Characterization of Genetic and Phenotypic Heterogeneity of Obstructive Sleep Apnea Using Electronic Health Records

Abstract

38Obstructive sleep apnea (OSA) is defined by frequent episodes of reduced or complete 39 cessation of airflow during sleep and is linked to negative health outcomes. Understanding the 40 genetic factors influencing expression of OSA may lead to new treatment strategies. Electronic 41 health records can be leveraged to both validate previously reported OSA-associated genomic 42 variation and detect novel relationships between these variants and comorbidities. We identified 43 candidate single nucleotide polymorphisms (SNPs) via systematic literature review of existing 44 research. Using datasets available at Geisinger (n=39,407) and Vanderbilt University Medical 45Center (n=24,084), we evaluated associations between 48 SNPs and OSA diagnosis, defined 46 using clinical codes. We also evaluated associations between these SNPs and OSA severity 47 measures obtained from sleep reports at Geisinger (n=6,571). Finally, we used a phenome-wide 48 approach to perform discovery and replication analyses testing associations between OSA 49 candidate SNPs and other clinical codes and laboratory values. Ten SNPs were associated with 50 OSA diagnosis in at least one dataset, and one additional SNP was associated following meta-51 analysis across all datasets. Three other SNPs were solely associated in subgroups defined by 52 established risk factors (i.e., age, sex, and BMI). Five OSA diagnosis-associated SNPs, and 16 53 additional SNPs, were associated with OSA severity measures. SNPs associated with OSA 54 diagnosis were also associated with codes reflecting cardiovascular disease, diabetes, celiac 55 disease, peripheral nerve disorders and genitourinary symptoms. Results highlight robust OSA-56 associated SNPs, and provide evidence of convergent mechanisms influencing risk for co-57 occurring conditions. This knowledge can lead to more personalized treatments for OSA and 58 related comorbidities. 59 60In the United States (US), 50-70 million individuals suffer from a disorder of sleep and 62 wakefulness 1 . Among the most common sleep disorders is obstructive sleep apnea (OSA). OSA 63 is defined by frequent episodes of reduced (hypopnea) or complete cessation (apnea) of airflow 64 that occur as a consequence of upper airway obstruction during sleep. Approximately 34% of 65 men and 17% of women aged 30-70 exhibit mild OSA, and 13% and 6%, respectively, suffer 66 from moderate to severe OSA 2 . Notably, prevalence rates substantially increase by the age of 67 50 years old 2 . When left untreated, OSA represents a significant public health burden carrying a 68 higher risk of serious comorbidities such as cardiovascular disease 3-11 , cancer incidence 12 and 69 mortality, all causes 13; 14 , cognitive impairment 15 , and rate of progression of 70 neurodegeneration 16 . As such, identifying more effective diagnosis and management of OSA 71 are important areas of research. 72OSA is a complex, phenotypically heterogeneous disorder driven by both obesity-related 73 factors and other mechanisms [17][18][19] . A number of studies have ...