UK Biobank Research Articles

Association of healthy diet score and adiposity with risk of colorectal cancer: findings from the UK Biobank prospective cohort study.

To explore the joint association of dietary patterns and adiposity with colorectal cancer (CRC), and whether adiposity mediates the relationship between dietary patterns and CRC risk, which could provide deeper insights into the underlying pathogenesis of CRC. The data of 307,023 participants recruited between 2006 and 2010 were extracted from the UK Biobank study. Healthy diet scores were calculated based on self-reported dietary data at baseline, and participants were categorized into three groups, namely, low, intermediate, and high diet score groups. Cox regression models with hazard ratios (HRs) and 95% confidence intervals (CIs) were used to estimate the effects of the healthy diet score on CRC incidence, adjusting for various covariates. Furthermore, the mediation roles of obesity and central obesity between the healthy diet score and CRC risk were assessed using a counterfactual causal analysis based on Cox regression model. Additionally, joint association between dietary patterns and adiposity on CRC risks was assessed on the additive and multiplicative scales. Over a median 6.2-year follow-up, 3,276 participants developed CRC. After adjusting for sociodemographic and lifestyle factors, a lower risk of CRC incidence was found for participants with intermediate (HR = 0.83, 95% CI: 0.72 to 0.95) and high diet scores (HR = 0.73, 95% CI: 0.62 to 0.87) compared to those with low diet scores. When compared with the low diet score group, obesity accounted for 4.13% and 7.93% of the total CRC effect in the intermediate and high diet score groups, respectively, while central obesity contributed to 3.68% and 10.02% of the total CRC risk in the intermediate and high diet score groups, respectively. The mediating effect of adiposity on CRC risk was significant in men but not in women. Concurrent unhealthy diet and adiposity multiplied CRC risk. Adiposity-mediated effects were limited in the link between dietary patterns and CRC incidence, implying that solely addressing adiposity may not sufficiently reduce CRC risk. Interventions, such as improving dietary quality in people with adiposity or promoting weight control in those with unhealthy eating habits, may provide an effective strategy to reduce CRC risk.

Lifestyle and genetic predisposition are associated with incident irritable bowel syndrome: a population-based prospective cohort study

Few prospective studies have investigated the joint effect of lifestyle factors and genetic susceptibility on the risk of irritable bowel syndrome (IBS). This study aims to evaluate the associations of lifestyle and genetic factors with incident IBS in the UK Biobank. We analyzed data from 481,057 participants (54% female) without prevalent IBS at enrollment in the UK Biobank. An overall healthy lifestyle was defined using six modifiable lifestyle factors, including smoking, body mass index (BMI), sleep duration, diet, physical activity, and alcohol consumption, and hence categorized into ‘favorable’, ‘intermediate’, and ‘unfavorable’ lifestyles. A Cox proportional hazard model was used to investigate the association between a healthy lifestyle and incident IBS. Furthermore, we constructed a polygenic risk score (PRS) for IBS and assessed whether lifestyle modified the effect of genetics on the development of IBS. During a median follow-up of 12.1 years, 8,645 incident IBS were ascertained. Specifically, among the six modifiable lifestyle factors, adequate sleep demonstrates the greatest protective effect (hazard ratio [HR]: 0.72, 95% CI: 0.69,0.75) against IBS.Compared with a favorable lifestyle, an unfavorable lifestyle was associated with a 56% (95% CI: 46%-67%) increased risk of IBS (P = 8.99×10-40). The risk of incident IBS was 12% (95% CI: 4%-21%) higher among those at high genetic risk compared with those at low genetic risk (P = 0.005). When considering the joint effect of lifestyle and genetic susceptibility, the HR nearly doubled among individuals with high genetic risk and unfavorable lifestyle (HR: 1.80; 95% CI:1.51-2.15; P = 3.50×10-11) compared to those with low genetic risk and favorable lifestyle. No multiplicative or addictive interaction was observed between lifestyle and genetics. The findings from this study indicated that lifestyle and genetic factors were independently associated with the risk of incident IBS. All these results implicated a possible clinical strategy of lowering the incidence of IBS by advocating a healthy lifestyle.

