scholarly journals Increasing adiposity and metabolic dysfunction prolong QTc interval and increase risk of ventricular arrhythmias: results from the UK Biobank

EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
K Patel ◽  
X Li ◽  
X Xu ◽  
L Sun ◽  
M Ardissino ◽  
...  
Keyword(s):  
Ventricular Arrhythmias ◽  
Additive Effect ◽  
Public Institution ◽  
Qtc Interval ◽  
Metabolic Dysfunction ◽  
Uk Biobank ◽  
Qtc Prolongation ◽  
Males And Females ◽  
The Uk ◽  
Genetically Determined

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): National Institute for Health Research Background/purpose: Small-scale studies have associated obesity and metabolic ill-health with QTc interval prolongation. Whether these associations are modulated by an underlying genetic predilection and translate into higher risks of ventricular arrhythmias (VA) is unknown. Methods  Using the UK Biobank and adjusted multivariate regression analysis, we studied the associations between QTc and clinical measures of adiposity and metabolic ill-health. A polygenic risk score was used to determine whether these associations are modulated by a genetic predilection for QTc prolongation. We compared QTc between four clinical phenotypes defined according to presence (+) or absence (-) of obesity (Ob), and metabolic ill-health (MU). Logistic regression was used to calculate odds ratios (OR) for VA amongst these groups. Results  23,683 individuals (11,563 male, mean age 61.0 + 7.5years) had ECG and clinical data available. QTc prolongs with increasing body mass index (0.76ms/kg/m2, 95%CI: 0.68-0.83ms/kg/m2), body fat (0.45ms/%, 95%CI:0.39-0.50ms/%), hip girth (0.35ms/cm, 95%CI:0.31-0.39ms/cm) and waist girth (0.32ms/cm, 95%CI:0.29-0.35ms/cm); all p < 0.001. Genetically determined repolarisation reserve has no significant modulatory effect on the QTc-prolonging effects of increasing adiposity. Referenced to Ob-MU-, Ob + MU- and Ob-MU+ independently prolong QTc to a comparable extent, and Ob + MU+ has an additive effect on QTc prolongation. With reference to Ob-MU-, OR for VA in Ob-MU+ males and females were 5.96 (95%CI:4.70-7.55) and 5.10 (95%CI:3.34-7.80), respectively. OR for Ob + MU+ were 6.99 (95%CI:5.72-8.54) and 3.56 (95%CI:2.66-4.77) in males and females, respectively, (all p < 0.001, see Table). Conclusion  Adiposity and metabolic perturbation prolong QTc to a similar extent, and their co-existence exerts an additive effect. These effects are independent of genetically determined repolarisation reserve. Despite their comparable QTc prolonging effects, metabolic ill-health is associated with higher OR for VA than obesity. VA in obesity and metabolic dysfunctionReference phenotypeOb + MU-Ob-MU+Ob + MU+Ob-MU+male1.10(0.87-1.39)ns5.96 (4.70-7.55)***6.99(5.72-8.54)***female0.87(0.64-1.18)ns5.10(3.34-7.80)***3.56(2.66-4.77)***Ob + MU-male--6.01(4.98-7.26)***female--5.61(4.18-7.52)***Ob + MU+male--1.25(1.05-1.49)*female--1.16(0.80-1.68)nsOb, obese; MU, metabolically unhealthy; +, presence; -, absence; ns, non-significant; *p < 0.05; ***p < 0.001. Abstract Figure. QTc in obesity and metabolic dysfunction

scholarly journals Using genetics to understand the causal influence of higher BMI on depression

2018 ◽  
Vol 48 (3) ◽  
pp. 834-848 ◽  
Author(s):  
Jessica Tyrrell ◽  
Anwar Mulugeta ◽  
Andrew R Wood ◽  
Ang Zhou ◽  
Robin N Beaumont ◽  
...  
Keyword(s):  
Risk Score ◽  
Genetic Risk ◽  
Mendelian Randomization ◽  
Genetic Risk Score ◽  
Self Report ◽  
Uk Biobank ◽  
Men And Women ◽  
Statistical Confidence ◽  
The Uk ◽  
Genetically Determined

