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BACKGROUND: This study aims to investigate age- and gender-specific effects of household solid fuels for heating on major depression and buffering effects of outdoor time in a high-income country. METHODS: Data were obtained from the UK Biobank. Participants with complete information on our studied variables and no prior diagnosis of major depression at baseline were included. Cox proportional hazards regression models were used to examine the effects of household solid fuels for heating on major depression. Subgroup analyses were conducted to investigate the buffering effects of outdoor time in summer and winter. Sensitivity analyses were performed to test the robustness of the main findings. RESULTS: Of 255,505 participants (50.2 % women), the 12-year cumulative incidence of major depression was 4.4 %. Household solid fuels for heating increased the risk of major depression only in women aged <45 years (HR (95%CI) = 1.30 (1.04, 1.63)). In this group, the solid fuel effect was moderated by outdoor time spending both in summer (HR (95%CI), ≤2 h/day: 1.61 (1.13, 2.28); >2 h/day: 1.13 (0.84, 1.52)) and winter (≤1 h/day: 1.35 (1.01, 1.08); >1 h/day: 1.24 (0.86, 1.77)). LIMITATIONS: Self-reported measures might lead to recall bias and some potential confounders, such as ventilation efficiency, were not measured and controlled in data analyses. CONCLUSIONS: Younger women are more vulnerable to the impact of domestic air pollution on major depression. Promoting outdoor activities is a cost-effective and efficient approach to mitigating the risk of major depression caused by household solid fuels.

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BACKGROUND: Although smoking heightens the risk of AF, it remains unknown if that risk is amenable to modification after smoking cessation. OBJECTIVES: This study sought to evaluate the association between smoking cessation and atrial fibrillation (AF) risk in a large longitudinal cohort. METHODS: After excluding those with prevalent AF and no history of smoking at baseline, we evaluated 146,772 UK Biobank participants with serial smoking assessments. We compared AF risk between former smokers at baseline and those who quit smoking during the study to current smokers. Incident AF was ascertained from outpatient and inpatient encounters and identified using International Classification of Diseases codes. Cox models were used to compare the risk of incident AF among current and former smokers as well as those who quit smoking during the study while controlling for age, sex, race, body mass index, education, cardiovascular comorbidities, alcohol use, and pack-years. RESULTS: Among the 146,772 participants (48.3% female; age: 57.3 ± 7.9 years), 37,377 (25.5%) currently smoked; 105,429 (72.0%) were former smokers; and 3,966 (2.7%) quit smoking during the study. Over a mean 12.7 ± 2.0 years of follow-up, 11,214 (7.6%) participants developed AF. Compared to current smokers, the adjusted risk of AF was 13% lower in former smokers (HR: 0.87; 95% CI: 0.83-0.91) and 18% lower in those who quit smoking during the study (HR: 0.82; 95% CI: 0.70-0.95). CONCLUSIONS: Compared to those who continue to smoke, smoking cessation was associated with a lower risk of AF.

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BACKGROUND: Cardiovascular diseases (CVDs) are a leading global health concern. Emerging evidence suggests a potential protective role of well-being in reducing CVD risk. METHODS AND RESULTS: We conducted a cohort analysis using the UK Biobank data set, encompassing 121 317 participants. We assessed the well-being of participants using a well-being index derived from baseline questionnaires. Well-being categories were derived by latent class analysis using general happiness and satisfaction with family, friendships, health, and finance situations. The relationship between well-being and 4 major CVDs was analyzed using Cox proportional hazards models and Mendelian randomization. The study also examined the impacts of well-being on lifestyle factors and inflammatory markers, and its mediating role in the well-being-CVD relationship. Higher well-being was associated with a significantly reduced risk of various CVDs. Latent class analysis identified 4 distinct well-being groups (low, variable, moderate-to-high, and high satisfaction), with higher satisfaction levels generally associated with lower risk of CVDs. Mendelian randomization suggested potential causal relationships between well-being and reduced risk of CVDs. Participants with greater well-being demonstrated healthier behaviors and lower levels of inflammatory markers. Mediation analysis indicated that lifestyle and inflammatory markers partially mediated the relationship between well-being and CVDs. CONCLUSIONS: This study demonstrates a robust inverse association between well-being and the risks of CVDs, suggesting that enhancing well-being may be a viable strategy for CVD prevention. The role of lifestyle factors and inflammation as a mediator provides insight into possible biological pathways linking psychological states and cardiovascular health.

