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Abstract Background Obesity and central obesity are multifactorial conditions with genetic and non-genetic (lifestyle and environmental) contributions. There is incomplete understanding of whether lifestyle modifies the translation from respective genetic risks into phenotypic obesity and central obesity, and to what extent genetic predisposition to obesity and central obesity is mediated via lifestyle factors. Methods This is a cross-sectional study of 201,466 (out of approximately 502,000) European participants from UK Biobank and tested for interactions and mediation role of lifestyle factors (diet quality; physical activity levels; total energy intake; sleep duration, and smoking and alcohol intake) between genetic risk for obesity and central obesity. BMI-PRS and WHR-PRS are exposures and obesity and central obesity are outcomes. Results Overall, 42.8% of the association between genetic predisposition to obesity and phenotypic obesity was explained by lifestyle: 0.9% by mediation and 41.9% by effect modification. A significant difference between men and women was found in central obesity; the figures were 42.1% (association explained by lifestyle), 1.4% (by mediation), and 40.7% (by modification) in women and 69.6% (association explained by lifestyle), 3.0% (by mediation), and 66.6% (by modification) in men. Conclusions A substantial proportion of the association between genetic predisposition to obesity/central obesity and phenotypic obesity/central obesity was explained by lifestyles. Future studies with repeated measures of obesity and lifestyle would be needed to clarify causation.

Abstract Background Preliminary evidence demonstrates some parameters of metabolic control, including glycaemic control, lipid control and insulin resistance, vary across the menstrual cycle. However, the literature is inconsistent, and the underlying mechanisms remain uncertain. This study aimed to investigate the association between the menstrual cycle phase and metabolites and to explore potential mediators and moderators of these associations. Methods We undertook a cross-sectional cohort study using UK Biobank. The outcome variables were glucose; triglyceride; triglyceride to glucose index (TyG index); total, HDL and LDL cholesterol; and total to HDL cholesterol ratio. Generalised additive models (GAM) were used to investigate non-linear associations between the menstrual cycle phase and outcome variables. Anthropometric, lifestyle, fitness and inflammatory markers were explored as potential mediators and moderators of the associations between the menstrual cycle phase and outcome variables. Results Data from 8694 regularly menstruating women in UK Biobank were analysed. Non-linear associations were observed between the menstrual cycle phase and total (p

Abstract Background The World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR) Cancer Prevention Recommendations are lifestyle-based recommendations which aim to reduce cancer risk. This study investigated associations between adherence, assessed using a standardised scoring system, and the risk of all cancers combined and of 14 cancers for which there is strong evidence for links with aspects of lifestyle in the UK. Methods We used data from 94,778 participants (53% female, mean age 56 years) from the UK Biobank. Total adherence scores (range 0–7 points) were derived from dietary, physical activity, and anthropometric data. Associations between total score and cancer risk (all cancers combined; and prostate, breast, colorectal, lung, uterine, liver, pancreatic, stomach, oesophageal, head and neck, ovarian, kidney, bladder, and gallbladder cancer) were investigated using Cox proportional hazard models, adjusting for age, sex, deprivation index, ethnicity, and smoking status. Results Mean total score was 3.8 (SD 1.0) points. During a median follow-up of 8 years, 7296 individuals developed cancer. Total score was inversely associated with risk of all cancers combined (HR: 0.93; 95%CI: 0.90–0.95 per 1-point increment), as well as breast (HR: 0.90; 95%CI: 0.86–0.95), colorectal (HR: 0.90; 95%CI: 0.84–0.97), kidney (HR: 0.82; 95%CI: 0.72–0.94), oesophageal (HR: 0.84; 95%CI: 0.71–0.98), ovarian (HR: 0.76; 95%CI: 0.65–0.90), liver (HR: 0.78; 95%CI: 0.63–0.97), and gallbladder (HR: 0.70; 95%CI: 0.53–0.93) cancers. Conclusions Greater adherence to lifestyle-based recommendations was associated with reduced risk of all cancers combined and of breast, colorectal, kidney, oesophageal, ovarian, liver, and gallbladder cancers. Our findings support compliance with the Cancer Prevention Recommendations for cancer prevention in the UK.

