Long-read sequencing (LRS) promises to improve characterization of structural variants (SVs), a major source of genetic diversity. We generated LRS data on 3,622 Icelanders using Oxford Nanopore Technologies, and identified a median of 22,636 SVs per individual (a median of 13,353 insertions and 9,474 deletions), spanning a median of 10 Mb per haploid genome. We discovered a set of 133,886 reliably genotyped SV alleles and imputed them into 166,281 individuals to explore their effects on diseases and other traits. We discovered an association with a rare (AF = 0.037%) deletion of the first exon of PCSK9. Carriers of this deletion have 0.93 mmol/L (1.31 SD) lower LDL cholesterol levels than the population average (p-value = 7.0•10 −20 ). We also discovered an association with a multi-allelic SV inside a large repeat region, contained within single long reads, in an exon of ACAN. Within this repeat region we found 11 alleles that differ in the number of a 57 bp-motif repeat, and observed a linear relationship (0.016 SD per motif inserted, p = 6.2•10 −18 ) between the number of repeats carried and height. These results show that SVs can be accurately characterized at population scale using long read sequence data in a genome-wide non-targeted approach and demonstrate how SVs impact phenotypes.Human sequence diversity is partially due to structural variants 1 (SVs); genomic rearrangements affecting at least 50 bp of sequence in forms of insertions, deletions, inversions, or translocations. The number of SVs carried by each individual is less than the number of single nucleotide polymorphisms (SNPs) and short (< 50 bp) insertions and deletions (indels), but their greater size makes them more likely to have a functional role 2 , as evident by their disproportionately large impact on diseases and other traits 2,3 .Extensive characterization of three trios sequenced using several technologies 4 and an annotated set based on one sample (HG002) 5 indicate that humans carry 23-31 thousand SVs .

The aim of this investigation was to study the relationship between psychologic status and respiratory health. The study comprised 715 persons aged 22 to 44 who participated in the European Commission Respiratory Health Survey. The study included a structural interview, spirometry, methacholine challenge, peak flow diary, skin prick test, and measurement of eosinophil activity in peripheral blood. The psychologic status was assessed by means of the hospital anxiety and depression (HAD) scale questionnaire. A significant correlation was found between anxiety and depression and the report of asthma-related symptoms, such as attacks of breathlessness after activity and waking with attacks of breathlessness (p < 0.01). However, there was no significant correlation between anxiety or depression and a self-reported diagnosis of asthma or objective asthma-related variables, such as peak flow variability or response to methacholine. When evaluating the combined influence of psychologic factors and objective variables, HAD score correlated independently with reported wheezing (p< 0.05), waking with attacks of breathlessness (p < 0.01), waking with chest tightness, attacks of breathlessness when at rest, and attacks of breathlessness after activity (p < 0.001). We conclude that there is an association between reported respiratory symptoms and psychologic status. However, there was no evidence that patients with diagnosed bronchial asthma had more anxiety and depression than those without asthma. This result indicates that it may be valuable to include psychologic status indicators in respiratory symptom questionnaires.

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Long-read sequencing (LRS) promises to improve characterization of structural variants (SVs), a major source of genetic diversity. We generated LRS data on 1,817 Icelanders using Oxford Nanopore Technologies, and identified a median of 23,111 autosomal structural variants per individual (a median of 11,506 insertions and 11,576 deletions), spanning cumulatively a median of 9.9 Mb. We found that rare SVs are larger in size than common ones and are more likely to impact protein function. We discovered an association with a rare deletion of the first exon ofPCSK9. Carriers of this deletion have 0.93 mmol/L (1.36 sd) lower LDL cholesterol levels than the population average (p-value = 2.4·10−22). We show that SVs can be accurately characterized at population scale using long read sequence data in a genomewide non-targeted fashion and how these variants impact disease.

Asthma is a common chronic disorder which may be increasing in prevalence. However, little is known of its distribution and determinants. The European Community Respiratory Health Survey (ECRHS) is a multicentre survey of the prevalence, determinants and management of asthma. This paper presents a descriptive account of the variation in self-reported attacks of asthma and asthma symptoms across Europe, and in part fulfils the first aim of the study. A screening questionnaire, including seven questions relating to the 12 month prevalence of symptoms of asthma, was distributed to representative samples of 20-44 year old men and women in 48 centers, predominantly in Western Europe. The median response rate to the questionnaire was 75% but, after removing from the denominator those who were the wrong age, were known to have moved out of the area, or had died, it was 78% (range 54-100). The prevalence of all symptoms varied widely. Although these were generally lower in northern, central and southern Europe and higher in the British Isles, New Zealand, Australia and the United States, there were wide variations even within some countries. Centres with a high prevalence of self-reported attacks of asthma also reported high prevalences of nasal allergies and of waking at night with breathlessness. The use of asthma medication was more common where wheeze and asthma attacks were more frequent. In most centres in The Netherlands, Sweden, New Zealand and the United Kingdom over 80% of those with a diagnosis of asthma were currently using asthma medication. In Italy, France and Spain the rate was generally less than 70%. These data are the best evidence to date that geographical differences in asthma prevalence exist, are substantial and are not an artefact of the use of noncomparable methods.

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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.

Background: COPD is a common cause of morbidity and mortality. The aim of this study was to explore patients’ experiences, self-reported needs, and needs-driven strategies to cope with self-management of COPD. Patients and methods: In this phenomenological study, 10 participants with mild to severe COPD were interviewed 1–2 times, until data saturation was reached. In total, 15 in-depth interviews were conducted, recorded, transcribed, and analyzed. Results: COPD negatively affected participants’ physical and psychosocial well-being, their family relationships, and social life. They described their experiences of COPD like fighting a war without weapons in an ever-shrinking world with a loss of freedom at most levels, always fearing possible breathlessness. Fourteen needs were identified and eight clusters of needs-driven strategies that participants used to cope with self-management of COPD. Coping with the reality of COPD, a life-threatening disease, meant coping with dyspnea, feelings of suffocation, indescribable smoking addiction, anxiety, and lack of knowledge about the disease. Reduced participation in family and social life meant loss of ability to perform usual and treasured activities. Having a positive mindset, accepting help and assuming healthy lifestyle was important, as well as receiving continuous professional health care services. The participants’ needs-driven strategies comprised conducting financial arrangements, maintaining hope, and fighting their smoking addiction, seeking knowledge about COPD, thinking differently, facing the broken chain of health care, and struggling with accepting support. Procrastination and avoidance were also evident. Finally, the study also found that participants experienced a perpetuating cycle of dyspnea, anxiety, and fear of breathlessness due to COPD which could lead to more severe dyspnea and even panic attacks. Conclusion: COPD negatively affects patients’ physical and psychosocial well-being, family relationships and, social life. Identifying patients’ self-reported needs and needs-driven strategies can enable clinicians to empower patients by educating them to improve their self-management.