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Background: Varicose veins (VV) are one of the common human diseases, but the role of genetics in its development is not fully understood. Methods: We conducted an exome-wide association study of VV using whole-exome sequencing data from the UK Biobank, and focused on common and rare variants using single-variant association analysis and gene-level collapsing analysis. Findings: A total of 13,823,269 autosomal genetic variants were obtained after quality control. We identified 36 VV-related independent common variants mapping to 34 genes by single-variant analysis and three rare variant genes (PIEZO1, ECE1, FBLN7) by collapsing analysis, and most associations between genes and VV were replicated in FinnGen. PIEZO1 was the closest gene associated with VV (P = 5.05 × 10−31), and it was found to reach exome-wide significance in both single-variant and collapsing analyses. Two novel rare variant genes (ECE1 and METTL21A) associated with VV were identified, of which METTL21A was associated only with females. The pleiotropic effects of VV-related genes suggested that body size, inflammation, and pulmonary function are strongly associated with the development of VV. Conclusions: Our findings highlight the importance of causal genes for VV and provide new directions for treatment. Author summary: In this study, whole-exome sequencing data from the UK Biobank were used to explore the effect of genetic variants on varicose veins (VV) and search for new VV-related genes. In contrast to traditional association studies, large-scale whole-exome sequencing analysis is more capable of identifying rare genetic variants (MAF < 1%) in diseases. The current study identified 34 VV-associated common variant genes by single-variant analysis and three rare variant genes (PIEZO1, ECE1, FBLN7) by collapsing analysis, and most associations were validated in FinnGen. In addition to replicating several genes reported in previous genome-wide association studies, we identified 17 novel genes that may be associated with VV. Through subsequent phenome-wide association analyses of identified genes, we found that these genes are also strongly associated with body size, inflammation, and pulmonary function. These findings contribute to understanding the underlying mechanisms of pathogenesis and developing novel therapeutic strategies for VV. [ABSTRACT FROM AUTHOR]

Background: Observational studies have suggested a possible association between hypothyroidism and increased risk of ischemic stroke. However, a causal relationship remains unclear. Methods: Data on single nucleotide polymorphisms (SNPs) associated with hypothyroidism and ischemic stroke were sourced from the FinnGens database and the UK Biobank of European descent. Both databases underwent separate two-sample Mendelian randomization (MR) analyses. A subsequent meta-analysis of MR results using a random-effects model was conducted to determine the causal relationship between hypothyroidism and ischemic stroke. Results: All five analyses indicated a positive causal relationship between hypothyroidism and ischemic stroke. MR analysis of the association between hypothyroidism and ischemic stroke yielded a result of the inverse variance weighted (IVW) method at 4.7411 (1.3598-16.5308), p = 0.0146. The analysis of ischemic stroke (without excluding controls) yielded a result of the IVW method of 4.5713 (1.3570-15.3986), p = 0.0142. MR analysis with cerebral infarction yielded a result of the IVW method at 1.0110 (1.0006-1.0215), p = 0.0373. The MR analysis with cerebrovascular disease sequelae yielded an IVW method result of 2.4556 (1.0291-5.8595), p = 0.0429. Analysis for the sequelae of cerebrovascular disease (without excluding controls) yielded an IVW method result of 2.4217 (1.0217-5.7402), p = 0.0446. No evidence of heterogeneity or horizontal pleiotropy was found. The meta-analysis of the five MR results was 2.24 (1.18-4.26), p = 0.025. Conclusion: Our two-sample Mendelian randomization study suggested a causal relationship between hypothyroidism and ischemic stroke, indicating that hypothyroidism could be a risk factor for ischemic stroke. However, further studies are required to elucidate the underlying biological mechanisms. [ABSTRACT FROM AUTHOR]

