UK Biobank Study Research Articles

Elevated risk for stroke in genetically predisposed bicuspid aortic valve disease: evidences from a mendelian randomization study

Abstract Background Patients with bicuspid aortic valve (BAV) have been recognized to have an elevated risk for stroke. However, the exact causal association between BAV and stroke remains elusive due to stroke-related comorbidities, residual confounding bias and sample size limitations of observational studies. Purpose To identify the causal relationship between genetically predisposed BAV and 15 cardiovascular diseases (CVDs), and whether calcific aortic valve stenosis (CAVS) or atrial fibrillation (AF) could serve as the mediator on the pathway from BAV to stroke by mendelian randomization (MR) approach. Methods Uncorrelated (r² < 0.001) and genome-wide significant (P < 5×10^-8) single nucleotide polymorphisms were extracted from the largest genome-wide association study statistics (2,236 patients and 11,604 controls) of BAV by Gehlen et al. Summary-level statistics for 15 CVDs were obtained from the UK Biobank study, FinnGen study, HERMES consortium, CARDIoGRAMplusC4D consortium and GIGASTROKE consortium. We used 2-sample MR to estimate the causal association between BAV and 15 CVDs, evaluated 12 potential mediators and mediated proportions within 2-step MR framework. Inverse variance weighted was utilized as primary MR analyses method. Results for each outcome from different sources were pooled using the random effect meta-analysis. False discovery rate (FDR) was calculated by Benjamini-Hochberg method to account for multiple comparisons. Results Genetically predicted per log-odds liability increase of BAV was significantly associated with aortic aneurysm (OR, 1.26; 95% CI, 1.13-1.40; FDR-adjusted P = 3.54 × 10^-4), any stroke (OR, 1.06; 95% CI, 1.02-1.09; FDR-adjusted P = 0.004), ischemic stroke (IS) (OR, 1.17; 95% CI, 1.03-1.11; FDR-adjusted P = 0.001) and cardioembolic stroke (CES) (OR, 1.15; 95% CI, 1.06-1.25; FDR-adjusted P = 0.004). No significant association were observed between BAV and another 11 CVD outcomes. Instead of CAVS, genetic liability to AF mediated the total effect of BAV on any stroke (proportion mediated = 13.2% [95% CI, 3.1% - 23.2%]), IS (proportion mediated = 10.8% [95% CI, 2.5% - 19.1%]) and CES (proportion mediated = 21.5% [95% CI, 5.3% - 37.7%]). Conclusions Genetically predisposed BAV is associated with a higher risk of any stroke, IS and CES, which could be mediated by AF. This study implies the pathophysiological processes from BAV towards stroke and highlights the clinical significance of AF intervention in reducing the incidence of stroke for BAV patients.Causal association between BAV and CVDs

The genetic architecture of exercise-induced ventricular ectopy

Abstract Background Previously, we have shown that the frequency of exercise-induced premature ventricular contractions (PVCs) during and after exercise are associated with increased risk of major adverse cardiovascular events in asymptomatic individuals from the UK Biobank study1. The underlying mechanisms are, however, unclear. Several electrocardiographic markers associated with arrhythmogenesis have a known hereditary component, but the genetic underpinnings of exercise-induced ventricular ectopy have not been investigated. Purpose Our aim was to explore the genetic basis of premature ventricular ectopy during and after exercise and unveil plausible candidate genes and biological mechanisms. Methods We conducted a genome-wide association study (GWAS) for PVC frequency during exercise and recovery in >44,000 asymptomatic individuals of European ancestry without known cardiovascular disease from the UK Biobank study. As the distribution of PVC frequency is highly skewed (e.g. absence of negative values and excess of zero values), we first applied Gaussian transformation. Simulation studies were performed to justify that this approach would lead to valid inference. In the GWAS model, we included sex, age, UK Biobank genotyping array, and the first 10 genetic principal components as covariates. Statistical power was boosted by joint analysis of exercise and recovery PVC traits using multi-trait analysis of GWAS (MTAG)2. Genetic risk scores were constructed in independent samples from UK Biobank (N=341,948) and were tested for association with heart failure and life-threatening ventricular arrhythmias. Results We identified 4 loci for PVC frequency during exercise, and 1 locus for PVC frequency during recovery (Picture 1). Candidate genes included CRIM1, FLNC, and BAG3 for which mutations have been linked in the pathogenesis of (arrhythmogenic) cardiomyopathy. Subjects in the top 10% of the genetic risk scores had a significantly higher risk of heart failure and life-threatening ventricular arrhythmias compared to the bottom 90%, (odds ratio (OR) (95% confidence interval): 1.14 (1.08 – 1.20), p < 0.001; and 1.13 (1.02 – 1.24), p < 0.001, respectively). Conclusions Ventricular ectopic burdens during exercise and recovery have a significant heritable component. Candidate genes highlight a possible shared genetic background with inherited cardiomyopathy and a genetic risk score was associated with heart failure and ventricular arrhythmias. These findings substantial advance our understanding of the genetic basis of exercise-induced ventricular ectopy in a population-based cohort without cardiovascular disease.Miami plot of ventricular ectopic burden

Circulating metabolites associate with the QT interval in individuals without prevalent cardiovascular disease