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PURPOSE: This study aimed to evaluate the relationship between plant protein, animal protein and biological aging through different dimensions of biological aging indices. Then explore the effects of substitution of plant protein, animal protein, and their food sources on biological aging. METHODS: The data came from 79,294 participants in the UK Biobank who completed at least two 24-h dietary assessments. Higher Klemera-Doubal Method Biological Age (HKDM-BA), higher PhenoAge (HPA), higher allostatic load (HAL), and longer telomere length (LTL) were estimated to assess biological aging. Logistic regression was used to estimate protein-biological aging associations. Substitution model was performed to assess the effect of dietary protein substitutions. RESULTS: Plant protein intake was inversely associated with HKDM-BA, HPA, HAL, and positively associated with LTL (odds ratios after fully adjusting and comparing the highest to the lowest quartile: 0.83 (0.79-0.88) for HKDM-BA, 0.86 (0.72-0.94) for HPA, 0.90 (0.85-0.95) for HAL, 1.06 (1.01-1.12) for LTL), while animal protein was not correlated with the four indices. Substituting 5% of energy intake from animal protein with plant protein, replacing red meat or poultry with whole grains, and replacing red or processed meat with nuts, were negatively associated with HKDM-BA, HPA, HAL and positively associated with LTL. However, an inverse association was found when legumes were substituted for yogurt. Gamma glutamyltransferase, alanine aminotransferase, and aspartate aminotransferase mediated the relationship between plant protein and HKDM-BA, HPA, HAL, and LTL (mediation proportion 11.5-24.5%; 1.9-6.7%; 2.8-4.5%, respectively). CONCLUSION: Higher plant protein intake is inversely associated with biological aging. Although there is no association with animal protein, food with animal proteins displayed a varied correlation.

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CONTEXT: Cardiometabolic multimorbidity (CM) is an increasing public health concern. Previous observational studies have suggested inverse associations between coffee, tea, and caffeine intake and risks of individual cardiometabolic diseases; however, their associations with CM and related biological markers are unknown. METHODS: This prospective study involved 172 315 (for caffeine analysis) and 188 091 (tea and coffee analysis) participants free of any cardiometabolic diseases at baseline from the UK Biobank; 168 metabolites were measured among 88 204 and 96 393 participants. CM was defined as the coexistence of at least 2 of the following conditions: type 2 diabetes, coronary heart disease, and stroke. RESULTS: Nonlinear inverse associations of coffee, tea, and caffeine intake with the risk of new-onset CM were observed. Compared with nonconsumers or consumers of less than 100 mg caffeine per day, consumers of moderate amount of coffee (3 drinks/d) or caffeine (200-300 mg/d) had the lowest risk for new-onset CM, with respective hazard ratios (95% CIs) of 0.519 (0.417-0.647) and 0.593 (0.499-0.704). Multistate models revealed that moderate coffee or caffeine intake was inversely associated with risks of almost all developmental stages of CM, including transitions from a disease-free state to single cardiometabolic diseases and subsequently to CM. A total of 80 to 97 metabolites, such as lipid components within very low-density lipoprotein, histidine, and glycoprotein acetyls, were identified to be associated with both coffee, tea, or caffeine intake and incident CM. CONCLUSION: Habitual coffee or caffeine intake, especially at a moderate level, was associated with a lower risk of new-onset CM and could play important roles in almost all transition phases of CM development. Future studies are warranted to validate the implicated metabolic biomarkers underlying the relation between coffee, tea, and caffeine intake and CM.