Relationships between orofacial pain and sleep: Analysis of UK biobank and genome-wide association studies data

Background/purposeOrofacial pain is common in dental practices. This study aimed to explore relationships between orofacial pain and sleep using the UK Biobank dataset and, based on epidemiological associations, to investigate the causal association using genome-wide association studies data. Materials and methodsFirst, a cross-sectional study was conducted with 196,490 participants from UK Biobank. Information on pain conditions and sleep traits was collected. Multivariable models were used to explore the relationships with odds ratio (OR). Second, Mendelian randomization analyses were conducted using data for orofacial pain, including temporomandibular joint disorders-related pain (n = 377,277) and atypical facial pain (n = 331,749), and sleep traits, including sleep duration (n = 446,118), short sleep (n = 411,934), long sleep (n = 339,926), snoring (n = 359,916), ease of getting up (n = 385,949), insomnia (n = 453,379), daytime dozing (n = 452,071), daytime napping (n = 452,633), and chronotype (n = 403,195). ResultsThe cross-sectional study confirmed the bidirectionality between pain and sleep. Participants experiencing pain all over the body showed a significant association with an unhealthy sleep pattern (OR = 1.18, P < 0.001) and other sleep traits (P < 0.05). Risks of chronic orofacial pain were associated with sleep duration in a non-linear relationship (P = 0.032). The Mendelian randomization analyses indicated that long sleep was causally associated with temporomandibular joint disorders-related pain (OR = 6.77, P = 0.006). ConclusionThe relationship between pain and sleep is bidirectional. Long sleep is found to be causally associated with chronic orofacial pain.

A Gap Analysis of UK Biobank Publications Reveals SNPs Associated with Intrinsic Subtypes of Breast Cancer.

Breast cancer is a multifaceted disease and a leading cause of cancer morbidity and mortality in females across the globe. In 2020 alone, 2.3 million women were diagnosed and 685,000 died of breast cancer worldwide. With the number of diagnoses projected to increase to 3 million per year by 2040 it is essential that new methods of detection and disease stratification are sought to decrease this global cancer burden.Although significant improvements have been made in breast cancer diagnosis and treatment, the prognosis of breast cancer remains poor in some patient groups (i.e. triple negative breast cancer), necessitating research into better patient stratification, diagnosis and drug discovery. The UK Biobank, a comprehensive biomedical and epidemiological database with a wide variety of multiomics data (genomics, proteomics, metabolomics) offers huge potential to uncover groundbreaking discoveries in breast cancer research leading to improved patient stratification. Combining genomic, proteomic, and metabolic profiles of breast cancer in combination with histological classification, can aid treatment decisions through accurate diagnosis and prognosis prediction of tumor behaviour.Here, we systematically reviewed PubMed publications reporting the analysis of UK Biobank data in breast cancer research. Our analysis of UK Biobank studies in the past five years identified 125 publications, of which 76 focussed on genomic data analysis. Interestingly, only two studies reported the analysis of metabolomics and proteomics data, with none performing multiomics analysis of breast cancer. A meta-analysis of the 76 publications identified 2,870 genetic variants associated with breast cancer across 445 genes. Subtype analysis revealed differential genetic alteration in 13 of the 445 genes and the identification of 59 well-established breast cancer genes. in differential pathways. Pathway interaction analyses illuminated their involvement in general cancer biomolecular pathways (e.g. DNA damage repair, Gene expression). While our meta-analysis only measured genetic differences in breast cancer due to current usage of UK Biobank data, minimal multi-omics analyses have been performed and the potential for harnessing multi-omics strategies within the UK Biobank cohort holds promise for unravelling the biological signatures of distinct breast cancer subtypes further in the future.

