Toll-like receptor 4 (TLR-4) polymorphisms and asthma risk in rural and urban settings: findings from the UK biobank.

Introduction And Aim: The risk of asthma and its phenotypes may be modified by gene-environmental interactions. The previous studies on the interactions between genetic variations in the toll like 4 (TLR4) the main receptor for bacterial endotoxin, and asthma were contradictory as they were underpowered and did not consider different asthma phenotypes. The main aim of this study was to identify interactions between two single nucleotide polymorphisms (SNPs) within the gene, Asp299Gly and Thr399Ile, and residential area (urban or rural) in females and males with asthma and different asthma phenotypes.

Advances in development of biomarkers for brain damage and ischemia.

Acquired brain injury is an urgent situation that requires rapid diagnosis and treatment. Magnetic resonance imaging (MRI) and computed tomography (CT) are required for accurate diagnosis. However, these methods are costly and require substantial infrastructure and specialized staff.

Copy number variations and their effect on the plasma proteome.

Structural variations, including copy number variations (CNVs), affect around 20 million bases in the human genome and are common causes of rare conditions. CNVs are rarely investigated in complex disease research because most CNVs are not targeted on the genotyping arrays or the reference panels for genetic imputation. In this study, we characterize CNVs in a Swedish cohort (N = 1,021) using short-read whole-genome sequencing (WGS) and use long-read WGS for validation in a subcohort (N = 15), and explore their effect on 438 plasma proteins.

Well-being spectrum traits are associated with polygenic scores for autism.

Individuals with autism spectrum disorder (ASD) tend to experience lower well-being as demonstrated mostly for children and adolescents in epidemiological studies. A further investigation of inclusive well-being, in terms of five well-being spectrum (5-WBS) traits including neuroticism, depression, loneliness, life satisfaction, and positive affect, among adults with ASD may deepen our understanding of their well-being, and lead to the possibility to further modify societal supportive mechanisms for individuals with ASD. This study aims to investigate if a genetic predisposition for ASD is associated with 5-WBS traits using polygenic risk score (PRS) analysis.

Adiposity and sex-specific cancer risk.

Obesity is associated with several types of cancer and fat distribution, which differs dramatically between sexes, has been suggested to be an independent risk factor. However, sex-specific effects on cancer risk have rarely been studied. Here we estimate the effects of fat accumulation and distribution on cancer risk in females and males.

Body Mass Index and the Risk of Rheumatic Disease: Linear and Nonlinear Mendelian Randomization Analyses.

Objective: Although the association between obesity and risk of rheumatic disease is well established, the precise causal relation has not been conclusively proven. Here, we estimate the causal effect of body mass index (BMI) on the risk of developing 5 different rheumatic diseases.

Methods: Linear and nonlinear mendelian randomization (MR) were used to estimate the effect of BMI on risk of rheumatic disease, and sex-specific effects were identified.

Migraine, inflammatory bowel disease and celiac disease: A Mendelian randomization study.

Objective: To assess whether migraine may be genetically and/or causally associated with inflammatory bowel disease (IBD) or celiac disease.

Background: Migraine has been linked to IBD and celiac disease in observational studies, but whether this link may be explained by a shared genetic basis or could be causal has not been established. The presence of a causal association could be clinically relevant, as treating one of these medical conditions might mitigate the symptoms of a causally linked condition.

Statins Induce Locomotion and Muscular Phenotypes in That Are Reminiscent of Human Myopathy: Evidence for the Role of the Chloride Channel Inhibition in the Muscular Phenotypes.

The underlying mechanisms for statin-induced myopathy (SIM) are still equivocal. In this study, we employ to dissect possible underlying mechanisms for SIM. We observe that chronic fluvastatin treatment causes reduced general locomotion activity and climbing ability.

Regeneration in the Auditory Organ in Cuban and African Dwarf Crocodiles ( and ) Can We Learn From the Crocodile How to Restore Our Hearing?

In several non-mammalian species, auditory receptors undergo cell renewal after damage. This has raised hope of finding new options to treat human sensorineural deafness. Uncertainty remains as to the triggering mechanisms and whether hair cells are regenerated even under normal conditions.

Youth with severe mental illness and complex non-somatic motor abnormalities: conflicting conceptualizations and unequal treatment.

Two emerging diagnostic concepts promote distinct treatments for youth with acute-onset motor abnormalities and severe concurrent psychiatric symptoms: Pediatric acute-onset neuropsychiatric syndrome (PANS) and pediatric catatonia. Both have institutional approval in parts of Europe and in the USA, meriting an unconditional comparison of supporting evidence. Here we report results of qualitative and quantitative analyses of literature and Swedish National Registry Data suggesting that (1) catatonic patients are liable to fulfilling diagnostic criteria for PANS, (2) three conservatively assessed PANS case-reports present with possible unrecognized catatonia, (3) lithium and electroconvulsive therapy usage frequencies in Swedish minors (exclusively recommended for severe mental illness) are strongly intercorrelated and unequally distributed across Swedish counties, (4) established severe mental disorders are rarely overtly considered amongst PANS-specific research and (5) best-available evidence treatments appear markedly superior for pediatric catatonia compared to PANS in both childhood and adolescence.