Abstract Background Depression is more common in obese than non-obese individuals, especially in women, but the causal relationship between obesity and depression is complex and uncertain. Previous studies have used genetic variants associated with BMI to provide evidence that higher body mass index (BMI) causes depression, but have not tested whether this relationship is driven by the metabolic consequences of BMI nor for differences between men and women. Methods We performed a Mendelian randomization study using 48 791 individuals with depression and 291 995 controls in the UK Biobank, to test for causal effects of higher BMI on depression (defined using self-report and Hospital Episode data). We used two genetic instruments, both representing higher BMI, but one with and one without its adverse metabolic consequences, in an attempt to ‘uncouple’ the psychological component of obesity from the metabolic consequences. We further tested causal relationships in men and women separately, and using subsets of BMI variants from known physiological pathways. Results Higher BMI was strongly associated with higher odds of depression, especially in women. Mendelian randomization provided evidence that higher BMI partly causes depression. Using a 73-variant BMI genetic risk score, a genetically determined one standard deviation (1 SD) higher BMI (4.9 kg/m2) was associated with higher odds of depression in all individuals [odds ratio (OR): 1.18, 95% confidence interval (CI): 1.09, 1.28, P = 0.00007) and women only (OR: 1.24, 95% CI: 1.11, 1.39, P = 0.0001). Meta-analysis with 45 591 depression cases and 97 647 controls from the Psychiatric Genomics Consortium (PGC) strengthened the statistical confidence of the findings in all individuals. Similar effect size estimates were obtained using different Mendelian randomization methods, although not all reached P < 0.05. Using a metabolically favourable adiposity genetic risk score, and meta-analysing data from the UK biobank and PGC, a genetically determined 1 SD higher BMI (4.9 kg/m2) was associated with higher odds of depression in all individuals (OR: 1.26, 95% CI: 1.06, 1.50], P = 0.010), but with weaker statistical confidence. Conclusions Higher BMI, with and without its adverse metabolic consequences, is likely to have a causal role in determining the likelihood of an individual developing depression.

scholarly journals Genetically Determined Chronic Low-Grade Inflammation and Hundreds of Health Outcomes in the UK Biobank and the FinnGen Population: A Phenome-Wide Mendelian Randomization Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Shucheng Si ◽  
Jiqing Li ◽  
Marlvin Anemey Tewara ◽  
Fuzhong Xue
Keyword(s):  
Mendelian Randomization ◽  
Neurological Diseases ◽  
Bipolar Disorders ◽  
Electrolyte Imbalance ◽  
Low Grade ◽  
Uk Biobank ◽  
Anemia Of Chronic Disease ◽  
The Uk ◽  
Genetically Determined ◽  
Low Grade Inflammation

BackgroundC-reactive protein (CRP) has been used as a biomarker of chronic low-grade inflammation in observational studies. We aimed to determine whether genetically determined CRP was associated with hundreds of human phenotypes to guide anti-inflammatory interventions.MethodsWe used individual data from the UK Biobank to perform a phenome-wide two-stage least squares (2SLS) Mendelian randomization (MR) analysis for CRP with 879 diseases. Summary-level data from the FinnGen consortium were utilized to perform phenome-wide two-sample MR analysis on 821 phenotypes. Systematic two-sample MR methods included MR-IVW, MR-WME, MR-Mod, and MR-PRESSO as sensitivity analyses combined with multivariable MR to identify robust associations. Genetic correlation analysis was applied to identify shared genetic risks.ResultsWe found genetically determined CRP was robustly associated with 15 diseases in the UK Biobank and 11 diseases in the FinnGen population (P &lt; 0.05 for all MR analyses). CRP was positively associated with tongue cancer, bronchitis, hydronephrosis, and acute pancreatitis and negatively associated with colorectal cancer, colon cancer, cerebral ischemia, electrolyte imbalance, Parkinson’s disease, epilepsy, anemia of chronic disease, encephalitis, psychophysical visual disturbances, and aseptic necrosis of bone in the UK Biobank. There were positive associations with impetigo, vascular dementia, bipolar disorders, hypercholesterolemia, vertigo, and neurological diseases, and negative correlations with degenerative macular diseases, metatarsalgia, interstitial lung disease, and idiopathic pulmonary fibrosis, and others. in the FinnGen population. The electrolyte imbalance and anemia of chronic disease in UK Biobank and hypercholesterolemia and neurological diseases in FinnGen pass the FDR corrections. Neurological diseases and bipolar disorders also presented positive genetic correlations with CRP. We found no overlapping causal associations between the populations. Previous causal evidence also failed to support these associations (except for bipolar disorders).ConclusionsGenetically determined CRP was robustly associated with several diseases in the UK Biobank and the FinnGen population, but could not be replicated, suggesting heterogeneous and non-repeatable effects of CRP across populations. This implies that interventions at CRP are unlikely to result in decreased risk for most human diseases in the general population but may benefit specific high-risk populations. The limited causal evidence and potential double-sided effects remind us to be cautious about CRP interventions.

