Thousands of genomic structural variants (SVs) segregate in the human population and can impact phenotypic traits and diseases. Their identification in whole-genome sequence data of large cohorts is ...a major computational challenge. Most current approaches identify SVs in single genomes and afterwards merge the identified variants into a joint call set across many genomes. We describe the approach PopDel, which directly identifies deletions of about 500 to at least 10,000 bp in length in data of many genomes jointly, eliminating the need for subsequent variant merging. PopDel scales to tens of thousands of genomes as we demonstrate in evaluations on up to 49,962 genomes. We show that PopDel reliably reports common, rare and de novo deletions. On genomes with available high-confidence reference call sets PopDel shows excellent recall and precision. Genotype inheritance patterns in up to 6794 trios indicate that genotypes predicted by PopDel are more reliable than those of previous SV callers. Furthermore, PopDel's running time is competitive with the fastest tested previous tools. The demonstrated scalability and accuracy of PopDel enables routine scans for deletions in large-scale sequencing studies.
Genetic studies have evaluated the influence of blood lipid levels on the risk of coronary artery disease (CAD), but less is known about how they are associated with the extent of coronary ...atherosclerosis.
To estimate the contributions of genetically predicted blood lipid levels on the extent of coronary atherosclerosis.
This genetic study included Icelandic adults who had undergone coronary angiography or assessment of coronary artery calcium using cardiac computed tomography. The study incorporates data collected from January 1987 to December 2017 in Iceland in the Swedish Coronary Angiography and Angioplasty Registry and 2 registries of individuals who had undergone percutaneous coronary interventions and coronary artery bypass grafting. For each participant, genetic scores were calculated for levels of non-high-density lipoprotein cholesterol (non-HDL-C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides, based on reported effect sizes of 345 independent, lipid-associated variants. The genetic scores' predictive ability for lipid levels was assessed in more than 87 000 Icelandic adults. A mendelian randomization approach was used to estimate the contribution of each lipid trait.
Genetic scores for levels of non-HDL-C, LDL-C, HDL-C, and triglycerides.
The extent of angiographic CAD and coronary artery calcium quantity.
A total of 12 460 adults (mean SD age, 65.1 10.7 years; 8383 men 67.3%) underwent coronary angiography, and 4837 had coronary artery calcium assessed by computed tomography. A genetically predicted increase in non-HDL-C levels by 1 SD (38 mg/dL to convert to millimoles per liter, multiply by 0.0259) was associated with greater odds of obstructive CAD (odds ratio OR, 1.83 95% CI, 1.63-2.07; P = 2.8 × 10-23). Among patients with obstructive CAD, there were significant associations with multivessel disease (OR, 1.26 95% CI, 1.11-1.44; P = 4.1 × 10-4) and 3-vessel disease (OR, 1.47 95% CI, 1.26-1.72; P = 9.2 × 10-7). There were also significant associations with the presence of coronary artery calcium (OR, 2.04 95% CI, 1.70-2.44; P = 5.3 × 10-15) and loge-transformed coronary artery calcium (effect, 0.70 95% CI, 0.53-0.87; P = 1.0 × 10-15). Genetically predicted levels of non-HDL-C remained associated with obstructive CAD and coronary artery calcium extent even after accounting for the association with LDL-C. Genetically predicted levels of HDL-C and triglycerides were associated individually with the extent of coronary atherosclerosis, but not after accounting for the association with non-HDL cholesterol.
In this study, genetically predicted levels of non-HDL-C were associated with the extent of coronary atherosclerosis as estimated by 2 different methods. The association was stronger than for genetically predicted levels of LDL-C. These findings further support the notion that non-HDL-C may be a better marker of the overall burden of atherogenic lipoproteins than LDL-C.
The aim of this study was to investigate occupational, environmental, early life and other risk factors associated with respiratory infections and antibiotics use in a general population and among ...asthmatic individuals.
This study included 15 842 participants of the Respiratory Health in Northern Europe (RHINE) study aged 25-54 years from five Nordic countries, who answered a questionnaire covering respiratory outcomes, exposures, demographic characteristics and numbers of infections and courses of antibiotics in the last 12 months. Multiple logistic regression with and without adjustment for age, sex, smoking status, body mass index and centre were used to study the risk of infection and antibiotics in relation to asthma, and also the association between infection and antibiotics and occupations.