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BACKGROUND: Physical activity reduces colorectal cancer risk, yet the diurnal timing of physical activity in colorectal cancer etiology remains unclear. METHODS: This study used 24-h accelerometry time series from UK Biobank participants aged 42 to 79 years to derive circadian physical activity patterns using functional principal component analysis. Multivariable Cox proportional hazard models were used to examine associations with colorectal cancer risk. RESULTS: Among 86,252 participants (56% women), 529 colorectal cancer cases occurred during a median 5.3-year follow-up. We identified four physical activity patterns that explained almost 100% of the data variability during the day. A pattern of continuous day-long activity was inversely associated with colorectal cancer risk (hazard ratio (HR) = 0.94, 95% confidence interval (CI) = 0.89-0.99). A second pattern of late-day activity was suggestively inversely related to risk (HR = 0.93, 95% CI = 0.85-1.02). A third pattern of early- plus late-day activity was associated with decreased risk (HR = 0.89, 95% CI = 0.80-0.99). A fourth pattern of mid-day plus night-time activity showed no relation (HR = 1.02, 95% CI = 0.88-1.19). Our results were consistent across various sensitivity analyses, including the restriction to never smokers, the exclusion of the first 2 years of follow-up, and the adjustment for shift work. CONCLUSIONS: A pattern of early- plus late-day activity is related to reduced colorectal cancer risk, beyond the benefits of overall activity. Further research is needed to confirm the role of activity timing in colorectal cancer prevention.

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BACKGROUND: High heritability of salt sensitivity suggests an essential role for genetics in the relationship between sodium intake and blood pressure (BP). The role of glycosaminoglycan genes, which are crucial for salinity tolerance, remains to be elucidated. METHODS: Interactions between 54 126 variants in 130 glycosaminoglycan genes and daily sodium excretion on BP were explored in 20 420 EPIC-Norfolk (European Prospective Investigation Into Cancer in Norfolk) subjects. The UK Biobank (n=414 132) and the multiethnic HELIUS study (Healthy Life in an Urban Setting; n=2239) were used for validation. Afterward, the urinary glycosaminoglycan composition was studied in HELIUS participants (n=57) stratified by genotype and upon dietary sodium loading in a time-controlled crossover intervention study (n=12). RESULTS: rs2892799 in NDST3 (heparan sulfate N-deacetylase/N-sulfotransferase 3) showed the strongest interaction with sodium on mean arterial pressure (false discovery rate 0.03), with higher mean arterial pressure for the C allele in high sodium conditions. Also, rs9654628 in HS3ST5 (heparan sulfate-glucosamine 3-sulfotransferase 5) showed an interaction with sodium on systolic BP (false discovery rate 0.03). These interactions were multiethnically validated. Stratifying for the rs2892799 genotype showed higher urinary expression of N-sulfated heparan sulfate epitope D0S0 for the T allele. Conversely, upon dietary sodium loading, urinary D0S0 expression was higher in participants with stable BP after sodium loading, and sodium-induced effects on this epitope were opposite in individuals with and without BP response to sodium. CONCLUSIONS: The C allele of rs2892799 in NDST3 exhibits higher BP in high sodium conditions when compared with low sodium conditions, whereas no differences were detected for the T allele. Concomitantly, both alleles demonstrate distinct expressions of D0S0, which, in turn, correlates with sodium-mediated BP elevation. These findings underscore the potential significance of genetic glycosaminoglycan variation in human BP regulation.

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BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) causes profound impairments in neurological function, and a cure for this devastating disease remains elusive. This study aimed to identify pre-disposing genetic, phenotypic, and exposure-related factors for amyotrophic lateral sclerosis using multi-modal data and assess their joint predictive potential. METHODS: Utilizing data from the UK (United Kingdom) Biobank, we analyzed an unrelated set of 292 ALS cases and 408,831 controls of European descent. Two polygenic risk scores (PRS) are constructed: "GWAS Hits PRS" and "PRS-CS," reflecting oligogenic and polygenic ALS risk profiles, respectively. Time-restricted phenome-wide association studies (PheWAS) were performed to identify pre-existing conditions increasing ALS risk, integrated into phenotypic risk scores (PheRS). A poly-exposure score ("PXS") captures the influence of environmental exposures measured through survey questionnaires. We evaluate the performance of these scores for predicting ALS incidence and stratifying risk, adjusting for baseline demographic covariates. RESULTS: Both PRSs modestly predicted ALS diagnosis but with increased predictive power when combined (covariate-adjusted receiver operating characteristic [AAUC] = 0.584 [0.525, 0.639]). PheRS incorporated diagnoses 1 year before ALS onset (PheRS1) modestly discriminated cases from controls (AAUC = 0.515 [0.472, 0.564]). The "PXS" did not significantly predict ALS. However, a model incorporating PRSs and PheRS1 improved the prediction of ALS (AAUC = 0.604 [0.547, 0.667]), outperforming a model combining all risk scores. This combined risk score identified the top 10% of risk score distribution with a fourfold higher ALS risk (95% CI [2.04, 7.73]) versus those in the 40%-60% range. DISCUSSION: By leveraging UK Biobank data, our study uncovers pre-disposing ALS factors, highlighting the improved effectiveness of multi-factorial prediction models to identify individuals at highest risk for ALS.