scholarly journals Metabolic subgroups and cardiometabolic multimorbidity in the UK Biobank

2021 ◽  
Author(s):  
Anwar Mulugeta ◽  
Elina Hypponen ◽  
Mika Ala-Korpela ◽  
Ville-Petteri Makinen
Keyword(s):  
Cox Regression ◽  
Population Based ◽  
Self Organizing Map ◽  
Metabolic Dysfunction ◽  
Uk Biobank ◽  
Metabolic Diversity ◽  
Hazard Ratios ◽  
Random Expectation ◽  
The Uk ◽  
Aggregate Burden

Background: Ischemic heart disease (IHD), diabetes, cancer and dementia share features of age-associated metabolic dysfunction. We hypothesized that metabolic diversity explains the diversity of morbidity later in life. Methods: We analyzed data from the UK Biobank (N = 329,908). A self-organizing map (SOM, an artificial neural network) was trained with 51 metabolic traits adjusted for age and sex. The SOM analyses produced six subgroups that summarized the multi-variable metabolic diversity. The subgroup with the lowest adiposity and disease burden was chosen as the reference. Hazard ratios (HR) were modeled by Cox regression (P < 0.0001 unless otherwise indicated). Enrichment of multi-morbidity over random expectation was tested by permutation analysis. Results: The subgroup with the highest sex hormones was not associated with IHD (HR = 1.04, P = 0.14). The subgroup with high urinary excretion without kidney stress (HR = 1.24) and the subgroup with the highest apolipoprotein B and blood pressure (HR = 1.52) were associated with IHD. The subgroup with high adiposity, inflammation and kidney stress was associated with IHD (HR = 2.11), cancer (HR= 1.29), dementia (HR = 1.70) and mortality (HR = 2.12). The subgroup with high triglycerides and liver enzymes was at risk of diabetes (HR = 15.6). Paradoxical enrichment of multimorbidity in young individuals and in favorable subgroups was observed. Conclusions: These results support metabolic diversity as an explanation to diverging morbidity and demonstrate the potential value of population-based metabolic subgroups as public health targets for reducing aggregate burden of chronic diseases in ageing populations.

scholarly journals Association between physical activity and risk of incident arrhythmias in 402 406 individuals: evidence from the UK Biobank cohort

2020 ◽  
Vol 41 (15) ◽  
pp. 1479-1486 ◽  
Author(s):  
Adrian D Elliott ◽  
Dominik Linz ◽  
Ricardo Mishima ◽  
Kadhim Kadhim ◽  
Celine Gallagher ◽  
...  
Keyword(s):  
Physical Activity ◽  
Ventricular Arrhythmias ◽  
Hospital Admissions ◽  
Vigorous Physical Activity ◽  
Activity Levels ◽  
Uk Biobank ◽  
Physically Active ◽  
Activity Assessment ◽  
The Uk

Abstract Aims Physical activity reduces cardiovascular disease burden and mortality, although its relationship with cardiac arrhythmias is less certain. The aim of this study was to assess the association between self-reported physical activity and atrial fibrillation (AF), ventricular arrhythmias and bradyarrhythmias, across the UK Biobank cohort. Methods and results We included 402 406 individuals (52.5% female), aged 40–69 years, with over 2.8 million person-years of follow-up who underwent self-reported physical activity assessment computed in metabolic equivalent-minutes per week (MET-min/wk) at baseline, detailed physical assessment and medical history evaluation. Arrhythmia episodes were diagnosed through hospital admissions and death reports. Incident AF risk was lower amongst physically active participants, with a more pronounced reduction amongst female participants [hazard ratio (HR) for 1500 vs. 0 MET-min/wk: 0.85, 95% confidence interval (CI) 0.74–0.98] than males (HR for 1500 vs. 0 MET-min/wk: 0.90, 95% CI 0.82–1.0). Similarly, we observed a significantly lower risk of ventricular arrhythmias amongst physically active participants (HR for 1500 MET-min/wk 0.78, 95% CI 0.64–0.96) that remained relatively stable over a broad range of physical activity levels between 0 and 2500 MET-min/wk. A lower AF risk amongst female participants who engaged in moderate levels of vigorous physical activity was observed (up to 2500 MET-min/wk). Vigorous physical activity was also associated with reduced ventricular arrhythmia risk. Total or vigorous physical activity was not associated with bradyarrhythmias. Conclusion The risk of AF and ventricular arrhythmias is lower amongst physically active individuals. These findings provide observational support that physical activity is associated with reduced risk of atrial and ventricular arrhythmias.