Causal effects of inflammatory protein biomarkers on inflammatory diseases.

Many circulating proteins are associated with the presence or severity of disease. However, whether these protein biomarkers are causal for disease development is usually unknown. We investigated the causal effect of 21 well-known or exploratory protein biomarkers of inflammation on 18 inflammatory diseases using two-sample Mendelian randomization.

A combined genome-wide association and molecular study of age-related hearing loss in H. sapiens.

Background: Sensorineural hearing loss is one of the most common sensory deficiencies. However, the molecular contribution to age-related hearing loss is not fully elucidated.

Methods: We performed genome-wide association studies (GWAS) for hearing loss-related traits in the UK Biobank (N = 362,396) and selected a high confidence set of ten hearing-associated gene products for staining in human cochlear samples: EYA4, LMX1A, PTK2/FAK, UBE3B, MMP2, SYNJ2, GRM5, TRIOBP, LMO-7, and NOX4.

Modification of Heritability for Educational Attainment and Fluid Intelligence by Socioeconomic Deprivation in the UK Biobank.

Objective: Socioeconomic factors have been suggested to influence the effect of education- and intelligence-associated genetic variants. However, results from previous studies on the interaction between socioeconomic status and education or intelligence have been inconsistent. The authors sought to assess these interactions in the UK Biobank cohort of 500,000 participants.

Soluble ligands as drug targets.

Historically, the main classes of drug targets have been receptors, enzymes, ion channels and transporters. However, owing largely to the rise of antibody-based therapies in the past two decades, soluble protein ligands such as inflammatory cytokines have become an increasingly important class of drug targets. In this Review, we analyse drugs targeting ligands that have reached clinical development at some point since 1992.

meQTL and ncRNA functional analyses of 102 GWAS-SNPs associated with depression implicate HACE1 and SHANK2 genes.

Background: Little is known about how genetics and epigenetics interplay in depression. Evidence suggests that genetic variants may change vulnerability to depression by modulating DNA methylation (DNAm) and non-coding RNA (ncRNA) levels. Therefore, the aim of the study was to investigate the effect of the genetic variation, previously identified in the largest genome-wide association study for depression, on proximal DNAm and ncRNA levels.

Personality, lifestyle and job satisfaction: causal association between neuroticism and job satisfaction using Mendelian randomisation in the UK biobank cohort.

Job-related stress has been associated with poor health outcomes but little is known about the causal nature of these findings. We employed Mendelian randomisation (MR) approach to investigate the causal effect of neuroticism, education, and physical activity on job satisfaction. Trait-specific genetic risk score (GRS) based on recent genome wide association studies were used as instrumental variables (IV) using the UK Biobank cohort (N = 315,536).

Improved power and precision with whole genome sequencing data in genome-wide association studies of inflammatory biomarkers.

Genome-wide association studies (GWAS) have identified associations between thousands of common genetic variants and human traits. However, common variants usually explain a limited fraction of the heritability of a trait. A powerful resource for identifying trait-associated variants is whole genome sequencing (WGS) data in cohorts comprised of families or individuals from a limited geographical area.

Contribution of genetics to visceral adiposity and its relation to cardiovascular and metabolic disease.

Visceral adipose tissue (VAT)-fat stored around the internal organs-has been suggested as an independent risk factor for cardiovascular and metabolic disease, as well as all-cause, cardiovascular-specific and cancer-specific mortality. Yet, the contribution of genetics to VAT, as well as its disease-related effects, are largely unexplored due to the requirement for advanced imaging technologies to accurately measure VAT. Here, we develop sex-stratified, nonlinear prediction models (coefficient of determination = 0.

Genome-wide association analysis of 350 000 Caucasians from the UK Biobank identifies novel loci for asthma, hay fever and eczema.

Even though heritability estimates suggest that the risk of asthma, hay fever and eczema is largely due to genetic factors, previous studies have not explained a large part of the genetics behind these diseases. In this genome-wide association study, we include 346 545 Caucasians from the UK Biobank to identify novel loci for asthma, hay fever and eczema and replicate novel loci in three independent cohorts. We further investigate if associated lead single nucleotide polymorphisms (SNPs) have a significantly larger effect for one disease compared to the other diseases, to highlight possible disease-specific effects.

Genome-wide association study of body fat distribution identifies adiposity loci and sex-specific genetic effects.

Body mass and body fat composition are of clinical interest due to their links to cardiovascular- and metabolic diseases. Fat stored in the trunk has been suggested to be more pathogenic compared to fat stored in other compartments. In this study, we perform genome-wide association studies (GWAS) for the proportion of body fat distributed to the arms, legs and trunk estimated from segmental bio-electrical impedance analysis (sBIA) for 362,499 individuals from the UK Biobank.