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The global burden of disease attributable to obesity continues to rise. The disease incidence is substantially higher in elderly populations, but how obesity affects disease risk across a lifetime is largely unknown. To quantify the long-term temporal impact of obesity, access to large-scale longitudinal cohorts spanning many decades would typically be required. However, these longitudinal studies are rare and may be heavily biased by the presence of unaccountable confounding. Here, we develop a method-time-resolved Mendelian randomization-to estimate the cumulative effect of body mass index on disease risk at different ages. Using the UK Biobank, we find strong age-varying patterns for type 2 diabetes mellitus, coronary artery disease, and atrial fibrillation, as well as for osteoarthritis. We demonstrate that some of the most notable temporal characteristics are sex specific, while other features are shared between sexes. Analyses suggest that these features can be manifestations of primary prevention strategies.

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 TLR4 gene, Asp299Gly and Thr399Ile, and residential area (urban or rural) in females and males with asthma and different asthma phenotypes.

Method: This study was performed on 38,332 asthmatics and 322,852 non-asthma (both British Caucasians) subjects from the UK Biobank database. Asthma was also divided into phenotypes, such as asthma with/without allergy and early/late onset asthma. The residential area was based on the population area density and classified as urban or rural living. Multivariate regression models adjusted for age, body mass index, and smoking status were used to analyze interactions between the SNPs, residential area in asthma, and asthma phenotypes. The association between asthma and residential area or the SNPs was also determined.

Result: There were no significant associations between the SNPs and asthma risk (for Asp299Gly: OR (95% CI): 1.00 (0.97–1.02), for Thr399Ile: 0.99 (0.96–1.02) or between the SNPs and asthma phenotypes in either sex or combined cohorts. The effects of the SNPs were not modified by residential area population density in either sex with asthma or across asthma phenotypes. Asthma and its phenotypes were not associated with the SNPs or residential area.

Conclusions: Our study found no statistically significant association between TLR4 polymorphisms and asthma, regardless of sex or residential area. Further studies are needed to clarify the functional impact of TLR4 variation in asthma pathophysiology.

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. Circulatory biomarkers of acute brain injury may help in the management of patients with acute cerebrovascular events and prevent poor outcome and mortality. The purpose of this review is to provide an overview of the development of potential biomarkers of brain damage to increase diagnostic possibilities. For this purpose, we searched the PubMed database of studies on the diagnostic potential of brain injury biomarkers. We also accessed information from Clinicaltrials.gov to identify any clinical trials of biomarker measurements for the diagnosis of brain damage. In total, we present 41 proteins, enzymes and hormones that have been considered as biomarkers for brain injury, of which 20 have been studied in clinical trials. Several microRNAs have also emerged as potential clinical biomarkers for early diagnosis. Combining multiple biomarkers in a panel, along with other parameters, is yielding promising outcomes.

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. We performed a prospective study in 442,519 UK Biobank participants, for 19 cancer types and additional histological subtypes, with a mean follow-up time of 13.4 years. Cox proportional hazard models were used to estimate the effect of 14 different adiposity phenotypes on cancer rates, and a 5% false discovery rate was considered statistically significant. Adiposity-related traits are associated with all but three cancer types, and fat accumulation is associated with a larger number of cancers compared to fat distribution. In addition, fat accumulation or distribution exhibit differential effects between sexes on colorectal, esophageal, and liver cancer.

OBJECTIVE: While the association between obesity and risk of rheumatic disease is well established, the precise causal relation has not been conclusively proved. Here, we estimate the causal effect of body mass index (BMI) on the risk of developing five 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. Analyses were performed in 361,952 participants from the UK Biobank cohort for the five rheumatic diseases: rheumatoid arthritis (N=8,381 cases), osteoarthritis (N=87,430), psoriatic arthropathy (N=933), gout (N=13,638), and inflammatory spondylitis (N=4,328).

RESULTS: Using linear MR, we found that one standard deviation higher BMI increases the incidence rate for rheumatoid arthritis (IRR=1.52; 95% CI=1.36-1.69), osteoarthritis (IRR=1.49; 1.43-1.55), psoriatic arthropathy (IRR=1.80; 1.31-2.48), gout (IRR=1.73; 1.56-1.92), and inflammatory spondylitis (IRR=1.34; 1.14-1.57) in all individuals. BMI was found to be a stronger risk factor in women compared to men for psoriatic arthropathy (sex-interaction P=3.3×10^-4 ) and gout (P=4.3×10^-3 ), and the effect on osteoarthritis was stronger in premenopausal compared to postmenopausal women (P=1.8×10^-3 ). Nonlinear effects of BMI were identified for osteoarthritis and gout in men, and for gout in women. The nonlinearity for gout was also more extreme in men compared to women (P=0.03).

CONCLUSION: Higher BMI causes an increased risk for rheumatic disease, an effect that is more pronounced in women for both gout and psoriatic arthropathy. The novel sex- and BMI-specific causal effects identified here, give further insight into rheumatic-disease etiology and mark an important step towards personalized medicine.