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The association between the American Heart Association (AHA) Life's Essential 8 (LE8) and the risk of pancreatic cancer (PC) remains unclear. Our goal was to assess the relationships between LE8, genetic susceptibility, and PC risk. This cohort consisted of 234,102 participants from the UK Biobank. The components of LE8 include diet, nicotine exposure, sleep, physical activity, blood glucose, body mass index, blood lipids, and blood pressure. LE8 is classified into three categories: low cardiovascular health (CVH), moderate CVH, and high CVH. Measurements were made using Cox proportional risk models to estimate impact of associations between LE8, genetic susceptibility, and incidence of PC in participants. Compared to participants with low LE8 scores, those with moderate and high LE8 scores had a 53% (HR, 0.47; 95% CI, 0.39-0.57) and 70% (HR, 0.30; 95% CI, 0.22-0.41) lower risk of developing PC, respectively. Interestingly, among individuals with high genetic risk, high LE8 scores were associated with greater benefits (HR, 0.24; 95% CI, 0.15-0.40), whereas the protective effect was weaker among those with low genetic risk (HR, 0.40; 95% CI, 0.21-0.75). Participants with a high LE8 score and a low polygenic risk score (PRS) had the lowest risk of PC (HR, 0.19; 95% CI: 0.11-0.33). Furthermore, we observed a significant additive interaction between LE8 and PRS. A higher LE8 score is associated with a lower risk of PC, especially for participants with a high PRS. These findings have important implications for participants most genetically predisposed to PC and for targeted strategies for PC prevention.

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OBJECTIVE: Previous studies have suggested that irritable bowel syndrome (IBS) is strongly associated with psychiatric disorders. However, it is unclear whether this association is causal, concomitant, or accidental. Thus, we performed Mendelian randomization (MR) analysis to evaluate the causal effects of several psychiatric disorders on IBS. METHODS: Summary data of genome-wide association studies (GWASs) were obtained mainly from the Psychiatric Genomics Consortium (PGC) on individuals of European ancestry and from a recent GWAS on IBS. We used three MR methods, the inverse-variance weighting (IVW), weighted median (WM), and MR-Egger regression (MR-Egger). In addition, two other indicators, namely, the MR-IVW Cochran's Q statistic and MR-Egger intercept, were used to assess heterogeneity and detect directional horizontal pleiotropy, respectively. RESULTS: Heritability was high for bipolar disorder (81.18 %, 95 % CI = 73.18-148.18 %), schizophrenia (33.88 %, 95 % CI = 33.57-38.19 %), and panic disorder (30.66 %, 95 % CI = 20.74-40.58 %). For other disorders, there was a low liability-scale SNP heritability for major depressive disorder (MDD) (0.67 %, 95 % CI = 0.61-0.73 %), anxiety disorder (7.63 %, 95 % CI = 1.67-13.59 %), PTSD (0.96 %, 95 % CI = 0.12-1.8 %), and IBS (2.44 %, 95 % CI = 2.13-2.75 %). We also observed that schizophrenia had a significant causal effect on IBS according to MR-IVW. Notably, the individual causal estimates of genetic instruments for MDD and schizophrenia were heterogeneous, but no pleiotropic effects were observed. CONCLUSIONS: Our analyses revealed the causal effects of MDD and schizophrenia on IBS, a matter that has been subject to debate for decades, and also showed that IBS had causal effects on MDD.