Abstract Background Patients with metabolic syndrome have a higher prevalence of heart-rate corrected QT (QTc) interval prolongation. Despite this the effect of circulating metabolites on the QTc is largely unknown and limited to small studies. Purpose To test for association of circulating metabolites with the QTc interval in the UK Biobank study. Methods Participants were identified from the UK Biobank with same day plasma metabolite profiling and electrocardiograms. All 249 metabolites measured underwent quality control and log transformation to account for rightward skew and zero values. 149 metabolites with inter-correlations >0.7 were excluded. Participants taking QTc-prolonging medication or with a history of ischaemic heart disease or heart failure up to 6 months after the visit, were excluded. Participants were allocated to a training group (N=21,610) or an independent test group (N=5,304), if samples were obtained at recruitment or at a second visit, respectively. In the training group, each metabolite was tested separately for association with the QTc in linear regression analyses, adjusted for clinical covariates (age, sex, fasting time, body mass index (BMI), systolic blood pressure (SBP), smoking status, diabetes, lipid-lowering drug use and dietary factors). Significant metabolites (P<5x10-4) underwent validation in the test group. Sex-stratified analyses were also performed. In the training group, variables in two models underwent regularisation by LASSO regression (10-fold cross-validation) to reduce multicollinearity and downweigh less important variables; 1) clinical variables, 2) clinical variables and validated metabolites. Coefficients were used for QTc prediction in the test group. Significance between the models was evaluated by fisher’s transformation of R-squared statistics. Results In the per metabolite multivariate analysis, 56 metabolites were associated with the QTc interval. 19 metabolites validated in the test group. For 14 of these, absolute effect sizes were >5ms when comparing individuals in the top decile of the metabolite distribution verses the bottom (Figure 1), including the ketone body 3-hydroxybutyrate (9ms), and omega-6 fatty acid to total fatty acid ratio (7.2ms). For associations in males and females separately, significant effect size differences (P<0.05) were observed for 9 metabolites (Figure 2). In the training group, the combined LASSO model selected 17 (of 19) metabolites along with age, sex, SBP and BMI. In the test group, this model R-squared was 0.115 compared with 0.081 for clinical covariates alone, representing a significant 41.9% increase in QTc variation explained (P=0.002). Conclusions This study demonstrates clinically relevant metabolite associations with the QTc in individuals without cardiovascular disease and explain a significant proportion of QTc variation. Further investigation is warranted to test for direct effects on cardiac electrophysiology and proarrhythmic potential.Validated metabolitesSignificant sex differences

Can variants of genes associated with familial heart block predict conduction disease in the general population? A UK Biobank study.

Abstract Background Progressive familial heart block is a genetic disease that can present with worsening cardiac conduction disease (CCD) and risk of life-threatening bradycardia. The prevalence, penetrance, and expressivity of known rare pathogenic/likely pathogenic variants (P/LP) in the general population is unclear. In addition, the role of common genetic variation in this phenotypic expression is unknown. Understanding this is essential for patient management in clinic. Purpose 1). To investigate the prevalence of variants linked with early-onset CCD and phenotypic expression in a large biobank. 2). To investigate whether a PR interval polygenic risk score (PRS) improves risk prediction. Methods Early-onset conduction disease P/LP or variants of uncertain significance (VUS) were identified from ClinVar, genetic testing reports at a teaching hospital (6 variants), and the literature, mapping to 22 genes. From the full UK Biobank prospective cohort, 469,511 participants passed genetic quality control and were assigned to P/LP, VUS, or genotype negative (G-) groups, using whole exome sequencing analysed with bcftools. A PR-PRS was constructed using weights from a published meta-analysis excluding UKB data. The primary outcome was CCD (atrioventricular (AV) block, bundle branch block, pacemaker or ICD implantation) and secondary outcomes were high-grade AV block or pacemaker insertion, compared with lifetime risk Cox proportional hazards controlled for sex and age as a timescale. Results 55% of participants were female, 95% had European ancestry, and average age at censor was 71 years. There were 25 P/LP carriers, and 8,862 with a VUS, in 6 genes (MYH7, SCN5A, TNNI3K, TRPM4, TTN, and LMNA). Major demographic factors were the same between groups. CCD was significantly more prevalent in P/LP individuals (28% vs 5.8% in VUS vs 5.5% in G-; p<0.001) with a hazard ratio of HR 6.47 [95% CI=3.09-13.6] vs G-. This was driven by AV block and pacemaker implantation (HR 23.2 [95% CI=8.69-61.8] and 13.4 [95% CI=6.01-29.8], respectively). Results were similar in an unrelated subset and controlling for ischaemic heart disease and heart failure. The 7 P/LP individuals with conduction disease were mostly linked to a single LMNA variant (4 out of 6 carriers with penetrant disease). In the full cohort, the PR-PRS was predictive of CCD (HR=1.07 [95% CI=1.06-1.08]), AV block (HR=1.09 [95% CI=1.06-1.13]), and pacemaker implantation (HR=1.04 [95% CI=1.02-1.06]). When combined with P/LP status, both PR-PRS (HR=1.07 [95% CI=1.06-1.08]) and P/LP (HR=6.42 [95% CI=3.06-13.5]) were independent predictors of CCD. Conclusion(s) Rare variant carrier status predicts a 6.5-fold increased lifetime risk of CCD, a 23-fold increased risk of AV block and 13-fold risk for pacemaker requirement. However, phenotypic expression for some variants is highly variable. A PR-PRS captures risk independent of P/LP variants and warrants further investigation with updated PRS construction methods.