Air pollutants, genetic susceptibility, and incident schizophrenia in later life: A prospective study in the UK Biobank

ObjectiveAir pollution has been linked to multiple psychiatric disorders, but little is known on its long-term association with schizophrenia. The interaction between air pollution and genetic susceptibility on incident schizophrenia has never been reported. We aimed to explore the associations between long-term air pollution exposure and late-onset schizophrenia and evaluate whether genetic susceptibility could modify the association. MethodsThis population-based prospective cohort study included 437,802 middle-aged and elderly individuals free of schizophrenia at baseline in the UK Biobank. Land use regression models were applied in the estimation of the annual average concentrations of nitrogen dioxide (NO2), nitrogen oxides (NOx), fine particulate matter (PM2.5), and inhalable particulate matter (PM10) at residence. The associations between air pollutants and schizophrenia were evaluated by using Cox proportional hazard models. A polygenic risk score of schizophrenia was constructed for exploring potential interaction of air pollutants with genetic susceptibility. ResultsAn interquartile range increase in PM2.5, PM10, NO2, and NOx was associated with the hazard ratios (HR) for incident schizophrenia at 1.19, 1.16, 1.22, and 1.09, respectively. The exposure-response curves for the association of air pollution with incident schizophrenia were approximately linear. There are additive interactions of air pollution score (APS), PM10, NO2, and NOx with genetic risk. Specifically, compared with participants with low genetic susceptibility and low APS, the HR was 3.23 for individuals with high genetic risk and high APS, among which 0.49 excess risk could be attributed to the additive interaction, accounting for 15 % of the schizophrenia risk. ConclusionThis large-scale, prospective cohort study conveys the first-hand evidence that long-term air pollution exposure could elevate schizophrenia incidence in later life, especially for individuals with higher genetic risks. The findings highlight the importance of improving air quality for preventing the late-onset schizophrenia in an aging era, especially among those with high genetic risks.

Impact of ambient air pollution on colorectal cancer risk and survival: insights from a prospective cohort and epigenetic Mendelian randomization study

This study investigates the associations between air pollution and colorectal cancer (CRC) risk and survival from an epigenomic perspective. Using a newly developed Air Pollutants Exposure Score (APES), we utilized a prospective cohort study (UK Biobank) to investigate the associations of individual and combined air pollution exposures with CRC incidence and survival, followed by an up-to-date systematic review with meta-analysis to verify the associations. In epigenetic two-sample Mendelian randomization analyses, we examine the associations between genetically predicted DNA methylation related to air pollution and CRC risk. Further genetic colocalization and gene-environment interaction analyses provided different insights to disentangle pathogenic effects of air pollution via epigenetic modification. During a median 12.97-year follow-up, 5767 incident CRC cases among 428,632 participants free of baseline CRC and 533 deaths in 2401 patients with CRC were documented in the UK Biobank. A higher APES score was associated with an increased CRC risk (HR, 1.03, 95% CI= 1.01-1.06; P=0.016) and poorer survival (HR, 1.13, 95% CI= 1.03-1.23; P=0.010), particularly among participants with insufficient physical activity and ever smokers (Pinteraction > 0.05). A subsequent meta-analysis of seven observational studies, including UK Biobank data, corroborated the association between PM2.5 exposure (per 10μg/m3 increment) and elevated CRC risk (RR,1.42, 95% CI= 1.12-1.79; P=0.004; I2=90.8%). Genetically predicted methylation at PM2.5-related CpG site cg13835894 near TMBIM1/PNKD and cg16235962 near CXCR5, and NO2-related cg16947394 near TMEM110 were associated with an increased CRC risk. Gene-environment interaction analysis confirmed the epigenetic modification of aforementioned CpG sites with CRC risk and survival. Our study suggests the association between air pollution and CRC incidence and survival, underscoring the possible modifying roles of epigenomic factors. Methylation may partly mediate pathogenic effects of air pollution on CRC, with annotation to epigenetic alterations in protein-coding genes TMBIM1/PNKD, CXCR5 and TMEM110. Xue Li is supported by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001), the National Nature Science Foundation of China (No. 82204019) and Healthy Zhejiang One Million People Cohort (K-20230085). ET is supported by a Cancer Research UK Career Development Fellowship (C31250/A22804). MGD is supported by the MRC Human Genetics Unit Centre Grant (U127527198).