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Background: Modifiable (physical activity) and non-modifiable (sex and genotype) risk factors interact to affect Alzheimer's disease (AD) risk. Further investigation is necessary to understand if these factors influence brain volume and cognition. Objective: The study aimed to assess the effect of physical activity, APOE genotype, and sex on AD risk, brain volume, and cognition. Methods: UK Biobank data from 2006 to 2023 was accessed. Physical activity was measured by accelerometers, and International Physical Activity Questionnaire. Outcomes were AD incidence; brain volume (ventricular cerebrospinal fluid and total brain); and cognition (executive function, memory, visuospatial ability, processing speed, and reaction time). Logistic and linear regression models were conducted. Results: 69,060 participants met inclusion criteria (mean age: 62.28 years, SD: 7.84; 54.64% female). Higher self-reported (OR = 0.63, 95% CI [0.40, 1.00], p = 0.047) and accelerometer-assessed (OR = 0.96 [0.93, 0.98], p = 0.002) physical activity was associated with lower disease incidence. Smaller ventricular cerebrospinal fluid volume (ß= - 65.43 [- 109.68, - 17.40], p = 0.007), and larger total brain volume (ß= 4398.46 [165.11, 8631.82], p <  0.001) was associated with increased accelerometer-assessed and self-reported physical activity respectively. Both brain volume analyses were moderated by sex. Increased accelerometer-assessed physical activity levels were associated with faster reaction time (ß= - 0.43 [- 0.68, - 0.18], p = 0.001); though poorer visuospatial ability (ß= - 0.06 [- 0.09, - 0.03], p <  0.001), and executive function (ß= 0.49 [0.31, 0.66], p <  0.001; ß= 0.27 [0.10, 0.45], p = 0.002) was related to self-reported physical activity levels. Conclusions: Higher levels of physical activity reduce AD risk independently of non-modifiable risk factors. Moderation of sex on brain volume highlighted the importance of incorporating non-modifiable risk factors in analysis.

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BACKGROUND: Sedentary behavior (SB) has emerged as a significant health concern that deserves attention. This study aimed to examine the associations between prolonged sedentary behavior and the risk of all-cause and cause-specific mortality as well as to explore desirable alternatives to sitting in terms of physical activity (PA). METHODS: Two prospective cohort investigations were conducted using the UK Biobank and NHANES datasets, with a total of 490,659 and 33,534 participants, respectively. Cox proportional hazards regression models were used to estimate the associations between SB and the risk of all-cause and cause-specific mortality due to cancer, cardiovascular disease (CVD), respiratory diseases, and digestive diseases. In addition, we employed isotemporal substitution models to examine the protective effect of replacing sitting with various forms of PA. RESULTS: During the average follow-up times of 13.5 and 6.7 years, 36,109 and 3057 deaths were documented in the UK Biobank and NHANES, respectively. Both cohorts demonstrated that, compared with individuals sitting less than 5 h per day, individuals with longer periods of sitting had higher risks of all-cause and cause-specific mortality due to cancer, CVD, and respiratory diseases but not digestive diseases. Moreover, replacing SB per day with PA, even substituting 30 min of walking for pleasure, reduced the risk of all-cause mortality by 3.5% (hazard ratio [HR] 0.965, 95% confidence interval [CI] 0.954-0.977), whereas cause-specific mortality from cancer, CVD, and respiratory diseases was reduced by 1.6% (HR 0.984, 95% CI 0.968-1.000), 4.4% (HR 0.956, 95% CI 0.930-0.982), and 15.5% (HR 0.845, 95% CI 0.795-0.899), respectively. Furthermore, the protective effects of substitution became more pronounced as the intensity of exercise increased or the alternative duration was extended to 1 h. CONCLUSIONS: SB was significantly correlated with substantially increased risks of all-cause mortality and cause-specific mortality from cancer, CVD, and respiratory diseases. However, substituting sitting with various forms of PA, even for short periods involving relatively light and relaxing physical activity, effectively reduced the risk of both overall and cause-specific mortality.