Association of a healthy plant-based heart-protective diet with reduced cardiovascular disease incidence and mortality: findings from the UK Biobank Study

Abstract Importance Previous research examining the effects of omnivorous and plant-based diets on CVD outcomes has produced inconsistent findings, and the importance of diet quality is overlooked. Objective To assess the relation between adherence to a healthy plant-based, heart-protective diet and the risk of cardiovascular disease (CVD) events. Design: Prospective cohort study. Methods and Results 192,274 (mean age: 56.3±7.9 years, 43.3% males) participants in UK Biobank without CVD at baseline who completed a 24-hour recall questionnaire. Using data generated by Oxford WebQ, we developed a novel heart-protective diet score (HPDS) based on 22 food groups. Cox proportional hazard models were used to study associations. During a median follow-up of 12.3 years, there were 20,692 CVD events and 1,131 CVD deaths. After adjusting for demographics, Townsend deprivation index, lifestyle factors, and history of chronic diseases, participants in the top quartile of the HPDS were at the lower risk of overall CVD (HR: 0.92, 95% CI: 0.88 to 0.95), ischemic heart disease (HR: 0.88 [95% CI: 0.83 to 0.93]), myocardial infarction (HR: 0.82, 95% CI: 0.74 to 0.90), and heart failure (HR: 0.86, 95% CI: 0.78 to 0.95) than those in the bottom quartile. Participants who adhered closely to a healthy plant-based heart-protective diet had the lowest risk of overall CVD (HR: 0.72, 95% CI: 0.61 to 0.86), ischemic heart disease (HR: 0.68, 95% CI: 0.52 to 0.89), myocardial infarction (HR: 0.65, 95% CI: 0.46 to 0.91), and heart failure (HR: 0.51, 95% CI: 0.30 to 0.85) mortality. Conclusions and relevance: Adherence to a healthy plant-based heart-protective diet rich in non-starchy vegetables, fruits, whole grains, legumes, and fish, is associated with a reduced cardiovascular disease incidence and mortality. Further research in diverse ethnic populations is necessary to validate our findings and enhance their generalizability.

Genetic and lifestyle risks for coronary artery disease and risk of incident dementia

Abstract Background Lifestyle risk factors for coronary artery disease (CAD) have been associated with neurodegeneration and dementia. Whether an underlying genetic risk for the development of CAD further increases this risk, however, remains unclear. Purpose To examine whether an increased genetic risk for CAD is associated with an increased risk of dementia, and to investigate whether lifestyle factors modify these associations. Methods A prospective cohort study of 457,353 participants of European ancestry without dementia at baseline (mean [SD], age 57 [8] years; 55% were female) was conducted within the UK Biobank study. Exposures were a genome-wide polygenic risk score (PRS) for CAD and a modified version of the American Heart Association’s Life’s Essential 8 (LE8) cardiovascular health score comprising four biological (BMI, BP, lipids, glucose) and four lifestyle (smoking status, diet, physical activity, and sleep duration) risk factors previously linked to both CAD and dementia. Dementia diagnoses were obtained from death register and inpatient records. Results 9,337 cases of all-cause dementia were observed over a median 13.9-year follow-up. There were no significant interactions between genetic risk for CAD and lifestyle factors for all-cause dementia, or any other dementia subtype. After adjusting for potential demographic confounders, a higher genetic risk for CAD was associated with elevated risk of developing all-cause dementia (hazard ratio (HR) per 1-SD increase in PRS = 1.08 [95% CI, 1.05-1.10]), Alzheimer’s disease (HR 1.08 [1.03-1.12]), and vascular dementia (HR 1.13 [1.06-1.19]). An unfavourable LE8 cardiovascular health score was also associated with an increased risk of developing all-cause dementia (HR 1.05 [1.02-1.08]), predominantly through its association with vascular dementia (HR 1.14 [1.06-1.22]), as we found no evidence for any associations between LE8 and Alzheimer’s disease (HR 1.00 [0.97-1.02]). Conclusion These findings indicate that a high genetic risk for CAD is associated with an increased risk of developing major dementia subtypes. Regardless of this underlying genetic risk, however, our results suggest that lifestyle interventions designed to reduce the risk of CAD may also reduce one’s risk of developing dementia, particularly in those with underlying vascular pathology.

Association of serum testosterone levels with left atrial size, function, and risk of atrial fibrillation in adult men: observational and mendelian randomization analyses