Mendelian randomisation and mediation analysis of self-reported walking pace and coronary artery disease.

The aim of this study was to assess the causal relationship between habitual walking pace and cardiovascular disease risk using a Mendelian randomisation approach. We performed both one- and two-sample Mendelian randomisation analyses in a sample of 340,000 European ancestry participants from UK Biobank, applying a range of sensitivity analyses to assess pleiotropy and reverse causality. We used a latent variable framework throughout to model walking pace as a continuous exposure, despite being measured in discrete categories, which provided more robust and interpretable causal effect estimates. Using one-sample Mendelian randomisation, we estimated that a 1mph (i.e., 1.6kph) increase in self-reported habitual walking pace corresponds to a 63% (hazard ratio (HR) = 0.37, 95% confidence interval (CI), 0.25-0.55, P = 2.0 × 10-6) reduction in coronary artery disease risk. Using conditional analyses, we also estimated that the proportion of the total effect on coronary artery disease mediated through BMI was 45% (95% CI 16-70%). We further validated findings from UK Biobank using two-sample Mendelian randomisation with outcome data from the CARDIoGRAMplusC4D consortium. Our findings suggest that interventions that seek to encourage individuals to walk more briskly should lead to protective effects on cardiovascular disease risk.

Circulating metabolite abundances associated with risks of bipolar disorder, schizophrenia, and depression: a Mendelian randomization study

BackgroundPreventive measures and treatments for psychiatric disorders are limited. Circulating metabolites are potential candidates for biomarker and therapeutic target identification, given their measurability and essential roles in biological processes. MethodsLeveraging large-scale genome-wide association studies, we conducted Mendelian randomization (MR) analyses to assess the associations between circulating metabolite abundances and the risks of bipolar disorder, schizophrenia, and depression. Genetic instruments were selected for 94 metabolites measured in the Canadian Longitudinal Study of Aging (N=8,299) cohort. We repeated MR analyses based on the UK Biobank, INTERVAL, and EPIC-Norfolk studies. ResultsAfter validating MR assumptions and colocalization evidence, we found that a one standard deviation (SD) increase in genetically predicted circulating abundances of eicosapentaenoate (EPA) and docosapentaenoate (n3 DPA) was associated with odds ratios (ORs) of 0.72 (95% CI: 0.65-0.79) and 0.63 (95% CI: 0.55-0.72) for bipolar disorder, respectively. Genetically increased Ω-3 unsaturated fatty acids abundance and Ω-3-to-total fatty acids ratio, as well as genetically decreased Ω-6-to-Ω-3 ratio were negatively associated with the risk of bipolar disorder in the UK Biobank. Genetically increased circulating abundances of three N-acetyl-amino acids were associated with an increased risk of schizophrenia with a maximum OR of 1.31 (95% CI: 1.18-1.44) per one SD increase. Furthermore, a one SD increase in genetically predicted circulating abundance of hypotaurine was associated with an OR of 0.85 (95% CI: 0.78-0.93) for depression. ConclusionsThe biological mechanisms underlying Ω-3 unsaturated fatty acids, NAT8-catalyzed N-acetyl-amino acids, and hypotaurine warrant exploration to identify new biomarkers and potential therapeutic targets.