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Introduction: Cardiovascular disease (CVD) is responsible for over 30% of mortality worldwide. CVD arises from the complex influence of molecular, clinical, social, and environmental factors. Despite the growing number of autosomal genetic variants contributing to CVD, the cause of most CVDs is still unclear. Mitochondria are crucial in the pathophysiology, development and progression of CVDs; the impact of mitochondrial DNA (mtDNA) variants and mitochondrial haplogroups in the context of CVD has recently been highlighted. Aims: We investigated the role of genetic variants in both mtDNA and nuclear-encoded mitochondrial genes (NEMG) in CVD, including coronary artery disease (CAD), hypertension, and serum lipids in the UK Biobank, with sub-group analysis for diabetes. Methods: We investigated 371,542 variants in 2,527 NEMG, along with 192 variants in 32 mitochondrial genes in 381,994 participants of the UK Biobank, stratifying by presence of diabetes. Results: Mitochondrial variants showed associations with CVD, hypertension, and serum lipids. Mitochondrial haplogroup J was associated with CAD and serum lipids, whereas mitochondrial haplogroups T and U were associated with CVD. Among NEMG, variants within Nitric Oxide Synthase 3 (NOS3) showed associations with CVD, CAD, hypertension, as well as diastolic and systolic blood pressure. We also identified Translocase Of Outer Mitochondrial Membrane 40 (TOMM40) variants associated with CAD; Solute carrier family 22 member 2 (SLC22A2) variants associated with CAD and CVD; and HLA-DQA1 variants associated with hypertension. Variants within these three genes were also associated with serum lipids. Conclusion: Our study demonstrates the relevance of mitochondrial related variants in the context of CVD. We have linked mitochondrial haplogroup U to CVD, confirmed association of mitochondrial haplogroups J and T with CVD and proposed new markers of hypertension and serum lipids in the context of diabetes. We have also evidenced connections between the etiological pathways underlying CVDs, blood pressure and serum lipids, placing NOS3, SLC22A2, TOMM40 and HLA-DQA1 genes as common nexuses.

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INTRODUCTION: Given their antioxidative stress, anti-allergic, anti-inflammatory, and immune-modulating effects, flavonoids are hypothesised to play a role in preventing chronic obstructive pulmonary disease (COPD) and asthma. OBJECTIVE: The objective of this cohort study was to examine associations between flavonoid intake and COPD, asthma and lung function. METHODS: Among 119,466 participants of the UK Biobank, median [IQR] age of 60 [53, 65], we estimated intakes of flavonoids, flavonoid-rich foods and a flavodiet score from 24-hour diet assessments. Prospective associations with both incident COPD and asthma and cross-sectional associations with measures of lung function [%predicted forced expiratory volume in 1 second (FEV1); and FEV1/forced vital capacity (FVC)] were examined using multivariable-adjusted Cox proportional hazards and linear regression models, respectively. We investigated mediation by inflammation--represented by the INFLA score--and stratified analyses by smoking status. RESULTS: Compared to low intakes, moderate intakes of total flavonoids, flavonols, theaflavins + thearubigins, and flavanones, and moderate-high intakes of flavanol monomers, proanthocyanidins, anthocyanins, flavones, and the flavodiet score were associated with up to an 18% lower risk of incident COPD [e.g., [HR (95% CI) for total flavonoids: 0.83 (0.75, 0.92)] but not incident asthma. Furthermore, compared to low intakes, higher intakes of all flavonoid subclasses (except theaflavins + thearubigins), and the flavodiet score were associated with better percent predicted FEV1 baseline. Associations were most apparent in ever (current or former) smokers. Flavonoid intakes were inversely associated with the INFLA score, which appeared to mediate 11-14% of the association between intakes of proanthocyanidins and flavones and incident COPD. CONCLUSIONS: Moderate to high flavonoid intakes were associated with a lower risk of COPD and better lung function, particularly among ever smokers. Promoting intakes of healthy flavonoid-rich foods, namely tea, apples and berries, may improve respiratory health and lower COPD risk, particularly in individuals with a history of smoking.

