A genome-wide association study provides insights into the genetic etiology of 57 essential and non-essential trace elements in humans.

Trace elements are important for human health but may exert toxic or adverse effects. Mechanisms of uptake, distribution, metabolism, and excretion are partly under genetic control but have not yet been extensively mapped. Here we report a comprehensive multi-element genome-wide association study of 57 essential and non-essential trace elements. We perform genome-wide association meta-analyses of 14 trace elements in up to 6564 Scandinavian whole blood samples, and genome-wide association studies of 43 trace elements in up to 2819 samples measured only in the Trøndelag Health Study (HUNT). We identify 11 novel genetic loci associated with blood concentrations of arsenic, cadmium, manganese, selenium, and zinc in genome-wide association meta-analyses. In HUNT, several genome-wide significant loci are also indicated for other trace elements. Using two-sample Mendelian randomization, we find several indications of weak to moderate effects on health outcomes, the most precise being a weak harmful effect of increased zinc on prostate cancer. However, independent validation is needed. Our current understanding of trace element-associated genetic variants may help establish consequences of trace elements on human health.

Level of Education Modifies Asthma Mortality in Norway and Sweden. The Nordic EpiLung Study.

Background and Aim: The relationship between socioeconomic status (SES), asthma and mortality is complex and multifaceted, and it is not established if educational level modifies the association between asthma and mortality. The aim was to study the association between asthma and mortality in Sweden and Norway and to what extent educational level modifies this association. Participants and Methods: Within the Nordic EpiLung Study, >56,000 individuals aged 30-69 years participated in population-based surveys on asthma and associated risk factors in Sweden and Norway during 2005-2007. Data on educational level and 10-year all-cause mortality were linked by national authorities. The fraction of mortality risk attributable to asthma was calculated, and Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for mortality related to asthma, stratified by educational level. Results: In total, 5.5% of all deaths was attributed to asthma. When adjusted for potential confounders, the HR for mortality related to asthma was 1.71 (95% CI 1.52-1.93). Those with primary level of education had higher hazard of all-cause death related to asthma than those with tertiary level (HR 1.80, 95% CI 1.48-2.18, vs HR 1.39, 95% CI 0.99-1.95). Conclusion: Asthma was associated with an overall 71% increased all-cause mortality and 5.5% of deaths can be attributed to asthma. Educational levels modified the risk of mortality associated with asthma, with the highest risk among those with primary education.

Is there still a social gradient in respiratory symptoms? A population-based Nordic EpiLung-study.

BACKGROUND: Respiratory symptoms are a common public health issue that can partly be attributed to preventable risk factors, such as tobacco smoking and occupational exposure, which are more common in individuals with lower socioeconomic status. OBJECTIVE: Our aim was to evaluate the social gradient in respiratory symptoms in Nordic countries. METHODS: This study included participants aged 30-65 years from five cross-sectional population-based questionnaire surveys in 2016 in Finland and Sweden (N = 25,423) and in 2017-2019 in Norway (N = 27,107). Occupational skill levels 1 and 2 (occupations requiring compulsory education) were combined and compared to skill levels 3 and 4 (occupations requiring upper secondary and tertiary education). Meta-analysis was conducted to obtain pooled age- and sex adjusted odds ratios (aORs) of associations between occupational skill and the respiratory symptoms including recurrent wheeze, dyspnoea, and productive cough. RESULTS: In the meta-analysis, recurrent wheeze, dyspnoea, and productive cough showed a social gradient. The participants with occupational skill 1 and 2 had higher risk for recurrent wheeze (aOR 1.78, 95% CI 1.34-2.22) and dyspnoea (aOR 1.59, 95% CI 1.29-1.90) compared to occupational skill 3 and 4 in Sweden and Finland. Similarly increased risk was observed for combined assessment of dyspnoea and wheeze (aOR 1.05, 95% CI 1.03-1.07) in Norway. In a meta-analysis including all three countries, the aOR for productive cough was 1.31 95% CI 1.07-1.56. CONCLUSIONS: Occupations with lower, compared to higher, skill levels were associated with an increased risk of recurrent wheeze, dyspnoea, and productive cough.

