Genetic analysis of Obstructive Sleep Apnoea and its associations for cardiometabolic diseases and COVID-19

Obstructive sleep apnoea (OSA) is the most common sleep-related breathing disorder and is characterized by recurrent episodes of complete or partial obstruction of the upper airway leading to reduced or absent breathing during sleep. The prevalence of OSA in adults is approximately 25% in developed countries. The main known risk factors for OSA are increasing age, male sex, menopause, obesity and certain craniofacial structures and anomalies. The role of OSA on the risk of adverse cardiovascular outcomes has been widely studied, and mechanisms linking OSA to its cardiometabolic correlates through intermittent hypoxia, oxidative stress and increasing sympathetic activity are also recognized. Despite the fact that the epidemiology of OSA has been under research for decades, the genetics behind OSA risk have remained mainly unstudied. However, family studies have shown that family members are at a 2–4-fold greater risk of having OSA if there are OSA patients in the family. It is estimated that 40% of the variation in the apnoea-hypopnoea-index (AHI) is genetically regulated. Previous genome-wide-association studies (GWASes) have addressed OSA severity based on AHI or respiratory event duration, but case-control studies have not been previously published. The World Health Organization (WHO) announced COVID-19 as a pandemic in March 2020. Patients with COVID-19 have a wide range of symptoms ranging from mild flu-like symptoms to severe illness. The first studies regarding COVID-19 revealed that male gender, higher age, obesity and diabetes are risk factors for the severe form of the disease, indicating that OSA and COVID-19 share numerous common risk factors and comorbidities. Furthermore, studies have suggested that OSA is a risk factor for the severe form of COVID-19. We estimated the role of OSA in major cardiometabolic disease by utilizing population-based cohorts, including FINRISK, Health 2000 and a subset of the Botnia Study, and registry information to longitudinally assess OSA risk in the Finnish population. Our data consisted of 36,963 individuals with over 500,000 person-years and up to twenty-five years of follow-up data, including 1,568 OSA patients. Using Cox-proportional hazards models, our results revealed that OSA is associated with a 1.36-fold increased risk for coronary heart disease (CHD), including a 2.01-fold increased risk in women independent of other potential confounding factors. Similarly, type 2 diabetes (T2D) correlated with OSA independent of obesity status and revealed a 1.48-fold increased risk. This association was also significant in women, showing a 1.63-fold increased risk. The risk of diabetic kidney disease (DKD) was increased by 1.75-fold in patients with OSA among the T2D study sample. All-cause mortality was increased in individuals with both OSA and T2D by 35%. To study the genetic burden for the risk of OSA we proceeded to identify genetic loci associated with OSA risk and aimed to test if OSA and its comorbidities share a common genetic basis. To elucidate these aims, data from the FinnGen project was used. The FinnGen project combines patient genotype data and nationwide registry information with anthropometric measurements, such as body mass index (BMI) and smoking. Using this information, we conducted the first large-scale case-control GWAS of OSA with 217,955 individuals including 16,761 OSA patients. We identified five genetic loci associated with OSA, highlighting the importance of genetic variation on OSA predisposition. This was further supported by our single nucleotide polymorphism (SNP)-based heritability estimates. We also showed the causal relationship between obesity and OSA by utilizing Mendelian randomization (MR). Although BMI is the major risk factor, we were also able to find a BMI-independent genetic locus for OSA that is associated with antidepressant purchases. However, we could not replicate this locus in independent cohorts. In addition, we found strong genetic correlations between OSA and its comorbidities including BMI, hypertension, T2D, CHD, stroke, depression, hypothyroidism, asthma and inflammatory rheumatic diseases (IRD) in addition to other sleep traits such as sleepiness and sleep efficiency. These findings implicate OSA as a heterogenic disease with several distinct comorbidities, which would be beneficial to consider when treating patients with OSA. When COVID-19 emerged, it became apparent that the risk factors for the severe form of the disease showed similarities with OSA risk factors and comorbidities. Our aim was to study if OSA patients have a higher risk for hospitalisation due to COVID-19 disease in addition to other potential confounding factors, and if OSA associates with an increased risk of contracting COVID-19. We studied 445 individuals with COVID-19 including thirty-eight OSA patients extracted from the FinnGen project data (N=260,405). Of the OSA patients, nineteen required hospital treatment due to COVID-19 infection. OSA was associated with a 2.93-fold increased risk of COVID-19 hospitalisation independent of age, sex, BMI and other comorbidities. The results were further confirmed in a meta-analysis including 15,835 individuals. Importantly, treatment information regarding OSA was also collected and suggested that moderate and severe OSA is a risk factor for severe COVID-19 even if the OSA is well managed. This thesis concentrates on studying OSA as a risk factor for cardiometabolic comorbidities, the genetic variation between OSA and non-OSA individuals and whether OSA creates an elevated risk for severe COVID-19 disease. These studies were conducted by utilizing large and accurate data sets with an epidemiological and longitudinal ascertainment, and by applying modern genetic methods to show that OSA is a relevant topic during the exceptional times of the global COVID-19 pandemic.