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BACKGROUND: Sex disparity between metabolic-obesity (defined by body mass index, BMI) phenotypes and obesity-related cancer (ORC) remains unknown. Considering BMI reflecting overall obesity but not fat distribution, we aimed to systematically assess the association of our newly proposed metabolic-anthropometric phenotypes with risk of overall and site-specific ORC by sex. METHODS: A total of 141,579 men (mean age: 56.37 years, mean follow-up time: 12.04 years) and 131,047 women (mean age: 56.22 years, mean follow up time: 11.82 years) from the UK Biobank was included, and designated as metabolic-anthropometric phenotypes based on metabolic status (metabolically healthy/unhealthy), BMI (non-obesity/obesity) and body shape (pear/slim/apple/wide). The sex-specific association of different phenotypes with overall and site-specific ORC was assessed by hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox proportional hazards regression models. RESULTS: We found metabolically unhealthy and/or obesity phenotypes conveyed a higher risk in men than in women for overall ORC and colorectal cancer compared with metabolically healthy non-obesity phenotype (Pinteraction < 0.05). Of note, metabolically healthy obesity phenotype contributed to increased risks of most ORC in men (HRs: 1.58 ~ 2.91), but only correlated with higher risks of endometrial (HR = 1.89, 95% CI: 1.54-2.32) and postmenopausal breast cancers (HR = 1.17, 95% CI: 1.05-1.31) in women. Similarly, even under metabolically healthy, men carrying apple and wide shapes phenotypes (metabolically healthy apple/wide and metabolically healthy non-obesity apple/wide) suffered an increased risk of ORC (mainly colorectal, liver, gastric cardia, and renal cancers, HRs: 1.20 ~ 3.81) in comparison with pear shape or non-obesity pear shape. CONCLUSIONS: There was a significant sex disparity between metabolic-anthropometric phenotypes and ORC risk. We advised future ORC prevention and control worth taking body shape and sex disparity into account.

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The aim of this paper is to propose a novel method for estimating trans-ancestry genetic correlations in genome-wide association studies (GWAS) using genetically-predicted observations. These correlations describe how genetic architecture of complex traits varies among populations. Our new estimator corrects for biases arising from prediction errors in high-dimensional weak GWAS signals, while addressing the ethnic diversity inherent in GWAS data, such as linkage disequilibrium (LD) differences. A distinguishing feature of our approach is its flexibility regarding sample sizes: it necessitates a large GWAS sample only from one population, while the secondary population may have a much smaller cohort, even in the hundreds. This design directly addresses the existing imbalance in GWAS data resources, where datasets for European populations typically outnumber those of non-European ancestries. Through extensive simulations and real data analysis from the UK Biobank study encompassing 26 complex traits, we validate the reliability of our method. Our results illuminate the broader implications of transferring genetic findings across diverse populations.

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BACKGROUND: This study aimed to investigate the associations of time from waking to the first cigarette (TWFC) with all-cause mortality, cardiovascular disease (CVD) mortality and incident CVD among people smoking. METHODS: Data were from the UK Biobank, including 32 519 people smoking aged 40-70 years. TWFC was investigated using a touch-screen questionnaire. Outcomes included all-cause mortality and mortality from and incidence of CVD, ischemic heart disease (IHD) and stroke. RESULTS: Compared with participants reporting TWFC >120 min, those reporting TWFC between 61 and 120 min (HR, 1.30; 95% CI, 1.10-1.53), TWFC between 5 and 60 min (1.48, 1.30-1.70) and TWFC <5 min (1.65, 1.42-1.93) had a higher risk of all-cause mortality. Compared with participants reporting TWFC >120 min, those reporting TWFC between 5 and 60 min and TWFC <5 min had higher risks of CVD and IHD mortality and incident CVD and IHD, but those reporting TWFC between 61 and 120 min did not. The associations of TWFC with stroke mortality and incident stroke were not observed. CONCLUSION: In this cohort study, a shorter TWFC was associated with higher risks of all-cause mortality, mortality from CVD and IHD, as well as incident CVD and IHD.