In the whole population, 11.6% reported having three or more respiratory infections, and 14.7% had used antibiotics because of respiratory tract infections within the last year. Asthmatic participants reported tripled odds for such infections (adjusted OR 2.98, 95% CI 2.53-3.52) and antibiotics use (adjusted OR 3.67, 95% CI 3.18-4.24) as compared to non-asthmatic participants. Both in the general and the asthmatic population, female sex, obesity and exposure to building dampness were associated with respiratory infections. Female sex and current smoking and living in Tartu were associated with antibiotic use. The use of antibiotics was doubled in people hospitalised for severe respiratory infection in childhood.
In this study we identified several factors associated with increased respiratory infections and use of antibiotics in a general population and among asthmatic individuals. The frequency of respiratory infections and subsequent antibiotic treatment were increased among those with asthma.
Abstract
Aims
To explore whether variability in dietary cholesterol and phytosterol absorption impacts the risk of coronary artery disease (CAD) using as instruments sequence variants in the ABCG5/8 ...genes, key regulators of intestinal absorption of dietary sterols.
Methods and results
We examined the effects of ABCG5/8 variants on non-high-density lipoprotein (non-HDL) cholesterol (N up to 610 532) and phytosterol levels (N = 3039) and the risk of CAD in Iceland, Denmark, and the UK Biobank (105 490 cases and 844 025 controls). We used genetic scores for non-HDL cholesterol to determine whether ABCG5/8 variants confer greater risk of CAD than predicted by their effect on non-HDL cholesterol. We identified nine rare ABCG5/8 coding variants with substantial impact on non-HDL cholesterol. Carriers have elevated phytosterol levels and are at increased risk of CAD. Consistent with impact on ABCG5/8 transporter function in hepatocytes, eight rare ABCG5/8 variants associate with gallstones. A genetic score of ABCG5/8 variants predicting 1 mmol/L increase in non-HDL cholesterol associates with two-fold increase in CAD risk odds ratio (OR) = 2.01, 95% confidence interval (CI) 1.75–2.31, P = 9.8 × 10−23 compared with a 54% increase in CAD risk (OR = 1.54, 95% CI 1.49–1.59, P = 1.1 × 10−154) associated with a score of other non-HDL cholesterol variants predicting the same increase in non-HDL cholesterol (P for difference in effects = 2.4 × 10−4).
Conclusions
Genetic variation in cholesterol absorption affects levels of circulating non-HDL cholesterol and risk of CAD. Our results indicate that both dietary cholesterol and phytosterols contribute directly to atherogenesis.
The impact of active smoking, passive smoking, and obesity on habitual snoring in the population is mainly unknown. We aimed to study the relationship of habitual snoring with active and passive ...tobacco smoking in a population-based sample. A total of 15,555 of 21,802 (71%) randomly selected men and women aged 25-54 years from Iceland, Estonia, Denmark, Norway, and Sweden answered a postal questionnaire. Habitual snoring, defined as loud and disturbing snoring at least 3 nights a week, was more prevalent among current smokers (24.0%, p < 0.0001) and ex-smokers (20.3%, p < 0.0001) than in never-smokers (13.7%). Snoring was also more prevalent in never-smokers exposed to passive smoking at home on a daily basis than in never-smokers without this exposure (19.8% vs. 13.3%, p < 0.0001). The frequency of habitual snoring increased with the amount of tobacco smoked. Active smoking and passive smoking were related to snoring, independent of obesity, sex, center, and age. Ever smoking accounted for 17.1% of the attributable risk of habitual snoring, obesity (body mass index > or = 30 kg/m(2)) for 4.3%, and passive smoking for 2.2%. Smoking, both current and ex-smoking, is a major contributor to habitual snoring in the general population. Passive smoking is a previously unrecognized risk factor for snoring among adults.
Lipoprotein(a) Lp(a) is a causal risk factor for cardiovascular diseases that has no established therapy. The attribute of Lp(a) that affects cardiovascular risk is not established. Low levels of ...Lp(a) have been associated with type 2 diabetes (T2D).