Dengue fever complicated with ST elevation myocardial infarction with atypical features: A case report.

Dengue fever is an arboviral infection whose presentation ranges from a mild febrile illness to a multisystem complicated syndrome. We report a case of 58-year-old female presenting with fever, myalgia, arthralgia, and vomiting who was found to be infected with dengue and had electrocardiography changes revealing ST-segment elevation myocardial infarction, a rare manifestation in dengue. Dengue fever can affect the cardiovascular system leading to conduction abnormalities, hypotension, arrhythmias, myocarditis, cardiomyopathy, and occasionally myocardial infarction, which has been reported in only a few case reports prior to this. The differentiation between myocarditis and myocardial infarction is essential for which echocardiography and coronary angiography can be helpful. It is essential to keep an eye on the cardiovascular complications in a dengue patient as the presentation can be quite subtle with devastating consequences.

Acute oral poisoning due to pretilachlor herbicide - a rare case report from Nepal.

Introduction: Acute oral intoxication of pretilachlor, a synthetic chloroacetanilide herbicide, can present similar clinical manifestations of organophosphorus toxicity in humans. Case presentation: A 15-year-old male was admitted after suicidal ingestion of pretilachlor poison, with decreased consciousness and blood-mixed vomiting. Discussion: Pretilachlor is a colorless and odorless liquid that can cause neurotoxicity and carcinogenicity due to its prolonged exposure. The effects of acute oral exposure are mild and may differ from chronic exposure. Individuals exposed to chloroacetanilides may not show symptoms or experience vomiting and neurological issues. Clinical manifestations such as vomiting, excessive lacrimation, bowel and bladder incontinence, bradycardia, and hypotension can be observed in both organophosphate poisoning and pretilachlor poisoning, making accurate diagnosis challenging, particularly in resource-limited settings like ours. There is no specific antidote for pretilachlor poisoning. Treatment focuses on symptomatic care and monitoring the patient's hemodynamics as per standard protocol. Conclusion: This case underscores the need for prompt stabilization, vigilant monitoring, and supportive care to ensure timely recovery in pretilachlor poisoning cases despite similarities with organophosphate poisoning. It emphasizes the importance of educating and raising awareness among physicians about potential mimickers like organophosphates.

Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth.

A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n = 65,405), maternal (n = 61,228) and paternal (n = 52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth.

Investigating the causal interplay between sleep traits and risk of acute myocardial infarction: a Mendelian randomization study.

BACKGROUND: Few studies have investigated the joint effects of sleep traits on the risk of acute myocardial infarction (AMI). No previous study has used factorial Mendelian randomization (MR) which may reduce confounding, reverse causation, and measurement error. Thus, it is prudent to study joint effects using robust methods to propose sleep-targeted interventions which lower the risk of AMI. METHODS: The causal interplay between combinations of two sleep traits (including insomnia symptoms, sleep duration, or chronotype) on the risk of AMI was investigated using factorial MR. Genetic risk scores for each sleep trait were dichotomized at their median in UK Biobank (UKBB) and the second survey of the Trøndelag Health Study (HUNT2). A combination of two sleep traits constituting 4 groups were analyzed to estimate the risk of AMI in each group using a 2×2 factorial MR design. RESULTS: In UKBB, participants with high genetic risk for both insomnia symptoms and short sleep had the highest risk of AMI (hazard ratio (HR) 1.10; 95% confidence interval (CI) 1.03, 1.18), although there was no evidence of interaction (relative excess risk due to interaction (RERI) 0.03; 95% CI -0.07, 0.12). These estimates were less precise in HUNT2 (HR 1.02; 95% CI 0.93, 1.13), possibly due to weak instruments and/or small sample size. Participants with high genetic risk for both a morning chronotype and insomnia symptoms (HR 1.09; 95% CI 1.03, 1.17) and a morning chronotype and short sleep (HR 1.11; 95% CI 1.04, 1.19) had the highest risk of AMI in UKBB, although there was no evidence of interaction (RERI 0.03; 95% CI -0.06, 0.12; and RERI 0.05; 95% CI -0.05, 0.14, respectively). Chronotype was not available in HUNT2. CONCLUSIONS: This study reveals no interaction effects between sleep traits on the risk of AMI, but all combinations of sleep traits increased the risk of AMI except those with long sleep. This indicates that the main effects of sleep traits on AMI are likely to be independent of each other.