scholarly journals Long-Term Exposure to Elevated Lipoprotein(a) Levels, Parental Lifespan and Risk of Mortality

2019 ◽  
Author(s):  
Benoit J. Arsenault ◽  
William Pelletier ◽  
Yannick Kaiser ◽  
Nicolas Perrot ◽  
Christian Couture ◽  
...  
Keyword(s):  
Cardiovascular Mortality ◽  
Event Rate ◽  
Human Longevity ◽  
Uk Biobank ◽  
Lipoprotein A ◽  
The Uk ◽  
Genetically Determined ◽  
The Impact ◽  
Age Of Death

ABSTRACTBackgroundElevated Lipoprotein(a) (Lp[a]) levels are associated with a broad range of atherosclerotic cardiovascular diseases (CVD). The impact of high Lp(a) levels on human longevity is however controversial. Our objectives were to determine whether genetically-determined Lp(a) levels are associated with parental lifespan and to assess the association between measured and genetically-determined Lp(a) levels and long-term all-cause and cardiovascular mortality.MethodsWe determined the association between a genetic risk score of 26 single nucleotide polymorphisms weighted for their impact on Lp(a) levels (wGRS) and parental lifespan (at least one long-lived parent; father still alive and older than 90 or father’s age of death ≥90 or mother still alive and older than 93 or mother’s age of death ≥93) in 139,362 participants from the UK Biobank. A total of 17,686 participants were considered as having high parental lifespan. We also investigated the association between Lp(a) levels and all-cause and cardiovascular mortality in 18,720 participants from the EPIC-Norfolk study.ResultsIn the UK Biobank, increases in the wGRS (weighted for a 50 mg/dL increase in Lp(a) levels) were inversely associated with a high parental lifespan (odds ratio=0.92, 95% confidence interval [CI]=0.89-0.94, p=2.7×10−8). During the 20-year follow-up of the EPIC-Norfolk study, 5686 participants died (2412 from CVD-related causes). Compared to participants with Lp(a) levels <50 mg/dL, those with Lp(a) levels ≥50 mg/dL had an increased hazard ratio (HR) for all-cause (HR=1.17, 95% CI=1.08-1.27) and cardiovascular (HR=1.54, 95% CI=1.37-1.72) mortality. Compared to individuals with Lp(a) levels below the 50th percentile of the Lp(a) distribution (in whom event rates were 29.8% and 11.3%, respectively for all-cause and cardiovascular mortality), those with Lp(a) levels equal or above the 95th percentile of the population distribution (≥70 mg/dL) had HRs of 1.22 (95% CI=1.09-1.37, event rate 37.5%) and 1.71 (95% CI=1.46-2.00, event rate 20.0%), for all-cause mortality and cardiovascular mortality, respectively.ConclusionsResults of this study suggest a potentially causal effect of Lp(a) on human longevity, support the use of parental lifespan as a tool to study the genetic determinants of human longevity, and provide a rationale for a trial of Lp(a)-lowering therapy in individuals with high Lp(a) levels.

scholarly journals Relationship between Serum 25(OH)D and Depression: Causal Evidence from a Bi-Directional Mendelian Randomization Study

Nutrients ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 109
Author(s):  
Anwar Mulugeta ◽  
Amanda Lumsden ◽  
Elina Hyppönen
Keyword(s):  
Vitamin D ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Uk Biobank ◽  
Reverse Causality ◽  
Hydroxyvitamin D ◽  
Inverse Variance ◽  
The Uk ◽  
Genetically Determined ◽  
The Relationship

The relationship between depression and vitamin D deficiency is complex, with evidence mostly from studies affected by confounding and reverse causality. We examined the causality and direction of the relationship between 25-hydroxyvitamin D (25(OH)D) and depression in bi-directional Mendelian randomization (MR) analyses using information from up to 307,618 white British participants from the UK Biobank and summary results from the SUNLIGHT (n = 79,366) and Psychiatric Genomics consortia (PGC 113,154 cases and 218,523 controls). In observational analysis, the odds of depression decreased with higher 25(OH)D concentrations (adjusted odds ratio (OR) per 50% increase 0.95, 95%CI 0.94–0.96). In MR inverse variance weighted (IVW) using the UK Biobank, there was no association between genetically determined serum 25(OH)D and depression (OR per 50% higher 0.97, 95%CI 0.90–1.05) with consistent null association across all MR approaches and in data from PGC consortium. In contrast, genetic liability to depression was associated with lower 25(OH)D concentrations (MR IVW −3.26%, −4.94%–−1.55%), with the estimates remaining generally consistent after meta-analysing with the consortia. In conclusion, we found genetic evidence for a causal effect of depression on lower 25(OH)D concentrations, however we could not confirm a beneficial effect of nutritional vitamin D status on depression risk.

