Genetic analysis of obstructive sleep apnoea and its associations to 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.Obstruktiivisella uniapnealla (uniapnea) tarkoitetaan toistuvia unenaikaisia vähintään kymmenen sekunnin mittaisia hengityskatkoksia (apnea) tai hengityksen vaimentumia (hypopnea), jotka johtuvat ylähengitysteiden ahtautumisesta. Uniapnean prevalenssin on arvioitu olevan jopa 25 % aikuisväestössä. Sen tunnetuimmat riskitekijät ovat korkea ikä, miessukupuoli, vaihdevuosi-ikä, ylipaino ja tietyt kraniofakiaaliset piirteet, kuten pieni tai takana sijaitseva alaleuka. Uniapnean ja sydän- ja verisuonitautien yhteyttä on tutkittu laajasti epidemiologisin tutkimusmenetelmin, ja niitä yhdistävät mekanismit, kuten jaksottainen hapenpuute, oksidatiivinen stressi ja uniapnean vaikutukset sympaattisen hermoston aktiivisuuden lisääntymiseen, tunnetaan. Epidemiologisista tutkimuksista ja tuloksista huolimatta uniapean genetiikan tutkimus on ollut melko vähäistä. Viitteitä on saatu siitä, että uniapneapotilaan perheenjäsenellä on 2–4-kertainen riski sairastua uniapneaan ja lisäksi on arvioitu, että 40 % apnea-hypopnea-indeksin variaatiosta on geneettisesti säädelty. Genominlaajuinen assosiaatioanalyysi on tuonut uuden menetelmän analysoida yleisiä kompleksisia tauteja, kuten uniapneaa. Näissä aiemmissa uniapneaa koskevissa tutkimuksissa on tutkittu taudin vaikeusastetta ja hengitystapahtuman kestoa. Kuitenkaan tapaus-verrokki -tutkimusta koskien uniapneaa ei ole aiemmin julkaistu. Joulukuussa 2019 Kiinan Wuhanista alkoi epidemia, jonka aiheuttajana on ihmiselle uusi koronavirus. Sen aiheuttama tauti on viralliselta nimeltään COVID-19. Virus levisi nopeasti maailmanlaajuisesti ja maaliskuussa 2020 Maailman terveysjärjestö WHO julisti koronavirusepidemian pandemiaksi. COVID-19 aiheuttaa useimmille lieväoireisen hengitystieinfektion, mutta osalle potilaista infektio voi olla jopa henkeä uhkaava. Vakavan COVID-19 infektion riskitekijöihin kuuluvat mm. korkea ikä, ylipaino ja diabetes. Näin ollen COVID-19 ja uniapnea jakavat suuren määrän samoja riskitekijöitä ja liitännäissairauksia. Lisäksi on havaittu, että uniapnea voi lisätä riskiä vakalle COVID-19-infektiolle. Arvioimme uniapnean aiheuttamaa riskiä koronaaritaudille, tyypin 2 diabetekselle, diabeteskomplikaatioille ja kuolleisuudelle hyödyntämällä FINRISKI ja Terveys 2000 kohortteja sekä osajoukkoa Botnia-tutkimuksesta. Tutkimuksemme sisälsi 36 963 henkilöä ja se kattoi yli 500 000 henkilövuotta yltäen jopa yli 25-vuoden seuranta-aikaan. Käyttämällä Cox-elinaikamallia havaitsimme, että uniapnea liittyy koronaaritaudin riskiin 1.36-kertaisesti riippumatta muista riskitekijöistä, kuten verenpainetaudista tai painoindeksistä. Tämä yhteys nähtiin myös naisilla, joilla yhteys riskiin nousi 2.01-kertaiseksi. Vastaavasti uniapnean havaittiin olevan ylipainosta riippumaton riskitekijä tyypin 2 diabetekselle liittyen riskiin 1.48-kertaisesti. Vaikutus havaittiin myös naisilla, joilla uniapnea yhdistyi 1.63-kertaiseen riskiin. Lisäksi uniapnea assosioitui kohonneeseen riskiin diabeetikkojen munuaissairauksille 1.75-kertaisesti ja uniapnean nähtiin lisäävän kuolleisuutta 35 % tyypin 2 diabeetikoilla. Tutkiaksemme