Abstract Background Numerous studies have investigated the association between serum testosterone levels, testosterone replacement therapy (TRT), and cardiovascular risk. However, research examining the relationship between testosterone levels and atrial fibrillation (AF) risk remains limited. We comprehensively analyzed the association between total testosterone (TT) levels, intermediary phenotypes such as left atrium (LA) size and function, and the risk of AF in middle-aged and older men. Methods We utilized data from the UK Biobank, a population-based prospective cohort, focusing on 179,988 White men who had complete serum TT level data and no AF history. Observational associations between TT levels and LA imaging traits, as well as AF risk, were estimated using multivariable regression and time-dependent Cox regression models, treating TT levels as a time-varying variable. Genetic associations were examined by Mendelian randomization (MR), using both UK Biobank and external large consortia genome-wide association study data. Results During the median follow-up of 11.8 years (IQR 10.9–12.5), we observed 13,847 incident AF cases (7.7%). Participants with normal TT levels (≥ 300 ng/dL) showed a 15% reduced risk of AF (HR of 0.85 [95% CI, 0.82–0.89]) compared to those with low TT (< 300 ng/dL). Interestingly, participants undergoing TRT experienced a 51% higher risk of AF (1.51 [1.09–2.07]). Furthermore, each 1-standard deviation increase in TT levels was associated with a reduced AF risk (OR of 0.91 [0.89–0.93]) and an improved LA emptying fraction (1.29 [1.06–1.58]). Applying age-specific cutoff values for low TT levels highlighted a more pronounced AF risk reduction in participants with normal TT. MR analyses supported these observations, suggesting potential causal relationships between TT levels and both LA function and AF risk. Conclusions Our findings suggest that low TT levels are associated with reduced LA function and increased risk of AF, both observationally and genetically, indicating that serum TT could serve as a surrogate marker or even a potential causal mediator in the development of AF.Abstract tableAbstract figure

Mapping renal impairment and cardiac structure and function: observation and genetic insights from 30,000 cardiac magnetic resonance images

Abstract Background The elevated risk of heart failure in kidney dysfunction is well-identified. However, the early alteration of renal impairment on cardiac structure and function, as well as genetic susceptibility associations have not been well reported. We sought to map the early effects of kidney dysfunction on cardiac remodeling with the cardiac magnetic resonance images (MRI) and identify share genetic correlation in community population. Methods Of 29,592 subjects underwent MRI test were recruited from the population-based UK Biobank study from 2006-2010. Renal function was assessed by historical identified chronic kidney disease (CKD), log-transfrom estimated glomerular filtration rate (eGFR) based on cystatin C (eGFRCysC) or serum creatine (eGFRSCr) and urine albumin-to-creatinine ratio (uACR). Multivariable generalized linear regression was used to analyse the association of 4 different kidney function indexes with six cardiac MRI-derived traits: left atria and ventricle, right atria and ventricle, and ascending and descending aortas. Genetic correlation between renal function decline and cardiac traits were evaluated by Mendelian randomization (MR). Results The mean (SD) age of subjects was 54.9 (7.5) years, and 51.1% were women. Observational and MR analysis showed a reliable relationship of lower level of eGFRCysC with reduced biventricular end systolic volume, biventricular ventricular end diastolic volume and left ventricular mass, and lower level of eGFRSCr with reduced left ventricular cardiac output. Conclusions Our study indicates the observational and genetic correlation between kidney function decline and cardiac measurements. These findings provide insights into the potential mechanisms behind their comorbidity and the future development of therapeutics.Renal function decline & Cardiac Imaging

Associations of body composition measures with circulating insulin-like growth factor-I, testosterone, and sex hormone-binding globulin concentrations in 16,000 men.

Adiposity is positively associated with risk of some cancer sites and other health conditions in men; however, it is unclear if endogenous hormones play a role in these associations. We examined how body composition, measured from magnetic resonance imaging (MRI) and common measures of adiposity (e.g., body mass index (BMI)), are related to hormone concentrations in men from the UK Biobank study. Up to 16,237 men with available body composition data (including visceral, subcutaneous, and liver fat, muscle fat infiltration (MFI), lean tissue, and common adiposity measures) and serum hormone measurements (insulin-like growth factor-I (IGF-I), total testosterone, sex hormone-binding globulin (SHBG), and calculated free testosterone) were included. Multivariable-adjusted linear regression models were used to determine the geometric mean hormone and SHBG concentrations across categories of each exposure. Common measurements of adiposity were highly correlated with MRI measures of central and total adiposity (r = 0.76-0.91), although correlations with ectopic fat (liver fat and MFI) were lower (r = 0.43-0.54). Most adiposity measurements showed an inverse U- or J-shaped association with circulating IGF-I and free testosterone; however, MFI was linearly inversely associated, and lean tissue volume was positively associated with both IGF-I and free testosterone concentrations. All body composition measures were inversely associated with total testosterone and SHBG concentrations (relative geometric mean difference between Q5 vs. Q1: 20-30%). Our results show that common adiposity and most MRI measures of adiposity relate similarly to serum hormone concentrations; however, associations with ectopic fat (particularly MFI) and lean tissue were different.

Prospective associations of genetic susceptibility to high blood pressure and muscle strength with incident cardiovascular disease outcomes.

This study explored the prospective associations of genetic susceptibility to high blood pressure (BP) and muscle strength with cardiovascular disease (CVD) mortality, incident coronary heart disease (CHD) and incident stroke. This study included 349 085 white British individuals from the UK Biobank study. Genetic risk of high BP was estimated using a weighted polygenic risk score that incorporated 136 and 135 nonoverlapping single-nucleotide polymorphisms for systolic BP and diastolic BP, respectively. Muscle strength was assessed using a hand dynamometer and expressed relative to fat-free mass. Sex- and age-specific tertiles were used to classify muscle strength into three categories. Cox regressions with age as the underlying timescale were fit for CVD mortality (n = 8275), incident CHD (n = 14 503), and stroke (n = 7518). Compared with the lowest genetic risk of high BP (bottom 20%), the highest (top 20%) had greater hazards of each outcome. Low muscle strength was associated with higher hazards of CVD mortality [hazard ratio (HR): 1.51, 95% confidence interval (CI): 1.43-1.59], incident CHD (HR: 1.16, 95% CI: 1.11-1.21), and stroke (HR: 1.20, 95% CI: 1.14-1.27), independently of confounders and genetic predisposition to high BP, compared with high muscle strength. Joint analyses revealed that the estimated 10-year absolute risks of each outcome were lower for high muscle strength combined with high genetic risk, compared with low muscle strength combined with low or medium genetic risk. Individuals who are genetically predisposed to high BP but have high muscle strength could have lower risk of major CVD events, compared with those who have low or medium genetic risk but low muscle strength.