Polygenic prediction of preeclampsia and gestational hypertension.

Preeclampsia and gestational hypertension are common pregnancy complications associated with adverse maternal and child outcomes. Current tools for prediction, prevention and treatment are limited. Here we tested the association of maternal DNA sequence variants with preeclampsia in 20,064 cases and 703,117 control individuals and with gestational hypertension in 11,027 cases and 412,788 control individuals across discovery and follow-up cohorts using multi-ancestry meta-analysis. Altogether, we identified 18 independent loci associated with preeclampsia/eclampsia and/or gestational hypertension, 12 of which are new (for example, MTHFR-CLCN6, WNT3A, NPR3, PGR and RGL3), including two loci (PLCE1 and FURIN) identified in the multitrait analysis. Identified loci highlight the role of natriuretic peptide signaling, angiogenesis, renal glomerular function, trophoblast development and immune dysregulation. We derived genome-wide polygenic risk scores that predicted preeclampsia/eclampsia and gestational hypertension in external cohorts, independent of clinical risk factors, and reclassified eligibility for low-dose aspirin to prevent preeclampsia. Collectively, these findings provide mechanistic insights into the hypertensive disorders of pregnancy and have the potential to advance pregnancy risk stratification.

Interaction of smoking and social status on the risk of respiratory outcomes in a Swedish adult population: A Nordic Epilung study.

BACKGROUND: Evidence abounds on the independent roles of social class and smoking in relation to obstructive airway diseases, but data are sparse on the impact of their interaction. We evaluated whether and to what extent social class and smoking interact in relation to risk of respiratory diseases in adults. METHODS: Data from the population-based studies, West Sweden Asthma Study (WSAS, n = 23,753) and Obstructive Lung Disease in Northern Sweden studies (OLIN, n = 6519), were used, constituting randomly selected adults aged 20-75 years. Bayesian network analysis was used to estimate the probability for the interaction between smoking and socioeconomic status in relation to respiratory outcomes. RESULTS: Occupational and educational SES modified the association between smoking and the probability of allergic and non-allergic asthma. Former smokers who were at intermediate non manual employees and manual workers in service had higher probability of allergic asthma compared to professionals and executives. Furthermore, former smokers with primary education had higher probability of non-allergic asthma than those with secondary and tertiary education. Similarly, former smokers among professionals and executives had higher probability of non-allergic asthma than manual and home workers and primary educated. Likewise, allergic asthma due to former smoking was higher among highly educated compared to low educated. CONCLUSIONS: Beyond their independent roles, socioeconomic status and smoking interact in defining the risk of respiratory diseases. Clearer understanding of this interaction can help to identify population subgroups at most need of public health interventions.

Global Biobank analyses provide lessons for developing polygenic risk scores across diverse cohorts.

Polygenic risk scores (PRSs) have been widely explored in precision medicine. However, few studies have thoroughly investigated their best practices in global populations across different diseases. We here utilized data from Global Biobank Meta-analysis Initiative (GBMI) to explore methodological considerations and PRS performance in 9 different biobanks for 14 disease endpoints. Specifically, we constructed PRSs using pruning and thresholding (P + T) and PRS-continuous shrinkage (CS). For both methods, using a European-based linkage disequilibrium (LD) reference panel resulted in comparable or higher prediction accuracy compared with several other non-European-based panels. PRS-CS overall outperformed the classic P + T method, especially for endpoints with higher SNP-based heritability. Notably, prediction accuracy is heterogeneous across endpoints, biobanks, and ancestries, especially for asthma, which has known variation in disease prevalence across populations. Overall, we provide lessons for PRS construction, evaluation, and interpretation using GBMI resources and highlight the importance of best practices for PRS in the biobank-scale genomics era.