Association between lung function and risk of microvascular diseases in patients with diabetes: A prospective cohort and mendelian randomization study

Background and aimsTo investigate causal relationships of lung function with risks microvascular diseases among participants with diabetes, type 2 diabetes mellitus (T2DM) and type 1 diabetes mellitus (T1DM), respectively, in prospective and Mendelian randomization (MR) study. Methods and results14,617 participants with diabetes and without microvascular diseases at baseline from the UK Biobank were included in the prospective analysis. Of these, 13,421 had T2DM and 1196 had T1DM. The linear MR analyses were conducted in the UK Biobank with 6838 cases of microvascular diseases and 10,755 controls. Lung function measurements included forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1). The study outcome was microvascular diseases, a composite outcome including chronic kidney diseases, retinopathy and peripheral neuropathy. During a median follow-up of 12.1 years, 2668 new-onset microvascular diseases were recorded. FVC (%predicted) was inversely associated with the risk of new-onset microvascular diseases in participants with diabetes (Per SD increment, adjusted HR = 0.86; 95%CI:0.83–0.89), T2DM (Per SD increment, adjusted HR = 0.86; 95%CI:0.82–0.90) and T1DM (Per SD increment, adjusted HR = 0.87; 95%CI: 0.79–0.97), respectively. Similar results were found for FEV1 (%predicted). In MR analyses, genetically predicted FVC (adjusted RR = 0.55, 95%CI:0.39–0.77) and FEV1 (adjusted RR = 0.48, 95%CI:0.28–0.83) were both inversely associated with microvascular diseases in participants with T1DM. No significant association was found in those with T2DM. Similar findings were found for each component of microvascular diseases. ConclusionThere was a causal inverse association between lung function and risks of microvascular diseases in participants with T1DM, but not in those with T2DM.

Ribosomal DNA copy number variation associates with hematological profiles and renal function in the UK Biobank

Ribosomal DNA copy number variation associates with hematological profiles and renal function in the UK Biobank

Association of COVID-19 vaccination with risks of hospitalization due to cardiovascular and other diseases: a study using data from the UK Biobank

ObjectivesTo explore whether COVID-19 vaccination protects against hospital admission by preventing infections and severe disease. MethodsWe leveraged the UK-Biobank(UKBB) and studied associations of COVID-19 vaccination (BioNTech-BNT162b2 or Oxford-AstraZeneca-ChAdOx1) with hospitalizations from cardiovascular and other selected diseases(N=393,544; median follow-up=54 days among vaccinated). Multivariable Cox, Poisson regression, propensity score matching(PSM) and inverse probability treatment weighting(IPTW) analyses were performed. We also performed adjustment using prescription-time distribution matching(PTDM) and prior-event rate ratio(PERR). ResultsWe observed that COVID-19 vaccination(at least one dose), when compared to no vaccination, was associated with reduced short-term risks of hospitalizations from stroke(hazard ratio[HR]=0.178, 95%CI:0.127-0.250,P=1.50e-23), venous thromboembolism(VTE) (HR=0.426,CI:0.270-0.673,P=2.51e-4), dementia (HR=0.114,CI:0.060-0.216;P=2.24e-11), non-COVID-19 pneumonia(NCP) (HR=0.108,CI:0.080-0.145;P=2.20e-49), coronary artery disease(CAD) (HR=0.563,CI:0.416-0.762;P=2.05e-4), chronic obstructive pulmonary disease(COPD) (HR=0.212,CI:0.126-0.357;P=4.92e-9), type-2 diabetes(T2DM) (HR=0.216,CI:0.096-0.486,P=2.12e-4), heart failure (HR=0.174,CI:0.118-0.256,P=1.34e-18) and renal failure (HR=0.415,CI:0.255- 0.677,P=4.19e-4), based on standard Cox regression models. Among the above results, reduced hospitalizations for stroke, heart failure, NCP and dementia were consistently observed across regression, PSM/IPTW, PTDM, and PERR. The results for 2-dose vaccination were similar. ConclusionsTaken together, this study provides further support to the safety and benefits of COVID-19 vaccination, and such benefits may extend beyond reduction of infection risk or severity per se. However, causal relationship cannot be concluded and further studies are required.