scholarly journals A sex-specific evolutionary interaction between ADCY9 and CETP

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Isabel Gamache ◽  
Marc-André Legault ◽  
Jean-Christophe Grenier ◽  
Rocio Sanchez ◽  
Eric Rhéaume ◽  
...  
Keyword(s):  
Epistatic Interaction ◽  
Human Populations ◽  
Uk Biobank ◽  
Rna Seq ◽  
Specific Result ◽  
Transfer Protein ◽  
Clinical Responses ◽  
Males And Females ◽  
The Uk ◽  
Pharmacogenomic Studies

Pharmacogenomic studies have revealed associations between rs1967309 in the adenylyl cyclase type 9 (ADCY9) gene and clinical responses to the cholesteryl ester transfer protein (CETP) modulator dalcetrapib, however, the mechanism behind this interaction is still unknown. Here, we characterized selective signals at the locus associated with the pharmacogenomic response in human populations and we show that rs1967309 region exhibits signatures of positive selection in several human populations. Furthermore, we identified a variant in CETP, rs158477, which is in long-range linkage disequilibrium with rs1967309 in the Peruvian population. The signal is mainly seen in males, a sex-specific result that is replicated in the LIMAA cohort of over 3,400 Peruvians. Analyses of RNA-seq data further suggest an epistatic interaction on CETP expression levels between the two SNPs in multiple tissues, which also differs between males and females. We also detected interaction effects of the two SNPs with sex on cardiovascular phenotypes in the UK Biobank, in line with the sex-specific genotype associations found in Peruvians at these loci. We propose that ADCY9 and CETP coevolved during recent human evolution due to sex-specific selection, which points towards a biological link between dalcetrapib’s pharmacogene ADCY9 and its therapeutic target CETP.

Low birthweight is associated with poorer limb muscle mass and grip strength in middle age: findings from the UK Biobank Imaging Enhancement

2019 ◽  
Author(s):  
Elizabeth Curtis ◽  
Justin Liu ◽  
Kate Ward ◽  
Karen Jameson ◽  
Zahra Raisi-Estabragh ◽  
...  
Keyword(s):  
Grip Strength ◽  
Muscle Mass ◽  
Low Birthweight ◽  
Middle Age ◽  
Limb Muscle ◽  
Uk Biobank ◽  
The Uk

Contrasting Broad- and Clinically- defined Polygenic Indicators of Depression and Depression-related Phenotypes in Adults and Children

2020 ◽  
Author(s):  
John E. McGeary ◽  
Chelsie Benca-Bachman ◽  
Victoria Risner ◽  
Christopher G Beevers ◽  
Brandon Gibb ◽  
...  
Keyword(s):  
Suicidal Ideation ◽  
Cognitive Reappraisal ◽  
Twin Studies ◽  
European Ancestry ◽  
Summary Statistics ◽  
Depression Severity ◽  
Uk Biobank ◽  
Polygenic Scores ◽  
Adults And Children ◽  
The Uk

Twin studies indicate that 30-40% of the disease liability for depression can be attributed to genetic differences. Here, we assess the explanatory ability of polygenic scores (PGS) based on broad- (PGSBD) and clinical- (PGSMDD) depression summary statistics from the UK Biobank using independent cohorts of adults (N=210; 100% European Ancestry) and children (N=728; 70% European Ancestry) who have been extensively phenotyped for depression and related neurocognitive phenotypes. PGS associations with depression severity and diagnosis were generally modest, and larger in adults than children. Polygenic prediction of depression-related phenotypes was mixed and varied by PGS. Higher PGSBD, in adults, was associated with a higher likelihood of having suicidal ideation, increased brooding and anhedonia, and lower levels of cognitive reappraisal; PGSMDD was positively associated with brooding and negatively related to cognitive reappraisal. Overall, PGS based on both broad and clinical depression phenotypes have modest utility in adult and child samples of depression.

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