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 sub-cohort (N = 15), and explore their effect on 438 plasma proteins. We detected 184,182 polymorphic CNVs and identified 15 CNVs to be associated with 16 proteins (p<8.22×10-10). Of these, five CNVs could be perfectly validated using long-read sequencing, including a CNV which was associated to measurements of the osteoclast-associated immunoglobulin-like receptor (OSCAR) and located upstream of OSCAR, a gene important for bone health. Two other CNVs were identified to be clusters of many short repetitive elements and another represented a complex rearrangement including an inversion. Our findings provide insights into the structure of common CNVs and their effects on the plasma proteome, and highlights the importance of investigating common CNVs, also in relation to complex diseases.

Some individuals with obesity have a healthy metabolic profile and are not at increased risk for diabetes or cardiovascular disease. The mechanisms behind this phenomenon are poorly understood, but recent work now characterizes the biological underpinnings of the metabolically healthy obese phenotype.

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.

METHODS: Linkage disequilibrium score regression and two-sample bidirectional Mendelian randomization analyses were performed using summary statistics from cohort-based genome-wide association studies of migraine (59,674 cases; 316,078 controls), IBD (25,042 cases; 34,915 controls) and celiac disease (11,812 or 4533 cases; 11,837 or 10,750 controls). Migraine with and without aura were analyzed separately, as were the two IBD subtypes Crohn's disease and ulcerative colitis. Positive control analyses and conventional Mendelian randomization sensitivity analyses were performed.

RESULTS: Migraine was not genetically correlated with IBD or celiac disease. No evidence was observed for IBD (odds ratio [OR] 1.00, 95% confidence interval [CI] 0.99-1.02, p = 0.703) or celiac disease (OR 1.00, 95% CI 0.99-1.02, p = 0.912) causing migraine or migraine causing either IBD (OR 1.08, 95% CI 0.96-1.22, p = 0.181) or celiac disease (OR 1.08, 95% CI 0.79-1.48, p = 0.614) when all participants with migraine were analyzed jointly. There was some indication of a causal association between celiac disease and migraine with aura (OR 1.04, 95% CI 1.00-1.08, p = 0.045), between celiac disease and migraine without aura (OR 0.95, 95% CI 0.92-0.99, p = 0.006), as well as between migraine without aura and ulcerative colitis (OR 1.15, 95% CI 1.02-1.29, p = 0.025). However, the results were not significant after multiple testing correction.

CONCLUSIONS: We found no evidence of a shared genetic basis or of a causal association between migraine and either IBD or celiac disease, although we obtained some indications of causal associations with migraine subtypes.

Advanced psychiatric treatments remain uncertain in preventing suicide among adolescents. Across the 21 Swedish regions, using nationwide registers between 2016-2020, we found negative correlation between adolescent excess suicide mortality (AESM) and regional frequencies of clozapine, ECT, and lithium (CEL) usage among adolescents (beta=-0.613, p=0.0003, 95% CI: -0.338, -0.889) and males (beta=-0.404, p=0.009, 95% CI: -0.130, -0.678). No correlation was found among females (p=0.197). Highest CEL usage among male adolescents was seen in regions with lowest quartile (Q1) AESM (W=74, p=0.012). Regional CEL treatment frequency in 15-19-year-olds was related to lower AESM in males, reflecting potential treatment efficacy, treatment compliance or better-quality mental health care. Suicide prevention may benefit from early recognition and CEL treatment for severe mental illness in male adolescents. The results indicate association but further research, using independent samples and both prospective and observational methodologies, is needed to confirm causality. There are conflicting results on the effectiveness of pharmacologic interventions for suicide prevention in adolescence. Here, the authors show, in a retrospective registry study from Sweden during 2016-2020, that regional utilization rates of clozapine, electroconvulsive therapy and lithium in 15-19-year-olds were associated with lower excess suicide death rates in male adolescents

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. PRS for ASD were calculated based on the latest genome-wide association study of ASD by the Psychiatric Genetics Consortium (18,381 cases, 27,969 controls) and were created in the independent cohort UK Biobank. Regression analyses were performed to investigate the association between ASD PRS and 5-WBS traits in the UK Biobank population including 337,423 individuals. ASD PRS were significantly associated with all 5-WBS traits, showing a positive association with the negative WBS traits, neuroticism (max R² = 0.04%, p < 1 × 10⁻⁴), depression (max R² = 0.06%, p < 1 × 10⁻⁴), loneliness (max R² = 0.04%, p < 1 × 10⁻⁴), and a negative association with the positive WBS traits, life satisfaction (max R² = 0.08%, p < 1 × 10⁻⁴), positive affect (max R² = 0.10%, p < 1 × 10⁻⁴). The findings suggest that adults carrying a high load of risk single nucleotide peptides (SNPs) for ASD are more likely to report decreased well-being. The study demonstrates a considerable connection between susceptibility to ASD, its underlying genetic etiology and well-being.