C6ORF183/CCDC162P, P = 4.88 3 10 28 for respiratory event duration) and seven additional loci were identified with suggestive significance (P , 5 3 10 27 ). Secondary sex-stratified analyses also identified one significant and several suggestive associations. Multiple loci overlapped genes with biologic plausibility.Conclusions: These are the first genome-level significant findings reported for obstructive sleep apnea-related physiologic traits in any population. These findings identify novel associations in inflammatory, hypoxia signaling, and sleep pathways.

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.

Sleep disordered breathing (SDB)-related overnight hypoxemia is associated with cardiometabolic disease and other comorbidities. Understanding the genetic bases for variations in nocturnal hypoxemia may help understand mechanisms influencing oxygenation and SDB-related mortality. We conducted genome-wide association tests across 10 cohorts and 4 populations to identify genetic variants associated with three correlated measures of overnight oxyhemoglobin saturation: average and minimum oxyhemoglobin saturation during sleep and the percent of sleep with oxyhemoglobin saturation under 90%. The discovery sample consisted of 8,326 individuals. Variants with p < 1 × 10 −6 were analyzed in a replication group of 14,410 individuals. We identified 3 significantly associated regions, including 2 regions in multi-ethnic analyses (2q12, 10q22). SNPs in the 2q12 region associated with minimum SpO 2 (rs78136548 p = 2.70 × 10 −10 ). SNPs at 10q22 were associated with all three traits including average SpO 2 (rs72805692 p = 4.58 × 10 −8 ). SNPs in both regions were associated in over 20,000 individuals and are supported by prior associations or functional evidence. Four additional significant regions were detected in secondary sex-stratified and combined discovery and replication analyses, including a region overlapping Reelin, a known marker of respiratory complex neurons.These are the first genome-wide significant findings reported for oxyhemoglobin saturation during sleep, a phenotype of high clinical interest. Our replicated associations with HK1 and IL18R1 suggest that variants in inflammatory pathways, such as the biologically-plausible NLRP3 inflammasome, may contribute to nocturnal hypoxemia.

ClinicalTrials.gov; No.: NCT01261390; URL: www.clinicaltrials.gov.

In patients with moderate-severe OSA at high risk of cardiovascular events and without severe sleepiness, CPAP improved daytime sleepiness and multiple domains of HRQOL over 6 to 12 months of follow-up, with the largest improvement observed for bodily pain.

A model for sorted patterned ground shows that some types arise from density-driven Rayleigh free convection that occurs during thawing of water-saturated recurrently frozen soils. The regularly spaced convection cells result in an uneven melting of the underlying ice front. Frost action causes stones to be upthrusted and to form in a pattern on the ground surface that mirrors the corrugation in the underlying ice front. The implications of the water circulation direction in the cells on the sorting process are considered.

To provide a comprehensive mechanistic interpretation of how known trait-associated SNPs affect complex traits, we propose a method, Primo, for integrative analysis of GWAS summary statistics with multiple sets of omics QTL summary statistics from different cellular conditions or studies. Primo examines association patterns of SNPs to complex and omics traits. In gene regions harboring known susceptibility loci, Primo performs conditional association analysis to account for linkage disequilibrium. Primo allows for unknown study heterogeneity and sample correlations. We show two applications using Primo to examine the molecular mechanisms of known susceptibility loci and to detect and interpret pleiotropic effects.

To provide a comprehensive mechanistic interpretation of how SNPs affect complex traits, we propose a method -Primo -for integrative analysis of GWAS summary statistics with multiple sets of omics QTL summary statistics from different cellular conditions or studies. Primo identifies SNPs in various association patterns to complex and omics traits and performs conditional association analysis in a region to account for linkage disequilibrium. Primo allows for unknown study heterogeneity and sample correlations. We show two types of applications using Primo to examine the molecular mechanisms of known susceptibility loci and to detect and interpret pleiotropic effects.