Background: Blood-based biomarkers for dementia are gaining attention due to their non-invasive nature and feasibility in regular healthcare settings. Here, we explored the associations between 249 metabolites with all-cause dementia (ACD), Alzheimer's disease (AD), and vascular dementia (VaD) and assessed their predictive potential. Methods: This study included 274,160 participants from the UK Biobank. Cox proportional hazard models were employed to investigate longitudinal associations between metabolites and dementia. The importance of these metabolites was quantified using machine learning algorithms, and a metabolic risk score (MetRS) was subsequently developed for each dementia type. We further investigated how MetRS stratified the risk of dementia onset and assessed its predictive performance, both alone and in combination with demographic and cognitive predictors. Results: During a median follow-up of 14.01 years, 5274 participants developed dementia. Of the 249 metabolites examined, 143 were significantly associated with incident ACD, 130 with AD, and 140 with VaD. Among metabolites significantly associated with dementia, lipoprotein lipid concentrations, linoleic acid, sphingomyelin, glucose, and branched-chain amino acids ranked top in importance. Individuals within the top tertile of MetRS faced a significantly greater risk of developing dementia than those in the lowest tertile. When MetRS was combined with demographic and cognitive predictors, the model yielded the area under the receiver operating characteristic curve (AUC) values of 0.857 for ACD, 0.861 for AD, and 0.873 for VaD. Conclusions: We conducted the largest metabolome investigation of dementia to date, for the first time revealed the metabolite importance ranking, and highlighted the contribution of plasma metabolites for dementia prediction. [ABSTRACT FROM AUTHOR]

The relationship between liver dysfunction and dementia has been researched extensively but remains poorly understood. In this study, we investigate the longitudinal and cross‐sectional associations between liver function and liver diseases and risk of incident dementia, impaired cognition, and brain structure abnormalities using Cox proportion hazard model and linear regression model. 431 699 participants with a mean of 8.65 (standard deviation [SD] 2.61) years of follow‐up were included from the UK Biobank; 5542 all‐cause dementia (ACD), 2427 Alzheimer's disease (AD), and 1282 vascular dementia (VaD) cases were documented. We observed that per SD decreases in alanine transaminase (ALT; hazard ratio [HR], 0.917; PFDR <0.001) and per SD increases in aspartate aminotransferase (AST; HR, 1.048; PFDR = 0.010), AST to ALT ratio (HR, 1.195; PFDR <0.001), gamma‐glutamyl transpeptidase (GGT; HR, 1.066; PFDR <0.001), alcoholic liver disease (ALD; HR, 2.872; PFDR <0.001), and fibrosis and cirrhosis of liver (HR, 2.285; PFDR = 0.002), being significantly associated with a higher risk of incident ACD. Restricted cubic spline models identified a strong U‐shaped association between Alb and AST and incident ACD (Pnonlinear <0.05). Worse cognition was positively correlated with AST, AST to ALT ratio, direct bilirubin (DBil), and GGT; negatively correlated with ALT, Alb, and total bilirubin (TBil); and ALD and fibrosis and cirrhosis of liver (PFDR <0.05). Moreover, changes in ALT, GGT, AST to ALT ratio, and ALD were significantly associated with altered cortical and subcortical regions, including hippocampus, amygdala, thalamus, pallidum, and fusiform (PFDR <0.05). In sensitivity analysis, metabolic dysfunction‐associated steatotic liver disease (MASLD) was associated with the risk of ACD and brain subcortical changes. Our findings provide substantial evidence that liver dysfunction may be an important factor for incident dementia. Early intervention in the unhealthy liver may help prevent cognitive impairment and dementia incidence. [ABSTRACT FROM AUTHOR]

Background: The correlations between genetic risk for Alzheimer's disease (AD) with comprehensive brain regions at a regional scale are still not well understood. We aim to explore whether these associations vary across different age stages. Methods: This study used large existing genome-wide association datasets to calculate polygenic risk score (PRS) for AD in two populations from the UK Biobank (N ~ 23 000) and Adolescent Brain Cognitive Development Study (N ~ 4660) who had multimodal macrostructural and microstructural magnetic resonance imaging (MRI) metrics. We used linear mixed-effect models to assess the strength of the association between AD PRS and multiple MRI metrics of regional brain structures at different stages of life. Results: Compared to those with lower PRSs, adolescents with higher PRSs had thinner cortex in the caudal anterior cingulate and supramarginal. In the middle-aged and elderly population, AD PRS had correlations with regional structure shrink primarily located in the cingulate, prefrontal cortex, hippocampus, thalamus, amygdala, and striatum, whereas the brain expansion was concentrated near the occipital lobe. Furthermore, both adults and adolescents with higher PRSs exhibited widespread white matter microstructural changes, indicated by decreased fractional anisotropy (FA) or increased mean diffusivity (MD). Conclusions: In conclusion, our results suggest genetic loading for AD may influence brain structures in a highly dynamic manner, with dramatically different patterns at different ages. This age-specific change is consistent with the classical pattern of brain impairment observed in AD patients. [ABSTRACT FROM AUTHOR]