Abstract Background Most studies investigating the association between physical activity (PA) and the risk of type 2 diabetes are derived from self-reported questionnaires, with limited evidence using device-based measurements. Therefore, this study aimed to investigate the dose–response relationship between device-measured PA and incident type 2 diabetes. Methods This prospective cohort study included 40,431 participants of the UK Biobank. Wrist-worn accelerometers were used to estimate total, light, moderate, vigorous and moderate-to-vigorous PA. The associations between PA and incident type 2 diabetes were analysed using Cox-proportional hazard models. The mediating role of body mass index (BMI) was tested under a causal counterfactual framework. Results The median follow-up period was 6.3 years (IQR: 5.7–6.8), with 591 participants developing type 2 diabetes. Compared to those achieving 600 min/week were at 49% (95% CI 62–32%), 62% (95% CI 71–50%) and 71% (95% CI 80–59%) lower risk of type 2 diabetes, respectively. For vigorous PA, compared to those achieving 75 min/week were at 38% (95% CI 48–33%), 48% (95% CI 64–23%) and 64% (95% CI 78–42%) lower type 2 diabetes risk, respectively. Twelve per cent and 20% of the associations between vigorous and moderate PA and type 2 diabetes were mediated by lower BMI, respectively. Conclusions PA has clear dose-response relationship with a lower risk of type 2 diabetes. Our findings support the current aerobic PA recommendations but suggest that additional PA beyond the recommendations is associated with even greater risk reduction. Trial registration The UK Biobank study was approved by the North West Multi-Centre Research Ethics Committee (Ref 11/NW/0382 on June 17, 2011).

Abstract Background Although non-alcoholic fatty liver disease (NAFLD) is linked to inflammation, whether an inflammatory diet increases the risk of NAFLD is unclear. This study aimed to examine the association between the Energy-adjusted Diet Inflammatory Index (E-DII) score and severe NAFLD using UK Biobank. Methods This prospective cohort study included 171,544 UK Biobank participants. The E-DII score was computed using 18 food parameters. Associations between the E-DII and incident severe NAFLD (defined as hospital admission or death) were first investigated by E-DII categories (very/moderately anti-inflammatory [E-DII 1]) using Cox proportional hazard models. Nonlinear associations were investigated using penalised cubic splines fitted into the Cox proportional hazard models. Analyses were adjusted for sociodemographic, lifestyle and health-related factors. Results Over a median follow-up of 10.2 years, 1489 participants developed severe NAFLD. After adjusting for confounders, individuals in the very/moderately pro-inflammatory category had a higher risk (HR: 1.19 [95% CI: 1.03 to 1.38]) of incident severe NAFLD compared with those in the very/moderately anti-inflammatory category. There was some evidence of nonlinearity between the E-DII score and severe NAFLD. Conclusions Pro-inflammatory diets were associated with a higher risk of severe NAFLD independent of confounders such as the components of the metabolic syndrome. Considering there is no recommended treatment for the disease, our findings suggest a potential means to lower the risk of NAFLD.

Abstract Background Studies on physical activity (PA) and mental health are largely limited to self-reported PA. This study aims to use prospective cohort data to investigate the association between device-measured PA and affective disorders. Methods A total of 37,327 participants from UK Biobank who had not had any prior affective disorder diagnoses were included in this prospective cohort study. Wrist-worn accelerometers were used to measure total, light (LPA), moderate (MPA), and vigorous (VPA) PA. Associations between PA domains and affective disorders were analysed using penalised splines in Cox proportional hazard models. Analyses were adjusted for other intensity-specific PA and sociodemographic and lifestyle factors. Sensitivity analyses were conducted adjusting for body mass index and longstanding illnesses as well as excluding events in the first 2 years of follow-up. Preventable fractions for the population were estimated for MPA and VPA. Results Over a median follow-up of 6.8 years, 1262 (3.4%) individuals were diagnosed with affective disorders. Replacing 30 min of sedentary behaviour in a week with MPA (HR 0.95, 95% CI 0.94–0.97) or VPA (HR 0.91, 95% CI 0.85–0.98) was associated with lower risk of affective behaviours, up to 500 and 120 min of MPA and VPA. Assuming causality, 5.14% and 18.88% of affective disorders could have been prevented if MPA ≥150 min/week and VPA ≥75 min/week were achieved, respectively, across the study population. Conclusions Device-measured MPA and VPA were associated with lower risk of affective disorders. The potential mental health benefits of MPA continue to accrue above the current World Health Organization recommendation.

Abstract Background Ethnic differences in cardiovascular disease (CVD) risk have been known for decades, but a systematic exploration of how exposure and susceptibility to risk factors may contribute is lacking. This study aimed to investigate the potential impact of differential exposure and susceptibility between South Asian, Black, and White individuals. Methods This is a population-based prospective cohort study of UK Biobank participants with a median follow-up of 11.3 years. The association between ethnic group and CVD risk was studied. Additional risk factors were then adjusted to examine mediations. Moderation analysis was conducted to identify whether risk factors had a stronger association in the ethnic minority groups. Population attributable fractions were also calculated to quantify the relative contributions of risk factors for each ethnic group. Results When adjusted for only age and sex, there was a higher risk of CVD among South Asian (n=8815; HR [95% CI] 1.69 [1.59–1.79]) and Black (n=7526; HR [95% CI] 1.12 [1.03–1.22]) compared with White participants (n=434,809). The excess risk of Black participants was completely attenuated following adjustment for deprivation. Compared with White participants, the associations of BMI, triglycerides, and HbA1c with CVD were stronger in South Asians. Adiposity was attributable to the highest proportion of CVD regardless of ethnicity. Smoking had the second largest contribution to CVD among White and Black participants, and HbA1c among South Asian participants. Conclusions Adiposity is an important risk factor for CVD regardless of ethnicity. Ethnic inequalities in CVD incidence may be best tackled by targeting interventions according to ethnic differences in risk profiles.

