FinnGen provides genetic insights from a well-phenotyped isolated population.

Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10-11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants.

Oral and non-oral lichen planus show genetic heterogeneity and differential risk for autoimmune disease and oral cancer.

Lichen planus (LP) is a T-cell-mediated inflammatory disease affecting squamous epithelia in many parts of the body, most often the skin and oral mucosa. Cutaneous LP is usually transient and oral LP (OLP) is most often chronic, so we performed a large-scale genetic and epidemiological study of LP to address whether the oral and non-oral subgroups have shared or distinct underlying pathologies and their overlap with autoimmune disease. Using lifelong records covering diagnoses, procedures, and clinic identity from 473,580 individuals in the FinnGen study, genome-wide association analyses were conducted on carefully constructed subcategories of OLP (n = 3,323) and non-oral LP (n = 4,356) and on the combined group. We identified 15 genome-wide significant associations in FinnGen and an additional 12 when meta-analyzed with UKBB (27 independent associations at 25 distinct genomic locations), most of which are shared between oral and non-oral LP. Many associations coincide with known autoimmune disease loci, consistent with the epidemiologic enrichment of LP with hypothyroidism and other autoimmune diseases. Notably, a third of the FinnGen associations demonstrate significant differences between OLP and non-OLP. We also observed a 13.6-fold risk for tongue cancer and an elevated risk for other oral cancers in OLP, in agreement with earlier reports that connect LP with higher cancer incidence. In addition to a large-scale dissection of LP genetics and comorbidities, our study demonstrates the use of comprehensive, multidimensional health registry data to address outstanding clinical questions and reveal underlying biological mechanisms in common but understudied diseases.

Reduced expiratory variability index (EVI) is associated with controller medication withdrawal and symptoms in wheezy children aged 1-5 years.

BACKGROUND: Lung function testing is an essential part of diagnostic workup and monitoring of asthma, but young children are lacking easy, routine testing methods. However, recent discoveries show reduced tidal breathing variability measured using impedance pneumography (IP) at home during sleep as a sign of airway obstruction. In this study, we assessed (a) the discriminative capacity of expiratory variability index (EVI) between healthy controls and young children with recurrent wheeze on-and-off controller medication, (b) association between EVI and parentally perceived obstructive symptoms (need for bronchodilator) and (c) measurement success rate. METHODS: We included 68 patients (aged 1.0-5.6) and 40 healthy controls (aged 1.0-5.9 years). The patients were prescribed a three-month inhaled corticosteroid (ICS) treatment due to recurrent obstructive bronchitis. We measured EVI using IP at home at the end of the treatment (0W) and 2 (2W) and 4 (4W) weeks after ICS withdrawal. RESULTS: EVI was higher in controls than in patients, and significant within-patient reduction occurred at 4W as compared to 2W or 0W. Area under curve of the ROC curve (controls vs all patients) at 4W was 0.78 (95% CI 0.70-0.85). Children who were administered bronchodilator by parental decision had lower EVI than those without bronchodilator need at 4W, but not at 0W or 2W. Patients with parent-reported airway infection, but no bronchodilator need, had normal EVI. Measurement success rate was 94%. CONCLUSION: EVI was lower in patients than in controls and it reduced further after controller medication withdrawal, especially in the presence of parentally perceived wheeze symptoms. This technique shows a significant potential for routine lung function testing of wheezy young children.

Risk of cardiovascular comorbidities before and after the onset of rheumatic diseases.

OBJECTIVES: To elucidate the risk and temporal relationship of cardiovascular (CV) comorbidities in rheumatic diseases. METHODS: Patients in the FinnGen study diagnosed between 2000 and 2014 with seropositive (n = 2368) or seronegative (n = 916) rheumatoid arthritis (RA), ankylosing spondylitis (AS, n = 715), psoriatic arthritis (PsA, n = 923), systemic lupus erythematosus (SLE, n = 190), primary Sjogren's syndrome (pSS, n = 412) or gout (n = 2034) were identified from healthcare registries. Each patient was matched based on age, sex, and birth region with twenty controls without any rheumatic conditions. Overall risk ratios (RR) were calculated by comparing the prevalence of seven CV diseases between patients and controls. Logistic regression models were used for estimating odds ratios (OR) for CV comorbidities before and after the onset of rheumatic diseases. RESULTS: The RR for 'any CVD' varied from 1.14 (95 % confidence interval [CI] 1.02-1.26) in PsA to 2.05 (95 % CI 1.67-2.52) in SLE. Patients with SLE or gout demonstrated over two-fold risks for several CV comorbidities. Among CV comorbidities, venous thromboembolism (VTE) showed the highest effect sizes in several rheumatic diseases. The ORs for CV comorbidities were highest within one year before and/or after the onset of the rheumatic disease. However, in gout the excess risk of CV disease was especially high before gout diagnosis. CONCLUSIONS: The risk of CV comorbidities was elevated in all studied rheumatic diseases, with highest risks observed in SLE and gout. The risk for CV diseases was highest immediately before and/or after rheumatic disease diagnosis, highlighting the increased risk for CV comorbidities across all rheumatic diseases very early on the disease course.

Tidal breathing flow profiles during sleep in wheezing children measured by impedance pneumography.