Objective: Epidemiological evidence investigating serum uric acid and kidney cancer risk remains unclear. We conducted this study to examine the relationship between serum uric acid and the incidence and mortality of kidney cancer. Methods: This is a prospective analysis of 444 462 participants without any cancer from the UK Biobank. Serum uric acid was measured at baseline and the incidence and mortality of kidney cancer was determined through contact with the cancer and death registry. Cox regression models were fitted to estimate the hazard ratio (HR) and 95% confidence interval (95%CI), adjusting for demography, lifestyle style, comorbidities, and medication use. Results: We documented 638 incidence cases and 188 mortality cases of kidney cancer over a median of 6.5 years follow‐up. People with the highest quartile had a 45% increased risk of kidney cancer compared to those with the lowest uric acid quartile (HR 1.45, 95%CI 1.08 to 1.93). Subgroup analyses showed that serum uric acid was associated with cancer risk among females but not among males (Q1 vs Q4: females HR1.47, 95%CI 1.01 to 2.16; males HR 1.19, 95%CI 0.91 to 1.56). Although we found serum uric acid was associated with an increased risk of kidney cancer mortality in age‐stratified model (HR 2.49, 95% CI 1.61 to 3.84), this association disappeared after further adjustment for other confounders. Conclusions: High uric acid is associated with a high incidence of kidney cancer, especially in women. More research is needed to confirm our findings. [ABSTRACT FROM AUTHOR]

This study aimed to analyze the impact of a wide spectrum of occupational characteristics on the incidence of anxiety and depression, and to determine the features affecting adaptation to specific characteristics. Participants in paid employment or self-employed at baseline in UKB were included, with occupational characteristics extracted from O*NET. Cox-proportional-hazard models were conducted in the main analyses and subgroup analyses. Direct work with the public and exposure to disease/infections were first time demonstrated to be risk factors for both anxiety and depression, along with occupations involving more physical activities and dealing with unpleasant/physically aggressive people. Protective factors for both: time spent sitting, communication, decision making, creativity and reasoning, and responsibility in work. Protective factors for anxiety only: Coordinating/leading, fluency of ideas, originality, problem sensitivity, decision latitude, and time pressure. Risk factor for depression only: Exposure to contaminants. Females were found more sensitive to dealing with unpleasant/physically aggressive people. The impact of exposure to disease/infections was more significant among those with lower education levels. Those with BMI over 24 were more sensitive to the risk factors. The short-term effect of the above exposures remained unclear. The scores of occupational characteristics were based on self-reported questionnaires. There was the potential for undiagnosed anxiety or depression events. The participants included only those aged from 40 to 69. Participants included in this cohort were mainly White British. Our findings advocate closer monitoring of the mental health of workers with risk work-related factors. Guideline of the study. Left, UK Biobank data used in the study. Top right, association between occupational characteristics and the incidence of anxiety and depression. Bottom right, subgroup analyses. [Display omitted] • Risk factors for both anxiety and depression included direct work with the public and exposure to disease or infections occupations involving more physical activities, and dealing with unpleasant and physically aggressive people. And protective factors for anxiety and depression included time spent sitting, communication, decision making, creativity and reasoning, and responsibility in work. • Protective factors for anxiety only included coordinating/leading, fluency of ideas, originality, problem sensitivity, decision latitude, and time pressure, while exposure to contaminants was a risk factor for depression only. • Females were found more sensitive to dealing with unpleasant and physically aggressive people. • The impact of exposure to disease/infections was more significant among those with lower education level. • Risk factors except for physical activities were found significant impact only among those with BMI over 24. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the associations between courses of depression, the application of depression treatment, and the risk of incident dementia. In this prospective cohort study, 354,313 participants ages 50–70 years were recruited from the UK Biobank between 2006 and 2010 and were followed until 2020, with a total of 4,212,929 person-years. We initially studied the effect of depression on dementia incidence across 4 subgroups characterized by courses of depressive symptoms. Then, 46,820 participants with a diagnosis of depression were further categorized into treated and untreated groups. We compared the risk of dementia among different depression treatment groups in all participants who were depressed as well as 4 courses of depressive symptoms by performing survival analyses. Depression was associated with a 51% higher risk of dementia, among which the increasing, chronically high, and chronically low courses were associated with increased dementia risk, while no association was found in the decreasing course. Compared to those who were depressed but untreated, receiving depression treatments corresponded to a hazard ratio of 0.7 (95% CI, 0.62–0.77). Among the 3 detrimental courses, treatments for increasing and chronically low symptoms of depression were associated with a 32% and 28% lower risk of dementia, respectively, while the reduction effect for chronically high symptoms was insignificant. The negative association between depression treatment and incident dementia was significant in the increasing and chronically low courses, highlighting the necessity of timely interventional strategies before depression progresses to a chronically severe state. [ABSTRACT FROM AUTHOR]