uniapnean genetiikkaa hyödynsimme FinnGen-aineistoa, joka yhdistää genomitietoja kansallisiin terveysrekistereihin. Tarkastelimme uniapneaa käyttämällä genominlaajuista assosiaatioanalyysiä sisältäen 217 955 henkilöä, joista 16 761:lla oli uniapneadiagnoosi. Löysimme viisi uniapneariskiin assosioituvaa lokusta. Tämä tutkimus korostaa geneettisen variaation merkitystä uniapnealle altistumisessa, jota heritabiliteettilöydöksemme vahvistaa. Näytimme lisäksi mendeliaanisen randomisaation avulla, että ylipainon ja uniapnean välillä on kausaalinen suhde, joka on ollut nähtävissä epidemiologisissa tutkimuksissa. Huolimatta siitä, että ylipaino on uniapnean tärkein riskitekijä, löysimme painoindeksistä riippumattoman lokuksen, joka oli spesifi uniapneadiagnoosille, ja joka yhdistyi masennuslääkeostoihin. Tätä tulosta emme kuitenkaan onnistuneet toistamaan itsenäisissä aineistoissa. Havaitsimme voimakkaita geneettisiä korrelaatioita uniapnean ja sen liitännäissairauksien, kuten verenpainetaudin, tyypin 2 diabeteksen, koronaaritaudin, depression, kilpirauhasen vajaatoiminnan, astman ja inflammatoristen reumasairauksien välillä. Lisäksi geneettiset korrelaatiot olivat vahvoja uniapean ja päiväväsymyksen sekä unen tehokkuuden välillä. Nämä havainnot viittaavat siihen, että uniapnea on heterogeeninen sairaus, johon liittyy useita eri tauteja, jotka tulisi huomioida uniapneapotilaita hoidettaessa. Tarkastelimme lisäksi uniapnean aiheauttamaa riskiä vakavalle COVID-19-infektiolle ja mahdollisesti uniapneapotilaiden suurentunutta riskiä saada infektio. Hyödyntämällä FinnGen-kohorttia (N=260,405) aineistomme sisälsi 445 COVID-19 positiivista henkilöä, joista 38:lla oli lisäksi uniapneadiagnoosi. Heistä 19 tarvitsi sairaalahoitoa COVID-19 aiheuttaman infektion vuoksi. Uniapnea liittyi 2.93-kertaiseen riskiin vakavalle infektiolle riippumatta muista riskitekijöistä, kuten iäistä, sukupuolesta, painoindeksistä, verenpainetaudista, tyypin 2 diabeteksesta, koronaaritaudista, keuhkoahtaumataudista ja astmasta. Lisäksi teimme meta-analyysin, joka sisälsi 15 835 COVID-19 positiiviseksi testattua henkilöä vahvistaen tietoutta uniapnean aiheuttamasta kohonneesta riskistä. Keräsimme uniapneapotilaiden hoitotietoja ennen sairastumista COVID-19-infektioon ja havaitsimme, että vaikka suurin osa uniapneapotilaista oli hoidettu, vaativat he silti sairaalahoitoa. Tämä antaa viitteitä siitä, että keskivaikea ja vaikea uniapnea on hoidettunakin riskitekijä vakavalle COVID-19-infektiolle. Tämä väitöskirja tutkii uniapnean yhteyttä kardiometabolisten sairauksien ilmaantuvuuteen ja niiden riskitekijöihin. Samalla se selvittää geneettistä vaihtelua uniapneapotilaiden ja ei-uniapneapotilaiden välillä tarkastellen lisäksi uniapnean geneettistä yhteyttä sen liitännäissairauksiin hyödyntämällä laajoja kansallisia aineistoja epidemiologisesta ja geneettisestä näkökulmasta luoden katsauksen uniapneasta suomalaisessa väestössä. Tutkimuksissa on hyödynnetty niin pitkittäistutkimukseen soveltuvia kuin uusimpia geneettiseen laskentaan kehiteltyjä menetelmiä. Lisäksi keskivaikean ja vaikean uniapnean yhteys COVID-19-infetion vakavaan muotoon nostaa sen hyvin ajankohtaiseksi aiheeksi pandemian aikana