Sex influences whether hippocampal volumes mediate the relationship between depression and cognition in older adults without dementia: A UK Biobank study.

Depression is a modifiable risk factor for dementia; however, it remains unclear whether there are sex differences in how depression affects dementia risk. To better understand sex-specific differences in how depression confers risk of dementia, the link between depression, hippocampal volumes, and cognition was evaluated in a sample of older adults without dementia from the UK Biobank cohort. A total of 18,220 participants (women n = 9,474; men n = 8,746) were selected based on completion of the Patient Health Questionnaire (PHQ-9), structural MRI, and cognitive assessments. Causal mediation analyses were used to evaluate if the relationship between depression and cognition is mediated by the hippocampus differently by sex. Women reported greater depression severity than men. Hippocampal volumes were found to mediate the relationship between depression severity and fluid intelligence only in women. Upon categorization of the depression symptoms as either cognitive/affective or somatic, the mediation effect of the hippocampus was seen for both cognitive/affective and somatic symptom severity in women for fluid intelligence. These results offer insight into the sex-specific pathways underlying the relationship between depression, hippocampal volumes, and cognition in older adults without dementia with a focus on the type of depression symptoms. This knowledge could aid in the development of sex-focused dementia prevention strategies and treatments.

Uncovering mediational pathways behind racial and socioeconomic disparities in brain volumes: insights from the UK Biobank study.

Mediation pathways explaining racial/ethnic and socioeconomic (SES) disparities in structural MRI markers of brain health remain underexplored. We examined racial/ethnic and SES disparities in sMRI markers and tested total, direct, and indirect effects through lifestyle, health-related, and cognition factors using a structural equations modeling approach among 36,184 UK Biobank participants aged 40-70years at baseline assessment (47% men). Race (non-White vs. White) and lower SES-predicted poorer brain sMRI volumetric outcomes at follow-up, with racial/ethnic disparities in sMRI outcomes involving multiple pathways and SES playing a central role in those pathways. Mediational patterns differed across outcomes, with the SES-sMRI total effect being partially mediated for all outcomes. Over 20% of the total effect (TE) of race/ethnicity on WMH was explained by the indirect effect (IE), by a combination of different pathways going through SES, lifestyle, health-related, and cognition factors. This is in contrast to < 10% for total brain, gray matter (GM), white matter (WM), and frontal GM left/right. Another significant finding is that around 57% of the total effect for SES and the normalized white matter hyperintensity (WMH) was attributed to an indirect effect. This effect encompasses many pathways that involve lifestyle, health-related, and cognitive aspects. Aside from WMH, the percent of TE of SES mediated through various pathways ranged from ~ 5% for WM to > 15% up to 36% for most of the remaining sMRI outcomes, which are composed mainly of GM phenotypes. Race and SES were important determinants of brain volumetric outcomes, with partial mediation of racial/ethnic disparities through SES, lifestyle, health-related, and cognition factors.

Causal impacts of smoking on pain conditions and the mediating pathways: a mendelian randomization study.

Smoking is a risk factor for multiple diseases. We performed mendelian randomization (MR) analyses to investigate the causal association of smoking initiation on pain conditions and the potential mediating pathways. Genetic associated with smoking initiation at the genome-wide significance level were selected as instrumental variables. Genetic associations with 10 pain conditions were derived from the FinnGen and UK Biobank study. Multivariable MR analysis was conducted to explore the mediation effects of depression, insomnia and sedentary behavior. A series of sensitivity analyses were conducted to assess the stability of our research findings. Genetic liability to smoking initiation was associated with an increased risk of angina pectoris, dorsalgia, low back pain, pain in limb, pain in joint, pain in thoracic spine and sciatica in both FinnGen and UK Biobank study. These causal associations were largely mediated by major depression (2.9- 39.5%), sedentary behavior (13.0- 31.2%), insomnia (10.3- 33.1%) and combination of all three mediators (30.2- 65.3%). The effects of smoking on outcomes were partly attenuated after adjusting for depression, sedentary behavior and insomnia respectively, and the direct effect of smoking initiation on pain was diminished toward null after adjusting for combined three mediators. These results were robust to sensitivity analyses. Our findings illustrated the causal effect of smoking and a broad range of pain conditions, and major depression, sedentary behavior and insomnia mediate many of these associations.

The Relationship Between Physical Activity and Non-Modifiable Risk Factors on Alzheimer's Disease and Brain Health Markers: A UK Biobank Study.

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. The study aimed to assess the effect of physical activity, APOE genotype, and sex on AD risk, brain volume, and cognition. 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. 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 (β= - 65.43 [- 109.68, - 17.40], p = 0.007), and larger total brain volume (β= 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 (β= - 0.43 [- 0.68, - 0.18], p = 0.001); though poorer visuospatial ability (β= - 0.06 [- 0.09, - 0.03], p < 0.001), and executive function (β= 0.49 [0.31, 0.66], p < 0.001; β= 0.27 [0.10, 0.45], p = 0.002) was related to self-reported physical activity levels. 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.