• Life-course risk for incident dementia was modulated by lung function. • Immunity, oxygen-carrying indices and specific metabolites are critical mediators. • Brain structures were substantially changed with poor lung function. • Monitoring lung function is of great significance for cognitive brain health. Whether lung function prospectively affects cognitive brain health independent of their overlapping factors remains largely unknown. This study aimed to investigate the longitudinal association between decreased lung function and cognitive brain health and to explore underlying biological and brain structural mechanisms. This population-based cohort included 43,1834 non-demented participants with spirometry from the UK Biobank. Cox proportional hazard models were fitted to estimate the risk of incident dementia for individuals with low lung function. Mediation models were regressed to explore the underlying mechanisms driven by inflammatory markers, oxygen-carrying indices, metabolites, and brain structures. During a follow-up of 3,736,181 person-years (mean follow-up 8.65 years), 5,622 participants (1.30 %) developed all-cause dementia, which consisted of 2,511 Alzheimer's dementia (AD) and 1,308 Vascular Dementia (VD) cases. Per unit decrease in lung function measure was each associated with increased risk for all-cause dementia (forced expiratory volume in 1 s [liter]: hazard ratio [HR, 95 %CI], 1.24 [1.14–1.34], P = 1.10 × 10-07; forced vital capacity [liter]: 1.16 [1.08–1.24], P = 2.04 × 10-05; peak expiratory flow [liter/min]: 1.0013 [1.0010–1.0017], P = 2.73 × 10-13). Low lung function generated similar hazard estimates for AD and VD risks. As underlying biological mechanisms, systematic inflammatory markers, oxygen-carrying indices, and specific metabolites mediated the effects of lung function on dementia risks. Besides, brain grey and white matter patterns mostly affected in dementia were substantially changed with lung function. Life-course risk for incident dementia was modulated by individual lung function. Maintaining optimal lung function is useful for healthy aging and dementia prevention. [ABSTRACT FROM AUTHOR]

• The combined effects of multiple air pollutants may differ from those of single air pollutants. • The combined exposure to air pollutants was positively associated with the incidence of ischemic heart disease. • The association was more pronounced among individuals with diabetes compared to those without. Air pollution and type 2 diabetes (T2D) are both associated with an increased risk of ischemic heart disease (IHD). Little is known about the combined effects of multiple air pollutants on IHD risk, especially among individuals with T2D. We sought to assess the association of combined exposure to multiple air pollutants with incident IHD and examine the modification effect of T2D. This study included 388 780 individuals (20 036 individuals with T2D) free of cardiovascular disease and cancer from the UK Biobank. The combined exposure to multiple air pollutants, including particulate matter (PM) with diameters ≤ 2.5 μm (PM 2.5), PM with diameters between 2.5 and 10 µm (PM coarse), PM with diameters ≤ 10 μm (PM 10), nitrogen dioxide (NO 2), and nitrogen dioxides (NO x), was assessed by creating a weighted air pollution score (APS), with a higher APS representing a higher level of air pollution exposure. Hazard ratios (HR) and 95 % confidence intervals (CI) for incident IHD were assessed by multivariable-adjusted Cox proportional hazard models. During a median of 12.9 years of follow-up, 27 333 incident IHD cases were observed. Compared with the lowest tertile of the APS, the multivariable-adjusted HR (95 % CI) of IHD risk for the highest tertile was 1.13 (1.03–1.23) among individuals with T2D, while the HR was 1.06 (1.03–1.10) among individuals without T2D. Additionally, the associations between APS and IHD incidence showed a linear relationship among individuals with T2D (nonlinearity: P = 0.37), whereas a non-linear relationship was observed among individuals without T2D (nonlinearity: P = 0.02). For the joint analysis, individuals in the highest tertile of APS and with T2D had a 54 % higher risk of IHD compared to individuals in the lowest tertile of APS and without T2D, with a significant additive interaction (P interaction < 0.01). The proportion of relative excess risk was 17 % due to the interaction in categorical analyses. The combined exposure to multiple air pollutants has been associated with an elevated risk of incident IHD, and the association is more pronounced among individuals with T2D. [ABSTRACT FROM AUTHOR]