Abstract Background Previous cohort studies have investigated the relationship between self-reported physical activity (PA) and dementia. Evidence from objective device-measured PA data is lacking. This study aimed to explore the association of device-measured PA with the risk of dementia incidence and common subtypes (Alzheimer’s disease [AD] and vascular dementia) using the UK Biobank study. Methods 84,854 participants (55.8% women), invited to participate in the device-measured PA between 2013 and 2015, were included in this prospective cohort study. Wrist accelerometers were used to measure light, moderate, vigorous, moderate-to-vigorous PA (MVPA) and total PA intensity and duration (MET/min/week). Incident dementia (fatal and non-fatal) was extracted from hospital episodes records for incidence and death register for mortality. Incidence follow-up was carried out until the end of March 2021in England and Scotland and the end of March 2018 in Wales. Mortality data were available until February 2021. Nonlinear associations were first investigated using penalised cubic splines fitted in the Cox proportional hazard models. In addition, using MVPA, five categories were created. Associations of these categories with the outcomes were investigated using Cox proportional hazard models. Analyses were adjusted for sociodemographic, lifestyle and health-related factors. Results After a median follow-up of 6.3 years, 678 individuals were diagnosed with dementia. Evidence of nonlinearity was observed for all PA modes and all-cause dementia. For categories of MVPA, there was a significant trend towards a low risk of overall dementia when higher levels of MVPA were achieved (HRtrend 0.66 [95% CI 0.62 to 0.70]. The lowest risk was identified in individuals who performed more than 1200 MET/min/week, those who had 84% (95% CI 0.12 to 0.21) lower risk of incident dementia compared to those who performed

Abstract Background Adiposity is a strong risk factor for cancer incidence and mortality. However, most of the evidence available has focused on body mass index (BMI) as a marker of adiposity. There is limited evidence on relationships of cancer with other adiposity markers, and if these associations are linear or not. The aim of this study was to investigate the associations of six adiposity markers with incidence and mortality from 24 cancers by accounting for potential non-linear associations. Methods A total of 437,393 participants (53.8% women; mean age 56.3 years) from the UK Biobank prospective cohort study were included in this study. The median follow-up was 8.8 years (interquartile range 7.9 to 9.6) for mortality and 9.3 years (IQR 8.6 to 9.9) for cancer incidence. Adiposity-related exposures were BMI, body fat percentage, waist-hip ratio, waist-height ratio, and waist and hip circumference. Incidence and mortality of 24 cancers sites were the outcomes. Cox proportional hazard models were used with each of the exposure variables fitted separately on penalised cubic splines. Results During follow-up, 47,882 individuals developed cancer and 11,265 died due to cancer during the follow-up period. All adiposity markers had similar associations with overall cancer incidence. BMI was associated with a higher incidence of 10 cancers (stomach cardia (hazard ratio per 1 SD increment 1.35, (95% CI 1.23; 1.47)), gallbladder (1.33 (1.12; 1.58)), liver (1.27 (1.19; 1.36)), kidney (1.26 (1.20; 1.33)), pancreas (1.12 (1.06; 1.19)), bladder (1.09 (1.04; 1.14)), colorectal (1.10 (1.06; 1.13)), endometrial (1.73 (1.65; 1.82)), uterine (1.68 (1.60; 1.75)), and breast cancer (1.08 (1.05; 1.11))) and overall cancer (1.03 (1.02; 1.04)). All these associations were linear except for breast cancer in postmenopausal women. Similar results were observed when other markers of central and overall adiposity were used. For mortality, nine cancer sites were linearly associated with BMI and eight with waist circumference and body fat percentage. Conclusion Adiposity, regardless of the marker used, was associated with an increased risk in 10 cancer sites.