6719 Sex Differences In Lipoproteins And Excess Risk Of Coronary Heart Disease In Women With Type 2 Diabetes

Abstract Disclosure: Y. Yoshida: None. D. Li: None. X. Li: None. V.A. Fonseca: None. L. Qi: None. F. Mauvais-Jarvis: None. Background: Women with type 2 diabetes (T2D) have a greater risk of coronary heart disease (CHD) than men with T2D. We compared levels of lipoproteins and their associations with CHD in women and men with new-onset T2D, pre-diabetes (PDM), and euglycemia. Method: We obtained circulating metabolomic data, including lipoprotein classes, apolipoproteins, total triglycerides (TG), and TG in very large LDL (VLDL), LDL, and HDL by nuclear magnetic resonance for 95,108 CHD-free people at baseline and incident CHD from the national health registers of the UK Biobank study. We used multivariable linear regressions to examine the association between sex and lipoprotein markers (log(x)) in groups of new-onset T2D (new T2D diagnosis or diabetes medication use within two years from the baseline), PDM (HbA1c 5.7-6.5%), and euglycemia, accounting for age, race, Townsend Deprivation Index, income, smoking, obesity, medications for hypertension, hyperlipidemia, and diabetes. We used Cox proportional hazard models to evaluate the association between lipoproteins and CHD risk in men and women separately, adjusting the same covariates. We performed sensitivity analyses using the assay-measured lipoproteins of the same participants and accounted for menopausal status. False discovery rate adjusted for multiple comparisons. Results: 1328 individuals with newly diagnosed T2D, 6204 with PDM, and 87,576 with euglycemia were included in the analysis. In adjusted linear regressions, atherogenic lipoproteins, including total cholesterol (c), non-HDL-c, remnant-c, and LDL-c were significantly higher in women than in men across glycemic status, and this sex difference was the most striking in the T2D group (β 0.5, 0.3, 0.15, and 0.23 in T2D vs. 0.44, 0.16, 0.09, and 0.12 in PDM vs. 0.37, 0.08, 0.04, and 0.08 in euglycemia). In euglycemic individuals, levels of Apo B and VLDL were higher in men than in women (β -0.01 and -0.05); however, in T2D individuals, women had higher levels of VLDL(β 0.05 and 0.05). Total TG and TG in VLDL were significantly higher in men with euglycemia (β -0.22 and -0.23) and PDM (β -0.15 and -0.16), but the sex differences were not significant in the T2D group (β -0.01 and -0.04). During the median 10-year follow-up, one SD increase in total TG (women HR 2.5, 95% 1.3-4.9 vs. men 1.07, 0.7-1.7 P-interaction=0.03), TG in VLDL (W 2.1, 1.2-3.7 vs. M 1.06 0.7-1.6 P=0.03), TG in LDL (W 3.2, 1.2-8.8 vs. M 1.3, 0.7-2.6, P=0.1), and TG in HDL (W 3.7, 1.4-9.5 vs. M 0.9, 0.5-1.7, P=0.008) was significantly associated with increased risk of CHD in women with T2D, but the associations were not significant in male patients. Results from available assay-measured markers and menopausal stratification were generally consistent with the main results. Conclusions: Women had higher levels of atherogenic lipids than men with advancing glycemic status. Women with T2D are at a higher risk of CHD associated with TG than men with T2D. Presentation: 6/3/2024

9240 Role Of Genetics In The Age-Related Testosterone Decline In Men: A UK Biobank Study

Abstract Disclosure: L. Ogoniak: None. S. Sandmann: None. J. Varghese: None. A.S. Busch: None. Background: Age-related decline in circulating serum testosterone concentrations is a well-established phenomenon in men. While the decline is partially linked to comorbidities such as obesity, type 2 diabetes (T2D), and cardiovascular disease (CVD), healthy ageing men present with rather stable levels. Recent genetic mapping studies demonstrated a large influence of common genetic variation on testosterone levels in men. However, increasing incidence rates of comorbidities in the ageing population are posing a challenge for the disentanglement of effects. Objective: Our study aims to investigate the genetic component of age-dependent testosterone decline in men. We hypothesize that the decline in testosterone levels in ageing men is primarily influenced by comorbidities, without significant alterations in the genetic architecture of testosterone levels. Material and Methods: We included 6,406 men with baseline and follow-up measurements of circulating serum concentrations of total testosterone (T), bioavailable testosterone (BAT) and sex hormone-binding globulin (SHBG) representing an independent sub-cohort of the UK Biobank study. We 1) assessed the association of baseline levels with the decline in sex steroids and 2) developed and verified polygenic risk score (PRS) models for T, BAT and SHBG based on 183,909 men from the UK Biobank (sub cohorts: 70% base, 15% target and 15% validation, follow-up cohort excluded for PRS development). Results: In the follow-up sub cohort, mean age (SD) at baseline was 58.2 yrs ( 7.5) and mean (SD) follow-up period was 4.3 (1.0) yrs. Mean (SD) BAT at baseline were 5.2 (1.32) nmol/L with a mean (SD) decline of 1.6 (24.4) % at follow-up. Baseline BAT, T and SHBG levels were significantly associated with the relative change of the respective biomarker at follow-up (-7.8, -2.9 and -0.4% per nmol/L, respectively, all p &amp;lt;0.001). After correcting for age at baseline, follow-up period and principal components 1-10, PGSTestosterone and PGSBAT were not associated with relative decline of the respective biomarker (both p = n.s.). Conclusion: Our study did not find evidence supporting a genetic component in the age-related decline of circulating serum T or BAT concentrations. Instead, in accordance to previous observational studies, our results suggest that rather non-genetic factors, e.g. increasing incidence rates of comorbidities, drive the age-related decline in sex steroid levels in men. Our study contributes to understanding the intricate relationship between genetic and non-genetic factors with age-related testosterone decline in men and offers valuable insights for potential interventions targeting age-related hormonal changes and associated health outcomes. Presentation: 6/2/2024