Background: Shift work is associated with susceptibility to several neuropsychiatric disorders. This study aims to investigate the effect of shift work on the incidence of neuropsychiatric disorders, and highlighting how individual variability may influence the association., Methods: UK Biobank participants with employment information were included. Cox survival was conducted in main and subgroup analyses. Correlation analyses explored the impact of shift work on brain structures, and mediation analyses were performed to elucidate the shared underlying mechanisms. Shift work tolerance was evaluated through survival analyses contrasting the risks associated with five neuropsychiatric disorders in shift versus non-shift workers across different demographic or occupational strata., Results: The analysis encompassed 254,646 participants. Shift work was associated with higher risk of dementia (HR 1.29, 95 % CI 1.10-1.52), anxiety (1.08, 1.01-1.15), depression (1.29, 1.22-1.36), and sleep disorders (1.18, 1.09-1.28), but not stroke (p = 0.20). Shift work was correlated with decreasing volume of various brain regions, particularly in thalamus, lateral orbitofrontal, and middle temporal. Mediation analysis revealed that increased immune response and glucose levels are common pathways linking shift work to these disorders. We observed diversity in shift work tolerance across different individual characteristics, among which socioeconomic status and length of working hours were the most essential., Limitations: Self-reported employment information may cause misclassification and recall bias. And since we focused on the middle-aged population, the conclusions may not be representative of younger or older populations., Conclusions: Our findings indicated the need to monitor shift worker health and provide personalized management to help adapt to shift work., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

While numerous genomic loci have been identified for neuropsychiatric conditions, the contribution of protein-coding variants has yet to be determined. Here we conducted a large-scale whole-exome-sequencing study to interrogate the impact of protein-coding variants on 46 neuropsychiatric diseases and 23 traits in 350,770 adults from the UK Biobank. Twenty new genes were associated with neuropsychiatric diseases through coding variants, among which 16 genes had impacts on the longitudinal risks of diseases. Thirty new genes were associated with neuropsychiatric traits, with SYNGAP1 showing pleiotropic effects across cognitive function domains. Pairwise estimation of genetic correlations at the coding-variant level highlighted shared genetic associations among pairs of neurodegenerative diseases and mental disorders. Lastly, a comprehensive multi-omics analysis suggested that alterations in brain structures, blood proteins and inflammation potentially contribute to the gene-phenotype linkages. Overall, our findings characterized a compendium of protein-coding variants for future research on the biology and therapeutics of neuropsychiatric phenotypes., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Previous hypothesis-driven research has identified many risk factors linked to dementia. However, the multiplicity and co-occurrence of risk factors have been underestimated. Here we analysed data of 344,324 participants from the UK Biobank with 15 yr of follow-up data for 210 modifiable risk factors. We first conducted an exposure-wide association study and then combined factors associated with dementia to generate composite scores for different domains. We then evaluated their joint associations with dementia in a multivariate Cox model. We estimated the potential impact of eliminating the unfavourable profiles of risk domains on dementia using population attributable fraction. The associations varied by domain, with lifestyle (16.6%), medical history (14.0%) and socioeconomic status (13.5%) contributing to the majority of dementia cases. Overall, we estimated that up to 47.0%-72.6% of dementia cases could be prevented., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Although sleep, physical activity and sedentary behavior have been found to be associated with dementia risk, findings are inconsistent and their joint relationship remains unclear. This study aimed to investigate independent and joint associations of these three modifiable behaviors with dementia risks. A total of 431,924 participants (median follow-up 9.0 years) without dementia from UK Biobank were included. Multiple Cox regressions were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Models fitted with restricted cubic spline were conducted to test for linear and nonlinear shapes of each association. Sleep duration, leisure-time physical activity (LTPA), and screen-based sedentary behavior individually associated with dementia risks in different non-linear patterns. Sleep duration associated with dementia in a U-shape with a nadir at 7 h/day. LTPA revealed a curvilinear relationship with dementia in diminishing tendency, while sedentary behavior revealed a J-shaped relationship. The dementia risk was 17% lower in the high LTPA group (HR[95%CI]: 0.83[0.76-0.91]) and 22% higher in the high sedentary behavior group (1.22[1.10-1.35]) compared to the corresponding low-level group, respectively. A combination of seven-hour/day sleep, moderate-to-high LTPA, and low-to-moderate sedentary behavior showed the lowest dementia risk (0.59[0.50-0.69]) compared to the referent group (longer or shorter sleep/low LTPA/high sedentary behavior). Notably, each behavior was non-linearly associated with brain structures in a pattern similar to its association with dementia, suggesting they may affect dementia risk by affecting brain structures. Our findings highlight the potential to change these three daily behaviors individually and simultaneously to reduce the risk of dementia., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)