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BACKGROUND: Despite substantial evidence regarding independent associations between physical activity (PA) and ultra-processed foods (UPF) consumption with depression, the joint effects of these two factors remain unknown. METHODS: This study included 99,126 participants without depression in the UK Biobank at baseline. A 24-h recall method was used to assess UPF consumption, and self-reported total physical activity (TPA), moderate-to-vigorous physical activity (MVPA), and vigorous physical activity (VPA) were assessed by metabolic equivalent task (MET). A series of Cox proportional hazard regression models were used to explore the independent and joint effects of TPA, MVPA, VPA and UPF consumption on depression. RESULTS: The incidence rate of depression was 1.94 % [95 % confidence interval (CI): 1.80 %-2.10 %] per 1000 person-years after an average follow-up of 12.10 years. We found that MVPA and UPF consumption had additive interactions on depression risk (p < 0.05). Participants in Q1 of TPA and Q4 of UPF consumption (HR: 1.83, 95%CI: 1.45-2.31) showed a higher risk for depression than those in Q4 of TPA and Q1 of UPF consumption. Compared with the participants with WHO guideline-recommended MVPA and the lowest UPF consumption, those below recommended MVPA (HR: 1.51, 95%CI: 1.20-1.89) or above recommended MVPA (HR: 1.40, 95%CI: 1.10-1.78) and with the highest UPF consumption had a higher risk for depression. LIMITATIONS: Study limitations include use of self-reported data, observational study and concerns regarding generalizability. CONCLUSION: Higher UPF consumption, accompanied by lower PA levels regardless of TPA, MVPA, and VPA, is associated with a higher risk of depression. Our study offers insights on public health priorities to decrease the risk of depression in the population by addressing both PA and UPF consumption together.

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BACKGROUND: The mechanism linking BMI and asthma remains unclear. METHOD: Mendelian Randomization (MR) analysis was conducted using summary-level GWAS data from the FinnGen Biobank and the Open GWAS project. The analysis considering potential variables as mediators, including blood cell counts, blood pressure, and blood biomarkers. Three commonly used MR methods-the inverse-variance-weighted (IVW) method, weighted median (WM) method, and MR-Egger method-were employed to infer causal links. A two-step approach was used in mediation analysis to evaluate the causal links among BMI, candidate mediators, and asthma. RESULT: Elevated BMI demonstrated a substantial correlation with increased asthma risk. Thirteen biomarkers mediated the relationship between BMI and asthma, mainly including leukocyte count (5.070%), apolipoprotein A levels (7.395%), cystatin C levels (5.345%), urate levels (9.057%), diastolic blood pressure (7.365%), and albumin levels (10.888%). These factors collectively explained over 50% of the increased asthma risk associated with BMI elevation. Additionally, eosinophil count and C-reactive protein were also identified as important mediators using the WM method. CONCLUSION: This study highlights the complex relationship between obesity, blood biomarkers, and asthma risk. Additional studies are required to validate these results and investigate causal relationships in various populations.

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BACKGROUND: Health problems associated with shift work and night shift work are gaining increasing public attention. OBJECTIVE: To investigate the association between night shift work and the hazard of mortality. DESIGN: Prospective cohort study. PARTICIPANTS: A total of 283,579 individuals with paid employment or self-employment aged 37-73 years were included from the UK Biobank with a median follow-up period of 14.0 years. MAIN MEASURES: Participants were divided into day workers and shift workers, including the frequency of night shifts, to evaluate the association between baseline work schedules and all-cause and cause-specific mortality using the Cox proportional hazards model. Additionally, 75,760 participants with work histories were assessed for the association between average frequency and cumulative years of exposure to night shift work and all-cause and cause-specific mortality. KEY RESULTS: Compared with that of day workers, the adjusted hazard of all-cause mortality was increased by 12.0% (hazard ratio [HR], 1.12; 95% confidence interval [CI], 1.07-1.18) in shift workers, particularly in those with no or rare night shifts (approximately 16.1%; HR, 1.16; 95% CI, 1.08-1.25) and those with irregular night shifts (approximately 9.2%; HR, 1.09; 95% CI, 1.00-1.19). Moreover, a non-linear relationship was identified between cumulative night shift years and all-cause and cause-specific mortality. Only individuals who worked night shifts for 20-30 years exhibited a substantially increased hazard of all-cause (HR, 1.52; 95% CI, 1.15-2.00) and cardiovascular disease (CVD; HR, 2.08; 95% CI, 1.16-3.71) mortality. CONCLUSIONS: Shift workers, particularly those with rare or irregular night shifts, exhibited an increased hazard of mortality. Additionally, participants who worked night shifts for 20-30 years exhibited a substantially increased hazard of all-cause and CVD mortality.