For the first time, impedance pneumography (IP) enables a continuous analysis of the tidal breathing flow volume (TBFV), overnight. We studied how corticosteroid inhalation treatments, sleep stage, and time from sleep onset modify the nocturnal TBFV profiles of children. Seventy children, 1-5 years old and with recurrent wheezing, underwent three, full-night TBFVs recordings at home, using IP. The first recorded one week before ending a 3-months inhaled corticosteroids treatment, and remaining two, 2 and 4 weeks after treatment. TBFV profiles were grouped by hour from sleep onset and estimated sleep stage. Compared with on-medication, the off-medication profiles showed lower volume at exhalation peak flow, earlier interruption of expiration, and less convex middle expiration. The differences in the first two features were significant during non-rapid eye movement (NREM), and the differences in the third were more prominent during REM after 4 h of sleep. These combinations of TBFV features, sleep phase, and sleep time potentially indicate airflow limitation in young children.

Noninvasive Cardiorespiratory Signals Analysis for Asthma Evolution Monitoring in Preschool Children.

OBJECTIVE: Despite its increasing prevalence, diagnosis of asthma in children remains problematic due to their difficulties in producing repeatable spirometric maneuvers. Moreover, low adherence to inhaled corticosteroids (ICS) treatment could result in permanent airway remodeling. The growing interest in a noninvasive and objective way for monitoring asthma, together with the apparent role of autonomic nervous system (ANS) in its pathogenesis, have attracted interest towards heart rate variability (HRV) and cardiorespiratory coupling (CRC) analyses. METHODS: HRV and CRC were analyzed in 68 children who were prescribed ICS treatment due to recurrent obstructive bronchitis. They underwent three different electrocardiogram and respiratory signals recordings, during and after treatment period. After treatment completion, they were followed up during 6 months and classified attending to their current asthma status. RESULTS: Vagal activity, as measured from HRV, and CRC, were reduced after treatment in those children at lower risk of asthma, whereas it kept unchanged in those with a worse prognosis. CONCLUSION: Results suggest that HRV analysis could be useful for the continuous monitoring of ANS anomalies present in asthma, thus contributing to evaluate the evolution of the disease, which is especially challenging in young children. SIGNIFICANCE: Noninvasive ANS assessment using HRV analysis could be useful in the continuous monitoring of asthma in children.

Sources of variability in expiratory flow profiles during sleep in healthy young children.

Standard lung function tests are not feasible in young children, but recent studies show that the variability of expiratory tidal breathing flow-volume (TBFV) curves during sleep is a potential indirect marker of lower airway obstruction. However, the neurophysiological sources of the TBFV variability in normal subjects has not been established. We investigated sleep stages and body position changes as potential sources for the TBFV curve variability. Simultaneous impedance pneumography (IP), polysomnography (PSG) and video recordings were done in 20 children aged 1.4-6.9 years without significant respiratory disorders during sleep. The early part of expiratory TBFV curves are less variable between cycles of REM than NREM sleep. However, within individual sleep cycles, TBFV curves during N3 are the least variable. The differences in TBFV curve shapes between sleep stages are the main source of overnight variability in TBFV curves and the changes in body position have a lesser impact.

Expiratory variability index is associated with asthma risk, wheeze and lung function in infants with recurrent respiratory symptoms.

Impedance pneumography enables the measurement of the expiratory variability index (EVI) at home during a night's sleep in infants with recurrent respiratory symptoms. EVI is associated with asthma risk, symptoms and lung function. https://bit.ly/2PF2cx8.

Airway obstruction is associated with reduced variability in specific parts of the tidal breathing flow-volume curve in young children.

Impedance pneumography recordings during sleep at night show reduced variability in specific parts of the expiratory flow-volume curve in children with recurrent wheeze http://bit.ly/2Wkfap0.

Tidal breathing flow volume profiles during sleep in wheezing infants measured by impedance pneumography.

Overnight analysis of tidal breathing flow volume (TBFV) loops, recorded by impedance pneumography (IP), has been successfully applied in the home monitoring of children with wheezing disorders. However, little is known on how sleep physiology modifies the relationship between TBFV profiles and wheeze. We studied such interactions in wheezing infants. Forty-three infants recruited because of recurrent lower airway symptoms were divided into three groups based on their risk of asthma: high (HR), intermediate (IR), or low (LR). Sedated patients underwent infant lung function testing including assessment of airway responsiveness to methacholine at the hospital and a full-night recording of TBFV profiles at home with IP during natural sleep. Overnight TBFV indexes were estimated from periods of higher and lower respiration variability, presumably belonging to active [rapid eye movement (REM)] and quiet [non-REM (NREM)] sleep, respectively. From 35 valid recordings, absolute time indexes showed intrasubject sleep phase differences. Peak flow relative to time and volume was lower in HR compared with LR only during REM, suggesting altered expiratory control. Indexes estimating the concavity/convexity of flow decrease during exhalation suggested limited flow during passive exhale in HR compared with IR and LR, similarly during NREM and REM. Moreover, during REM convexity was negatively correlated with maximal flow at functional residual capacity and methacholine responsiveness. We conclude that TBFV profiles determined from overnight IP recordings vary because of sleep phase and asthma risk. Physiological changes during REM, most likely decrease in respiratory muscle tone, accentuate the changes in TBFV profiles caused by airway obstruction. NEW & NOTEWORTHY Impedance pneumography was used to investigate overnight tidal breathing flow volume (TBFV) indexes and their interactions with sleep phase [rapid eye movement (REM) vs. non-REM] at home in wheezing infants. The study shows that TBFV indexes vary significantly because of sleep phase and asthma risk of the infant and that during REM the changes in TBFV indexes caused by airway obstruction are accentuated and better associated with lung function of the infant.