8039 Role Of Genetics In The Age-Related Testosterone Decline In Men: A UK Biobank Study

Abstract Disclosure: L. Ogoniak: None. S. Sandmann: None. J. Varghese: None. A.S. Busch: None. Background: Age-related decline in circulating serum testosterone concentrations is a well-established phenomenon in men. While the decline is partially linked to comorbidities such as obesity, type 2 diabetes (T2D), and cardiovascular disease (CVD), healthy ageing men present with rather stable levels. Recent genetic mapping studies demonstrated a large influence of common genetic variation on testosterone levels in men. However, increasing incidence rates of comorbidities in the ageing population are posing a challenge for the disentanglement of effects. Objective: Our study aims to investigate the genetic component of age-dependent testosterone decline in men. We hypothesize that the decline in testosterone levels in ageing men is primarily influenced by comorbidities, without significant alterations in the genetic architecture of testosterone levels. Material and Methods: We included 6,406 men with baseline and follow-up measurements of circulating serum concentrations of total testosterone (T), bioavailable testosterone (BAT) and sex hormone-binding globulin (SHBG) representing an independent sub-cohort of the UK Biobank study. We 1) assessed the association of baseline levels with the decline in sex steroids and 2) developed and verified polygenic risk score (PRS) models for T, BAT and SHBG based on 183,909 men from the UK Biobank (sub cohorts: 70% base, 15% target and 15% validation, follow-up cohort excluded for PRS development). Results: In the follow-up sub cohort, mean age (SD) at baseline was 58.2 yrs ( 7.5) and mean (SD) follow-up period was 4.3 (1.0) yrs. Mean (SD) BAT at baseline were 5.2 (1.32) nmol/L with a mean (SD) decline of 1.6 (24.4) % at follow-up. Baseline BAT, T and SHBG levels were significantly associated with the relative change of the respective biomarker at follow-up (-7.8, -2.9 and -0.4% per nmol/L, respectively, all p &amp;lt;0.001). After correcting for age at baseline, follow-up period and principal components 1-10, PGSTestosterone and PGSBAT were not associated with relative decline of the respective biomarker (both p = n.s.). Conclusion: Our study did not find evidence supporting a genetic component in the age-related decline of circulating serum T or BAT concentrations. Instead, in accordance to previous observational studies, our results suggest that rather non-genetic factors, e.g. increasing incidence rates of comorbidities, drive the age-related decline in sex steroid levels in men. Our study contributes to understanding the intricate relationship between genetic and non-genetic factors with age-related testosterone decline in men and offers valuable insights for potential interventions targeting age-related hormonal changes and associated health outcomes. Presentation: 6/2/2024

9240 Role Of Genetics In The Age-Related Testosterone Decline In Men: A UK Biobank Study

Abstract Disclosure: L. Ogoniak: None. S. Sandmann: None. J. Varghese: None. A.S. Busch: None. Background: Age-related decline in circulating serum testosterone concentrations is a well-established phenomenon in men. While the decline is partially linked to comorbidities such as obesity, type 2 diabetes (T2D), and cardiovascular disease (CVD), healthy ageing men present with rather stable levels. Recent genetic mapping studies demonstrated a large influence of common genetic variation on testosterone levels in men. However, increasing incidence rates of comorbidities in the ageing population are posing a challenge for the disentanglement of effects. Objective: Our study aims to investigate the genetic component of age-dependent testosterone decline in men. We hypothesize that the decline in testosterone levels in ageing men is primarily influenced by comorbidities, without significant alterations in the genetic architecture of testosterone levels. Material and Methods: We included 6,406 men with baseline and follow-up measurements of circulating serum concentrations of total testosterone (T), bioavailable testosterone (BAT) and sex hormone-binding globulin (SHBG) representing an independent sub-cohort of the UK Biobank study. We 1) assessed the association of baseline levels with the decline in sex steroids and 2) developed and verified polygenic risk score (PRS) models for T, BAT and SHBG based on 183,909 men from the UK Biobank (sub cohorts: 70% base, 15% target and 15% validation, follow-up cohort excluded for PRS development). Results: In the follow-up sub cohort, mean age (SD) at baseline was 58.2 yrs ( 7.5) and mean (SD) follow-up period was 4.3 (1.0) yrs. Mean (SD) BAT at baseline were 5.2 (1.32) nmol/L with a mean (SD) decline of 1.6 (24.4) % at follow-up. Baseline BAT, T and SHBG levels were significantly associated with the relative change of the respective biomarker at follow-up (-7.8, -2.9 and -0.4% per nmol/L, respectively, all p &amp;lt;0.001). After correcting for age at baseline, follow-up period and principal components 1-10, PGSTestosterone and PGSBAT were not associated with relative decline of the respective biomarker (both p = n.s.). Conclusion: Our study did not find evidence supporting a genetic component in the age-related decline of circulating serum T or BAT concentrations. Instead, in accordance to previous observational studies, our results suggest that rather non-genetic factors, e.g. increasing incidence rates of comorbidities, drive the age-related decline in sex steroid levels in men. Our study contributes to understanding the intricate relationship between genetic and non-genetic factors with age-related testosterone decline in men and offers valuable insights for potential interventions targeting age-related hormonal changes and associated health outcomes. Presentation: 6/2/2024