Sleep apnoea is a risk factor for severe COVID-19

Background Obstructive sleep apnoea (OSA) is associated with higher body mass index (BMI), diabetes, older age and male gender, which are all risk factors for severe COVID-19. We aimed to study if OSA is an independent risk factor for COVID-19 infection or for severe COVID-19. Methods OSA diagnosis and COVID-19 infection were extracted from the hospital discharge, causes of death and infectious diseases registries in individuals who participated in the FinnGen study (n=260 405). Severe COVID-19 was defined as COVID-19 requiring hospitalisation. Multivariate logistic regression model was used to examine association. Comorbidities for either COVID-19 or OSA were selected as covariates. We performed a meta-analysis with previous studies. Results We identified 445 individuals with COVID-19, and 38 (8.5%) of them with OSA of whom 19 out of 91 (20.9%) were hospitalised. OSA associated with COVID-19 hospitalisation independent from age, sex, BMI and comorbidities (p-unadjusted=5.13x10(-5), OR-adjusted=2.93 (95% CI 1.02 to 8.39), p-adjusted=0.045). OSA was not associated with the risk of contracting COVID-19 (p=0.25). A meta-analysis of OSA and severe COVID-19 showed association across 15 835 COVID-19 positive controls, and n=1294 patients with OSA with severe COVID-19 (OR=2.37 (95% 1.14 to 4.95), p=0.021). Conclusion Risk for contracting COVID-19 was the same for patients with OSA and those without OSA. In contrast, among COVID-19 positive patients, OSA was associated with higher risk for hospitalisation. Our findings are in line with earlier works and suggest OSA as an independent risk factor for severe COVID-19.Peer reviewe

Obstructive sleep apnoea and the risk for coronary heart disease and type 2 diabetes : a longitudinal population-based study in Finland

Objective To evaluate if obstructive sleep apnoea (OSA) modifies the risk of coronary heart disease, type 2 diabetes (T2D) and diabetic complications in a gender-specific fashion. Design and setting A longitudinal population-based study with up to 25-year follow-up data on 36 963 individuals (>500 000 person years) from three population-based cohorts: the FINRISK study, the Health 2000 Cohort Study and the Botnia Study. Main outcome measures Incident coronary heart disease, diabetic kidney disease, T2D and all-cause mortality from the Finnish National Hospital Discharge Register and the Finnish National Causes-of-Death Register. Results After adjustments for age, sex, region, high-density lipoprotein (HDL) and total cholesterol, current cigarette smoking, body mass index, hypertension, T2D baseline and family history of stroke or myocardial infarction, OSA increased the risk for coronary heart disease (HR=1.36, p=0.0014, 95% CI 1.12 to 1.64), particularly in women (HR=2.01, 95% CI 1.31 to 3.07, p=0.0012). T2D clustered with OSA independently of obesity (HR=1.48, 95% CI 1.26 to 1.73, p=9.11x10(-7)). The risk of diabetic kidney disease increased 1.75-fold in patients with OSA (95% CI 1.13 to 2.71, p=0.013). OSA increased the risk for coronary heart disease similarly among patients with T2D and in general population (HR=1.36). All-cause mortality was increased by OSA in diabetic individuals (HR=1.35, 95% CI 1.06 to 1.71, p=0.016). Conclusion OSA is an independent risk factor for coronary heart disease, T2D and diabetic kidney disease. This effect is more pronounced even in women, who until now have received less attention in diagnosis and treatment of OSA than men.Peer reviewe

Large registry-based analysis of genetic predisposition to tuberculosis identifies genetic risk factors at HLA