This study investigated whether cardiovascular risk is conferred by Lp(a) molar concentration or apolipoprotein(a) apo(a) size, and whether the relationship between Lp(a) and T2D risk is causal.
This was a case-control study of 143,087 Icelanders with genetic information, including 17,715 with coronary artery disease (CAD) and 8,734 with T2D. This study used measured and genetically imputed Lp(a) molar concentration, kringle IV type 2 (KIV-2) repeats (which determine apo(a) size), and a splice variant in LPA associated with small apo(a) but low Lp(a) molar concentration to disentangle the relationship between Lp(a) and cardiovascular risk. Loss-of-function homozygotes and other subjects genetically predicted to have low Lp(a) levels were evaluated to assess the relationship between Lp(a) and T2D.
Lp(a) molar concentration was associated dose-dependently with CAD risk, peripheral artery disease, aortic valve stenosis, heart failure, and lifespan. Lp(a) molar concentration fully explained the Lp(a) association with CAD, and there was no residual association with apo(a) size. Homozygous carriers of loss-of-function mutations had little or no Lp(a) and increased the risk of T2D.
Molar concentration is the attribute of Lp(a) that affects risk of cardiovascular diseases. Low Lp(a) concentration (bottom 10%) increases T2D risk. Pharmacologic reduction of Lp(a) concentration in the 20% of individuals with the greatest concentration down to the population median is predicted to decrease CAD risk without increasing T2D risk.
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Epithelial damage is commonly found in airways of asthma patients. The aim of this study was to investigate epithelial damage in allergic and non-allergic asthma at the ultrastructural level.
...Bronchial biopsies obtained from patients with allergic asthma (
n
=
11
), non-allergic asthma (
n
=
7
), and healthy controls (
n
=
5
) were studied by transmission electron microscopy.
Epithelial damage was found to be extensive in both asthma groups. Both in basal and in columnar cells, relative desmosome length was reduced by 30–40%. In columnar cells, half-desmosomes (i.e., desmosomes of which only one side was present) were frequently noticed. Eosinophils showing piece-meal degranulation were commonly observed in allergic asthma. Degranulating mast cells were more often observed in allergic asthma. Goblet cell hyperplasia was only found in allergic asthma. Lymphocytes were increased in both groups. In both groups, the lamina densa of the basal lamina was thicker than the control by about 40–50%. In allergic asthma the lamina densa was irregular with focal thickening.
While there was always a tendency for changes (epithelial damage, desmosomes, degranulating mast cells, basal lamina) to be more extensive in allergic asthma compared to non-allergic asthma, there was no significant difference between the two groups in this respect. Reduced desmosomal contact may be an important factor in the epithelial shedding observed in patients with asthma.
Welding-related asthma is well recognised but less is known about rhinitis in relation to welding. The aim here, was to study associations between welding, rhinitis and asthma in a general population ...sample, and factors influencing selection into and out of a welding occupation.Adult-onset asthma and non-infectious rhinitis were investigated in the international multicentre population-based Respiratory Health in Northern Europe (RHINE) study, including 16,191 responders aged 26-54 years. Ever welding (n=2181), welding >25% of working time (n=747), and welding in stainless steel >6 months (n=173) were assessed by questionnaire. Subjects with rhinitis or asthma onset when aged <18 years were excluded. Incidence rates for asthma and rhinitis were calculated from year of disease onset, and start and end of welding job. Cox's proportional hazard models adjusting for age, sex, parental education and study centre, and Kaplan-Meier curves were used.Rhinitis incidence was higher among welders (hazard ratio (HR) 1.4, 95% CI 1.3-1.6), consistent in men and women, and across centres (pheterogeneity=0.4). In men, asthma incidence was higher among welders (HR 1.4, 95% CI 1.04-1.97). Quitting welding was indicated higher after adult-onset rhinitis (HR 1.1, 95% CI 1.0-1.3). Adult-onset rhinitis and asthma was higher among welders, consistent across population samples from Northern Europe. No pre-employment selection was found, whereas selection out of welding jobs was suggested.
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