8039 Role Of Genetics In The Age-Related Testosterone Decline In Men: A UK Biobank Study

Abstract Disclosure: L. Ogoniak: None. S. Sandmann: None. J. Varghese: None. A.S. Busch: None. Background: Age-related decline in circulating serum testosterone concentrations is a well-established phenomenon in men. While the decline is partially linked to comorbidities such as obesity, type 2 diabetes (T2D), and cardiovascular disease (CVD), healthy ageing men present with rather stable levels. Recent genetic mapping studies demonstrated a large influence of common genetic variation on testosterone levels in men. However, increasing incidence rates of comorbidities in the ageing population are posing a challenge for the disentanglement of effects. Objective: Our study aims to investigate the genetic component of age-dependent testosterone decline in men. We hypothesize that the decline in testosterone levels in ageing men is primarily influenced by comorbidities, without significant alterations in the genetic architecture of testosterone levels. Material and Methods: We included 6,406 men with baseline and follow-up measurements of circulating serum concentrations of total testosterone (T), bioavailable testosterone (BAT) and sex hormone-binding globulin (SHBG) representing an independent sub-cohort of the UK Biobank study. We 1) assessed the association of baseline levels with the decline in sex steroids and 2) developed and verified polygenic risk score (PRS) models for T, BAT and SHBG based on 183,909 men from the UK Biobank (sub cohorts: 70% base, 15% target and 15% validation, follow-up cohort excluded for PRS development). Results: In the follow-up sub cohort, mean age (SD) at baseline was 58.2 yrs ( 7.5) and mean (SD) follow-up period was 4.3 (1.0) yrs. Mean (SD) BAT at baseline were 5.2 (1.32) nmol/L with a mean (SD) decline of 1.6 (24.4) % at follow-up. Baseline BAT, T and SHBG levels were significantly associated with the relative change of the respective biomarker at follow-up (-7.8, -2.9 and -0.4% per nmol/L, respectively, all p &amp;lt;0.001). After correcting for age at baseline, follow-up period and principal components 1-10, PGSTestosterone and PGSBAT were not associated with relative decline of the respective biomarker (both p = n.s.). Conclusion: Our study did not find evidence supporting a genetic component in the age-related decline of circulating serum T or BAT concentrations. Instead, in accordance to previous observational studies, our results suggest that rather non-genetic factors, e.g. increasing incidence rates of comorbidities, drive the age-related decline in sex steroid levels in men. Our study contributes to understanding the intricate relationship between genetic and non-genetic factors with age-related testosterone decline in men and offers valuable insights for potential interventions targeting age-related hormonal changes and associated health outcomes. Presentation: 6/2/2024

Dose-response association of an accelerometer-measured physical activity with all-cause mortality and cardiovascular disease incidence: Prospective cohort with 76,074 participants

ObjectiveTo investigate the prospective dose-response association of accelerometer-measured moderate-to-vigorous physical activity (PA;MVPA) with all-cause mortality and cardiovascular disease (CVD) incidence. MethodsThis prospective cohort of 76,074 participants from the UK Biobank study contained one week of individual accelerometer-based PA data collected between June 1, 2013 and December 23, 2015. Using restricted cubic splines to allow for potential non-linearity, we examined dose-response associations of MVPA with all-cause mortality and incident CVD, respectively. ResultsThe median follow-up time was 8.0 years (IQR 7.5–8.5). The dose-response association of MVPA with all-cause mortality and CVD showed a similar L-shaped association, with significant risk reductions already from 10 min of MVPA per week for all-cause mortality (hazard ratio [HR], 0.98 [95 % CI,0.98–0.99]) and 15 min per week for CVD incidence (HR, 0.99 [95 % CI,0.98–0.99]). Doing more MVPA was associated with further risk reduction, but beyond around 500 min per week the benefits levelled off at HR's around 0.6 to 0.7. The highest additional benefit of adding more minutes per week for all-cause mortality and CVD incidence were observed between 100 and 250 weekly minutes of MVPA. From this point forward, the mean risk reduction rates decreased and were close to 0 beyond 500 weekly minutes. ConclusionsSignificant, but small, risk reductions in all-cause mortality and CVD incidence can be achieved with as little as 10 and 15 min of MVPA per week, respectively. However, public health organizations should promote the attainment of 250 min of MVPA per week (with 100 min as a possible first target for inactive individuals), as these thresholds are associated with the greatest efficiency. Beyond that, less pronounced risk reductions can be achieved by accumulating additional MVPA, with hardly any additional benefits beyond 500 weekly minutes.