Using Genomic Structural Equation Modeling to Partition the Genetic Covariance Between Birthweight and Cardiometabolic Risk Factors into Maternal and Offspring Components in the Norwegian HUNT Study.

The Barker Hypothesis posits that adverse intrauterine environments result in fetal growth restriction and increased risk of cardiometabolic disease through developmental compensations. Here we introduce a new statistical model using the genomic SEM software that is capable of simultaneously partitioning the genetic covariation between birthweight and cardiometabolic traits into maternally mediated and offspring mediated contributions. We model the covariance between birthweight and later life outcomes, such as blood pressure, non-fasting glucose, blood lipids and body mass index in the Norwegian HUNT study, consisting of 15,261 mother-eldest offspring pairs with genetic and phenotypic data. Application of this model showed some evidence for maternally mediated effects of systolic blood pressure on offspring birthweight, and pleiotropy between birthweight and non-fasting glucose mediated through the offspring genome. This underscores the importance of genetic links between birthweight and cardiometabolic phenotypes and offer alternative explanations to environmentally based hypotheses for the phenotypic correlation between these variables.

Proteome-wide Mendelian randomization in global biobank meta-analysis reveals multi-ancestry drug targets for common diseases.

Proteome-wide Mendelian randomization (MR) shows value in prioritizing drug targets in Europeans but with limited evidence in other ancestries. Here, we present a multi-ancestry proteome-wide MR analysis based on cross-population data from the Global Biobank Meta-analysis Initiative (GBMI). We estimated the putative causal effects of 1,545 proteins on eight diseases in African (32,658) and European (1,219,993) ancestries and identified 45 and 7 protein-disease pairs with MR and genetic colocalization evidence in the two ancestries, respectively. A multi-ancestry MR comparison identified two protein-disease pairs with MR evidence in both ancestries and seven pairs with specific effects in the two ancestries separately. Integrating these MR signals with clinical trial evidence, we prioritized 16 pairs for investigation in future drug trials. Our results highlight the value of proteome-wide MR in informing the generalizability of drug targets for disease prevention across ancestries and illustrate the value of meta-analysis of biobanks in drug development.

The causes and consequences of Alzheimer's disease: phenome-wide evidence from Mendelian randomization.

Alzheimer's disease (AD) has no proven causal and modifiable risk factors, or effective interventions. We report a phenome-wide association study (PheWAS) of genetic liability for AD in 334,968 participants of the UK Biobank study, stratified by age. We also examined the effects of AD genetic liability on previously implicated risk factors. We replicated these analyses in the HUNT study. PheWAS hits and previously implicated risk factors were followed up in a Mendelian randomization (MR) framework to identify the causal effect of each risk factor on AD risk. A higher genetic liability for AD was associated with medical history and cognitive, lifestyle, physical and blood-based measures as early as 39 years of age. These effects were largely driven by the APOE gene. The follow-up MR analyses were primarily null, implying that most of these associations are likely to be a consequence of prodromal disease or selection bias, rather than the risk factor causing the disease.

Ecosystem-based adaptation for increased agricultural productivity by smallholder farmers in Nepal.