425. Integrative Analysis of Neuroimaging Phenotypes and Genetic Associations in the UK Biobank

425. Integrative Analysis of Neuroimaging Phenotypes and Genetic Associations in the UK Biobank

Impact of healthy lifestyle on the incidence and progression trajectory of mental disorders: A prospective study in the UK Biobank

BackgroundHealthier lifestyle decreased the risk of mental disorders (MDs) such as depression and anxiety. However, research on the effects of a comprehensive healthy lifestyle on their progression is lacking. Methods385,704 individuals without baseline MDs from the UK Biobank cohort were included. A composite healthy lifestyle score was computed by assessing alcohol intake, smoking status, television viewing time, physical activity, sleep duration, fruit and vegetable intake, oily fish intake, red meat intake, and processed meat intake. Follow-up utilized hospital and death register records. Multistate model was used to examine the role of healthy lifestyle on the progression of specific MDs, while a piecewise Cox regression model was utilized to assess the influence of healthy lifestyle across various phases of disease progression. ResultsHigher lifestyle score reduced risks of transitions from baseline to anxiety and depression, as well as from anxiety and depression to comorbidity, with corresponding hazard ratios (HR) and 95 % confidence intervals (CI) of 0.94 (0.93, 0.95), 0.90 (0.89, 0.91), 0.94 (0.91, 0.98), and 0.95 (0.92, 0.98), respectively. Healthier lifestyle decreased the risk of transitioning from anxiety to comorbidity within 2 years post-diagnosis, with HR 0.93 (0.88, 0.98). Higher lifestyle scores at 2–4 years and 4–6 years post-depression onset were associated with reduced risk of comorbidity, with HR 0.93 (0.87, 0.99) and 0.92 (0.86, 0.99), respectively. LimitationThe generalizability to other ethnic groups is limited. ConclusionThis study observed a protective role of holistic healthy lifestyle in the trajectory of MDs and contributed to identifying critical progression windows.

Neuroticism polygenic risk predicts conversion from mild cognitive impairment to Alzheimer's disease by impairing inferior parietal surface area.

The high prevalence of conversion from amnestic mild cognitive impairment (aMCI) to Alzheimer's disease (AD) makes early prevention of AD extremely critical. Neuroticism, a heritable personality trait associated with mental health, has been considered a risk factor for conversion from aMCI to AD. However, whether the neuroticism genetic risk could predict the conversion of aMCI and its underlying neural mechanisms is unclear. Neuroticism polygenic risk score (N-PRS) was calculated in 278 aMCI patients with qualified genomic and neuroimaging data from ADNI. After 1-year follow-up, N-PRS in patients of aMCI-converted group was significantly greater than those in aMCI-stable group. Logistic and Cox survival regression revealed that N-PRS could significantly predict the early-stage conversion risk from aMCI to AD. These results were well replicated in an internal dataset and an independent external dataset of 933 aMCI patients from the UK Biobank. One sample Mendelian randomization analyses confirmed a potentially causal association from higher N-PRS to lower inferior parietal surface area to higher conversion risk of aMCI patients. These analyses indicated that neuroticism genetic risk may increase the conversion risk from aMCI to AD by impairing the inferior parietal structure.

401. Gene-Environment Interaction Study on the Correlates for Psychotic Experiences in the UK Biobank

401. Gene-Environment Interaction Study on the Correlates for Psychotic Experiences in the UK Biobank

Shared genetic architecture highlights the bidirectional association between major depressive disorder and fracture risk

BackgroundThere is limited evidence suggesting that osteoporosis might exacerbate depressive symptoms, while more studies demonstrate that depression negatively affects bone density and increases fracture risk.AimsTo explore the relationship between major...