Tuberculosis is a significant public health concern resulting in the death of over 1 million individuals each year worldwide. While treatment options and vaccines exist, a substantial number of infections still remain untreated or are caused by treatment resistant strains. Therefore, it is important to identify mechanisms that contribute to risk and prognosis of tuberculosis as this may provide tools to understand disease mechanisms and provide novel treatment options for those with severe infection. Our goal was to identify genetic risk factors that contribute to the risk of tuberculosis and to understand biological mechanisms and causality behind the risk of tuberculosis. A total of 1895 individuals in the FinnGen study had International Classification of Diseases-based tuberculosis diagnosis. Genome-wide association study analysis identified genetic variants with statistically significant association with tuberculosis at the human leukocyte antigen (HLA) region (P < 5e-8). Fine mapping of the HLA association provided evidence for one protective haplotype tagged by HLA DQB1*05:01 (P = 1.82E-06, OR = 0.81 [CI 95% 0.74-0.88]), and predisposing alleles tagged by HLA DRB1*13:02 (P = 0.00011, OR = 1.35 [CI 95% 1.16-1.57]). Furthermore, genetic correlation analysis showed association with earlier reported risk factors including smoking (P < 0.05). Mendelian randomization supported smoking as a risk factor for tuberculosis (inverse-variance weighted P < 0.05, OR = 1.83 [CI 95% 1.15-2.93]) with no significant evidence of pleiotropy. Our findings indicate that specific HLA alleles associate with the risk of tuberculosis. In addition, lifestyle risk factors such as smoking contribute to the risk of developing tuberculosis.Peer reviewe

Genetic analysis of obstructive sleep apnoea discovers a strong association with cardiometabolic health

There is currently limited understanding of the genetic aetiology of obstructive sleep apnoea (OSA). We aimed to identify genetic loci associated with OSA risk, and to test if OSA and its comorbidities share a common genetic background. We conducted the first large-scale genome-wide association study of OSA using the FinnGen study (217955 individuals) with 16761 OSA patients identified using nationwide health registries. We estimated 0.08 (95% CI 0.06-0.11) heritability and identified five loci associated with OSA (p 0.30). The polygenic risk score for BMI showed 1.98-fold increased OSA risk between the highest and the lowest quintile, and Mendelian randomisation supported a causal relationship between BMI and OSA. Our findings support the causal link between obesity and OSA, and the joint genetic basis between OSA and comorbidities.Peer reviewe

The public health impact of poor sleep on severe COVID-19, influenza and upper respiratory infections

Peer reviewe

Sleep apnoea is a risk factor for severe COVID-19

Background Obstructive sleep apnoea (OSA) is associated with higher body mass index (BMI), diabetes, older age and male gender, which are all risk factors for severe COVID-19.We aimed to study if OSA is an independent risk factor for COVID-19 infection or for severe COVID-19.Methods OSA diagnosis and COVID-19 infection were extracted from the hospital discharge, causes of death and infectious diseases registries in individuals who participated in the FinnGen study (n=260 405). Severe COVID-19 was defined as COVID-19 requiring hospitalisation. Multivariate logistic regression model was used to examine association. Comorbidities for either COVID-19 or OSA were selected as covariates. We performed a meta-analysis with previous studies.Results We identified 445 individuals with COVID-19, and 38 (8.5%) of them with OSA of whom 19 out of 91 (20.9%) were hospitalised. OSA associated with COVID-19 hospitalisation independent from age, sex, BMI and comorbidities (p-unadjusted=5.13×10−5, OR-adjusted=2.93 (95% CI 1.02 to 8.39), p-adjusted=0.045). OSA was not associated with the risk of contracting COVID-19 (p=0.25). A meta-analysis of OSA and severe COVID-19 showed association across 15 835 COVID-19 positive controls, and n=1294 patients with OSA with severe COVID-19 (OR=2.37 (95% 1.14 to 4.95), p=0.021).Conclusion Risk for contracting COVID-19 was the same for patients with OSA and those without OSA. In contrast, among COVID-19 positive patients, OSA was associated with higher risk for hospitalisation. Our findings are in line with earlier works and suggest OSA as an independent risk factor for severe COVID-19