Abstract Background Frailty has been associated with worse prognosis following COVID-19 infection. While several studies have reported the association between frailty and COVID-19 mortality or length of hospital stay, there have been no community-based studies on the association between frailty and risk of severe infection. Considering that different definitions have been identified to assess frailty, this study aimed to compare the association between frailty and severe COVID-19 infection in UK Biobank using two frailty classifications: the frailty phenotype and the frailty index. Methods A total of 383,845 UK Biobank participants recruited 2006–2010 in England (211,310 [55.1%] women, baseline age 37–73 years) were included. COVID-19 test data were provided by Public Health England (available up to 28 June 2020). An adapted version of the frailty phenotype derived by Fried et al. was used to define frailty phenotype (robust, pre-frail, or frail). A previously validated frailty index was derived from 49 self-reported questionnaire items related to health, disease and disability, and mental wellbeing (robust, mild frailty, and moderate/severe frailty). Both classifications were derived from baseline data (2006–2010). Poisson regression models with robust standard errors were used to analyse the associations between both frailty classifications and severe COVID-19 infection (resulting in hospital admission or death), adjusted for sociodemographic and lifestyle factors. Results Of UK Biobank participants included, 802 were admitted to hospital with and/or died from COVID19 (323 deaths and 479 hospitalisations). After analyses were adjusted for sociodemographic and lifestyle factors, a higher risk of COVID-19 was observed for pre-frail (risk ratio (RR) 1.47 [95% CI 1.26; 1.71]) and frail (RR 2.66 [95% CI 2.04; 3.47]) individuals compared to those classified as robust using the frailty phenotype. Similar results were observed when the frailty index was used (RR mildly frail 1.46 [95% CI 1.26; 1.71] and RR moderate/severe frailty 2.43 [95% CI 1.91; 3.10]). Conclusions Frailty was associated with a higher risk of severe COVID-19 infection resulting in hospital admission or death, irrespective of how it was measured and independent of sociodemographic and lifestyle factors. Public health strategies need to consider the additional risk that COVID-19 poses in individuals with frailty, including which additional preventive measures might be required.

Abstract Background Child maltreatment is associated with cardiovascular disease (CVD), but mediation pathways have not been fully elucidated. The aim of the current study was to determine and quantify the underlying pathways linking child maltreatment and CVD. Methods We conducted a retrospective cohort study using the UK Biobank. The number and types of child maltreatment, including abuse and neglect, were recalled by the participants. Lifestyle, biological, physical, and mental health factors measured at baseline were explored as potential mediators. Incident CVD was ascertained through record linkage after baseline measurement. Age, sex, ethnicity, area-based deprivation, and education level were adjusted for as confounders. Cox proportional hazard models were conducted to test for associations between child maltreatment and incident CVD. Results A total of 152,040 participants who completed the child maltreatment assessment were included in the analyses, and one third reported at least one type of child maltreatment. There was a dose-response relationship between the number of maltreatment types and incident CVD. On average, each additional type of child maltreatment was associated with an 11% (95% CI 8–14%, P

Abstract Background Understanding of the role of ethnicity and socioeconomic position in the risk of developing SARS-CoV-2 infection is limited. We investigated this in the UK Biobank study. Methods The UK Biobank study recruited 40–70-year-olds in 2006–2010 from the general population, collecting information about self-defined ethnicity and socioeconomic variables (including area-level socioeconomic deprivation and educational attainment). SARS-CoV-2 test results from Public Health England were linked to baseline UK Biobank data. Poisson regression with robust standard errors was used to assess risk ratios (RRs) between the exposures and dichotomous variables for being tested, having a positive test and testing positive in hospital. We also investigated whether ethnicity and socioeconomic position were associated with having a positive test amongst those tested. We adjusted for covariates including age, sex, social variables (including healthcare work and household size), behavioural risk factors and baseline health. Results Amongst 392,116 participants in England, 2658 had been tested for SARS-CoV-2 and 948 tested positive (726 in hospital) between 16 March and 3 May 2020. Black and south Asian groups were more likely to test positive (RR 3.35 (95% CI 2.48–4.53) and RR 2.42 (95% CI 1.75–3.36) respectively), with Pakistani ethnicity at highest risk within the south Asian group (RR 3.24 (95% CI 1.73–6.07)). These ethnic groups were more likely to be hospital cases compared to the white British. Adjustment for baseline health and behavioural risk factors led to little change, with only modest attenuation when accounting for socioeconomic variables. Socioeconomic deprivation and having no qualifications were consistently associated with a higher risk of confirmed infection (RR 2.19 for most deprived quartile vs least (95% CI 1.80–2.66) and RR 2.00 for no qualifications vs degree (95% CI 1.66–2.42)). Conclusions Some minority ethnic groups have a higher risk of confirmed SARS-CoV-2 infection in the UK Biobank study, which was not accounted for by differences in socioeconomic conditions, baseline self-reported health or behavioural risk factors. An urgent response to addressing these elevated risks is required.