The impacts of climate change are evident in the agriculture sector globally. These impacts are more severe and pronounced in a mountainous country like Nepal due to the high reliance on agro-economy and subsistence-based livelihoods by smallholder farmers that increase vulnerability and risks. Several ecosystem-based adaptation measures have proved to build the adaptive capacity of both agro-ecosystems and smallholder farmers by offering simple and affordable technologies however, these are yet to be prioritized by policy and programs for scaling. In this paper, we provide science-based evidence to traditionally used practices, such as jholmal (locally prepared bio-fertilizer and pesticides) and straw mulching by comparing their efficacy in terms of yield and reduction in disease pest infestation. The study was conducted in Kavre district of Nepal during 2017 and 2018 using participatory on-farm field trials for jholmal and straw mulching designed separately with Randomized Complete Block Design for selected vegetable crops like bitter gourd and tomato. The application of jholmal showed significant increase in bitter gourd yield both at the foothill and hilltop sites compared to the farmer's business usual practice (in 2017 and 2018, bitter gourd yield increased by 30.5% and 31.1% in foothill, while 26.6% and 28.7% in hilltops respectively). Further, a significant reduction on fruit infestation was observed in jholmal treated plots. Similarly, there was increase in tomato yield when straw mulch was used compared to the non-mulched trials (in 2017 and 2018, tomato yield increased by 16.5% and 20.3% respectively). These findings suggest that traditionally used practices have scientific basis and offer simple, affordable and climate friendly practices to improve the health of agro-ecosystem while supporting smallholder farmers to adapt to adverse impacts of climate change and build socio-ecological resilience. These practices can be also customized depending on the local context for wider adoption and scaling across Nepal and elsewhere as ecosystem-based adaptation measures for smallholder farmers.

Investigating a Potential Causal Relationship Between Maternal Blood Pressure During Pregnancy and Future Offspring Cardiometabolic Health.

Observational epidemiological studies have reported that higher maternal blood pressure (BP) during pregnancy is associated with increased future risk of offspring cardiometabolic disease. However, it is unclear whether this association represents a causal relationship through intrauterine mechanisms. We used a Mendelian randomization (MR) framework to examine the relationship between unweighted maternal genetic scores for systolic BP and diastolic BP and a range of cardiometabolic risk factors in the offspring of up to 29 708 genotyped mother-offspring pairs from the UKB study (UK Biobank) and the HUNT study (Trøndelag Health). We conducted similar analyses in up to 21 423 father-offspring pairs from the same cohorts. We confirmed that the BP-associated genetic variants from the general population sample also had similar effects on maternal BP during pregnancy in independent cohorts. We did not detect any association between maternal (or paternal) unweighted genetic scores and cardiometabolic offspring outcomes in the meta-analysis of UKB and HUNT after adjusting for offspring genotypes at the same loci. We find little evidence to support the notion that maternal BP is a major causal risk factor for adverse offspring cardiometabolic outcomes in later life.

The HUNT study: A population-based cohort for genetic research.

The Trøndelag Health Study (HUNT) is a population-based cohort of ∼229,000 individuals recruited in four waves beginning in 1984 in Trøndelag County, Norway. Approximately 88,000 of these individuals have available genetic data from array genotyping. HUNT participants were recruited during four community-based recruitment waves and provided information on health-related behaviors, self-reported diagnoses, family history of disease, and underwent physical examinations. Linkage via the Norwegian personal identification number integrates digitized health care information from doctor visits and national health registries including death, cancer and prescription registries. Genome-wide association studies of HUNT participants have provided insights into the mechanism of cardiovascular, metabolic, osteoporotic, and liver-related diseases, among others. Unique features of this cohort that facilitate research include nearly 40 years of longitudinal follow-up in a motivated and well-educated population, family data, comprehensive phenotyping, and broad availability of DNA, RNA, urine, fecal, plasma, and serum samples.

Bone mineral density and risk of cardiovascular disease in men and women: the HUNT study.

The association between bone mineral density (BMD) and cardiovascular disease (CVD) is not fully understood. We evaluated BMD as a risk factor for cardiovascular disease and specifically atrial fibrillation (AF), acute myocardial infarction (AMI), ischemic (IS) and hemorrhagic stroke (HS) and heart failure (HF) in men and women. This prospective population cohort utilized data on 22 857 adults from the second and third surveys of the HUNT Study in Norway free from CVD at baseline. BMD was measured using single and dual-energy X-ray absorptiometry in the non-dominant distal forearm and T-score was calculated. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated from adjusted cox proportional hazards models. The analyses were sex-stratified, and models were adjusted for age, age-squared, BMI, physical activity, smoking status, alcohol use, and education level. Additionally, in women, we adjusted for estrogen use and postmenopause. During a mean follow-up of 13.6 ± 5.7 years, 2 928 individuals (12.8%) developed fatal or non-fatal CVD, 1 020 AF (4.5%), 1 172 AMI (5.1%), 1 389 IS (6.1%), 264 HS (1.1%), and 464 HF (2.0%). For every 1 unit decrease in BMD T-score the HR for any CVD was 1.01 (95% CI 0.98 to 1.04) in women and 0.99 (95% CI 0.94 to 1.03) in men. Point estimates for the four cardiovascular outcomes ranged from slightly protective (HR 0.95 for AF in men) to slightly deleterious (HR 1.12 for HS in men). We found no evidence of association of lower distal forearm BMD with CVD, AF, AMI, IS, HS, and HF.