Distinguishing vulnerability and resilience to posttraumatic stress disorder evaluating traumatic experiences, genetic risk and electronic health records

What distinguishes vulnerability and resilience to posttraumatic stress disorder (PTSD) remains unclear. Levering traumatic experiences reporting, genetic data, and electronic health records (EHR), we investigated and predicted the clinical comorbidities (co-phenome) of PTSD vulnerability and resilience in the UK Biobank (UKB) and All of Us Research Program (AoU), respectively. In 60,354 trauma-exposed UKB participants, we defined PTSD vulnerability and resilience considering PTSD symptoms, trauma burden, and polygenic risk scores. EHR-based phenome-wide association studies (PheWAS) were conducted to dissect the co-phenomes of PTSD vulnerability and resilience. Significant diagnostic endpoints were applied as weights, yielding a phenotypic risk score (PheRS) to conduct PheWAS of PTSD vulnerability and resilience PheRS in up to 95,761 AoU participants. EHR-based PheWAS revealed three significant phenotypes positively associated with PTSD vulnerability (top association "Sleep disorders") and five outcomes inversely associated with PTSD resilience (top association "Irritable Bowel Syndrome"). In the AoU cohort, PheRS analysis showed a partial inverse relationship between vulnerability and resilience with distinct comorbid associations. While PheRSvulnerability associations were linked to multiple phenotypes, PheRSresilience showed inverse relationships with eye conditions. Our study unveils phenotypic differences in PTSD vulnerability and resilience, highlighting that these concepts are not simply the absence and presence of PTSD.

254. Empowering Genomic Discovery for Major Depression: A Workflow for GWAS Across the Ancestry Spectrum in the UK Biobank

254. Empowering Genomic Discovery for Major Depression: A Workflow for GWAS Across the Ancestry Spectrum in the UK Biobank

Rheumatoid Arthritis and Risk of Parkinson’s disease in the UK Biobank: A Prospective Study

Rheumatoid Arthritis and Risk of Parkinson’s disease in the UK Biobank: A Prospective Study

Lifetime effects and cost-effectiveness of standard and higher-intensity statin therapy across population categories in the UK: a microsimulation modelling study

Cardiovascular disease incidence and mortality have declined across developed economies and granular up-to-date cost-effectiveness evidence is required for treatments targeting large populations. To assess the health benefits and cost-effectiveness of standard and higher intensity statin therapy in the contemporary UK population 40-70 years old. A cardiovascular disease microsimulation model, developed using the Cholesterol Treatment Trialists' Collaboration data (117,896 participants; 5 years follow-up), and calibrated in the UK Biobank cohort (501,854 participants; 9 years follow-up), projected risks of myocardial infarction, stroke, coronary revascularization, diabetes, cancer and vascular and nonvascular death for all UK Biobank participants without and with statin treatment. Meta-analyses of trials and cohort studies informed statins' relative effects on cardiovascular events, incident diabetes, myopathy and rhabdomyolysis. UK healthcare perspective was taken (2020/2021 UK£) with costs per 28 tablets of £1.10 for standard (35%-45% LDL cholesterol (LDL-C) reduction) and £1.68 for higher intensity (≥45% LDL-C reduction) generic statin. Across categories by sex, age, LDL-C, and cardiovascular disease history/10-year cardiovascular risk, lifetime standard statin increased survival by 0.28-1.85 years (0.20-1.09 quality-adjusted life years (QALYs)), and higher intensity statin by further 0.06-0.40 years (0.03-0.20 QALYs) per person. Standard statin was cost-effective across all categories with incremental cost per QALY from £280 to £8530, with higher intensity statin cost-effective at higher cardiovascular risks and higher LDL-C levels. Stopping statin early reduced benefits and was not cost-effective. Lifetime low-cost statin therapy is cost-effective across all 40-70 years old in UK. Strengthening and widening statin treatment could cost-effectively improve population health. UK NIHR Health Technology Assessment Programme (17/140/02).