Age-of-onset information helps identify 76 genetic variants associated with allergic disease.

Risk factors that contribute to inter-individual differences in the age-of-onset of allergic diseases are poorly understood. The aim of this study was to identify genetic risk variants associated with the age at which symptoms of allergic disease first develop, considering information from asthma, hay fever and eczema. Self-reported age-of-onset information was available for 117,130 genotyped individuals of European ancestry from the UK Biobank study. For each individual, we identified the earliest age at which asthma, hay fever and/or eczema was first diagnosed and performed a genome-wide association study (GWAS) of this combined age-of-onset phenotype. We identified 50 variants with a significant independent association (P<3x10-8) with age-of-onset. Forty-five variants had comparable effects on the onset of the three individual diseases and 38 were also associated with allergic disease case-control status in an independent study (n = 222,484). We observed a strong negative genetic correlation between age-of-onset and case-control status of allergic disease (rg = -0.63, P = 4.5x10-61), indicating that cases with early disease onset have a greater burden of allergy risk alleles than those with late disease onset. Subsequently, a multivariate GWAS of age-of-onset and case-control status identified a further 26 associations that were missed by the univariate analyses of age-of-onset or case-control status only. Collectively, of the 76 variants identified, 18 represent novel associations for allergic disease. We identified 81 likely target genes of the 76 associated variants based on information from expression quantitative trait loci (eQTL) and non-synonymous variants, of which we highlight ADAM15, FOSL2, TRIM8, BMPR2, CD200R1, PRKCQ, NOD2, SMAD4, ABCA7 and UBE2L3. Our results support the notion that early and late onset allergic disease have partly distinct genetic architectures, potentially explaining known differences in pathophysiology between individuals.

GOLD Classifications, COPD Hospitalization, and All-Cause Mortality in Chronic Obstructive Pulmonary Disease: The HUNT Study.

Purpose: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has published three classifications of COPD from 2007 to 2017. No studies have investigated the ability of these classifications to predict COPD-related hospitalizations. We aimed to compare the discrimination ability of the GOLD 2007, 2011, and 2017 classifications to predict COPD hospitalization and all-cause mortality. Patients and Methods: We followed 1300 participants with COPD aged ≥40 years who participated in the HUNT Study (1995-1997) through to December 31, 2015. Survival analysis and time-dependent area under receiver operating characteristics curves (AUC) were used to compare the discrimination abilities of the GOLD classifications. Results: Of the 1300 participants, 522 were hospitalized due to COPD and 896 died over 20.4 years of follow-up. In adjusted models, worsening GOLD 2007, GOLD 2011, or GOLD 2017 categories were associated with higher hazards for COPD hospitalization and all-cause mortality, except for the GOLD 2017 classification and all-cause mortality (ptrend=0.114). In crude models, the AUCs (95% CI) for the GOLD 2007, GOLD 2011, and GOLD 2017 for COPD hospitalization were 63.1 (58.7-66.9), 60.9 (56.1-64.4), and 56.1 (54.0-58.1), respectively, at 20-years' follow-up. Corresponding estimates for all-cause mortality were 57.0 (54.8-59.1), 54.1 (52.1-56.0), and 52.6 (51.0-54.3). The differences in AUCs between the GOLD classifications to predict COPD hospitalization and all-cause mortality were constant over the follow-up time. Conclusion: The GOLD 2007 classification was better than the GOLD 2011 and 2017 classifications at predicting COPD hospitalization and all-cause mortality.