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Leisure sedentary behaviours are associated with increased risk of cardiovascular disease, but whether this relationship is causal is unknown. The aim of this study is to identify genetic determinants associated with leisure sedentary behaviours and to estimate the potential causal effect on coronary artery disease (CAD). Genome wide association analyses of leisure television watching, leisure computer use and driving behaviour in the UK Biobank identify 145, 36 and 4 genetic loci ( P  < 1×10 −8 ), respectively. High genetic correlations are observed between sedentary behaviours and neurological traits, including education and body mass index (BMI). Two-sample Mendelian randomization (MR) analysis estimates a causal effect between 1.5 hour increase in television watching and CAD (OR 1.44, 95%CI 1.25–1.66, P  = 5.63 × 10 −07 ), that is partially independent of education and BMI in multivariable MR analyses. This study finds independent observational and genetic support for the hypothesis that increased sedentary behaviour by leisure television watching is a risk factor for CAD. Epidemiological studies have shown an association between sedentary behaviours and cardiovascular disease risk. Here, van de Vegte et al . perform GWAS for self-reported sedentary behaviours (TV watching, computer use, driving) and Mendelian randomization analyses to explore potential causal relationships with coronary artery disease.

Coronary artery disease (CAD) is the major cause of morbidity and mortality in the world. Identification of novel genetic determinants may provide new opportunities for developing innovative strategies to predict, prevent and treat CAD. Therefore, we meta-analyzed independent genetic variants passing P <× 10 −5 in CARDIoGRAMplusC4D with novel data made available by UK Biobank. Of the 161 genetic variants studied, 71 reached genome wide significance (p < 5 × 10 −8 ) including 15 novel loci. These novel loci include multiple genes that are involved in angiogenesis ( TGFB1, ITGB5, CDH13 and RHOA ) and 2 independent variants in the TGFB1 locus. We also identified SGEF as a candidate gene in one of the novel CAD loci. SGEF was previously suggested as a therapeutic target based on mouse studies. The genetic risk score of CAD predicted recurrent CAD events and cardiovascular mortality. We also identified significant genetic correlations between CAD and other cardiovascular conditions, including heart failure and atrial fibrillation. In conclusion, we substantially increased the number of loci convincingly associated with CAD and provide additional biological and clinical insights.

Heart rate (HR) responds to exercise by increasing during exercise and recovering after exercise. As such, HR is an important predictor of mortality that researchers believe is modulated by the autonomic nervous system. However, the mechanistic basis underlying inter-individual differences has yet to be explained. Here, we perform a large-scale genome-wide analysis of HR increase and HR recovery in 58,818 UK Biobank individuals. Twenty-five independent SNPs in 23 loci are identified to be associated ( p  < 8.3 × 10 −9 ) with HR increase or HR recovery. A total of 36 candidate causal genes are prioritized that are enriched for pathways related to neuron biology. No evidence is found of a causal relationship with mortality or cardiovascular diseases. However, a nominal association with parental lifespan requires further study. In conclusion, the findings provide new biological and clinical insight into the mechanistic underpinnings of HR response to exercise. The results also underscore the role of the autonomous nervous system in HR recovery. Response of the heart rate (HR) to exercise is associated with cardiac fitness and risk of cardiac death. Here, in a genome-wide association study, Verweij et al. identify 23 loci for HR increase during exercise or HR recovery, and highlight pleiotropy with blood pressure by polygenic risk score analysis.

The acute heart rate response to exercise, i.e., heart rate increase during and heart rate recovery after exercise, has often been associated with all-cause and cardiovascular mortality. The long-term response of heart rate to exercise results in favourable changes in chronotropic function, including decreased resting and submaximal heart rate as well as increased heart rate recovery. Both the acute and long-term heart rate response to exercise have been shown to be heritable. Advances in genetic analysis enable researchers to investigate this hereditary component to gain insights in possible molecular mechanisms underlying interindividual differences in the heart rate response to exercise. In this review, we comprehensively searched candidate gene, linkage, and genome-wide association studies that investigated the heart rate response to exercise. A total of ten genes were associated with the acute heart rate response to exercise in candidate gene studies. Only one gene (CHRM2), related to heart rate recovery, was replicated in recent genome-wide association studies (GWASs). Additional 17 candidate causal genes were identified for heart rate increase and 26 for heart rate recovery in these GWASs. Nine of these genes were associated with both acute increase and recovery of the heart rate during exercise. These genes can be broadly categorized into four categories: (1) development of the nervous system (CCDC141, PAX2, SOX5, and CAV2); (2) prolongation of neuronal life span (SYT10); (3) cardiac development (RNF220 and MCTP2); (4) cardiac rhythm (SCN10A and RGS6). Additional 10 genes were linked to long-term modification of the heart rate response to exercise, nine with heart rate increase and one with heart rate recovery. Follow-up will be essential to get functional insights in how candidate causal genes affect the heart rate response to exercise. Future work will be required to translate these findings to preventive and therapeutic applications.

Small-scale studies have suggested a link between the human gut microbiome and highly prevalent diseases. However, the extent to which the human gut microbiome can be considered a determinant of disease and healthy aging remains unknown. We aimed to determine the spectrum of diseases that are linked to the human gut microbiome through the utilization of its genetic determinants as a proxy for its composition. 180 single nucleotide polymorphisms (SNPs) known to influence the human gut microbiome were used to assess the association with health and disease outcomes in 422,417 UK Biobank participants. Potential causal estimates were obtained using a Mendelian randomization (MR) approach. From the total sample analysed (mean age was 57 ± 8 years), 194,567 (46%) subjects were male. Median exposure was 66-person years (interquartile range 59–72). Eleven SNPs were significantly associated with 28 outcomes (Bonferroni corrected P value < 4.63·10 −6 ) including food intake, hypertension, atopy, COPD, BMI, and lipids. Multiple SNP MR pointed to a possible causal link between Ruminococcus flavefaciens and hypertension, and Clostridium and platelet count. Microbiota and their metabolites might be of importance in the interplay between overlapping pathophysiological processes, although challenges remain in establishing causal relationships.

The relationship between circulating total bilirubin and incident non-alcoholic fatty liver disease (NAFLD) is uncertain. We aimed to assess the association of total bilirubin with the risk of new-onset NAFLD and investigate any causal relevance to the association using a Mendelian randomization (MR) study. Plasma total bilirubin levels were measured at baseline in the PREVEND prospective study of 3824 participants (aged 28–75 years) without pre-existing cardiovascular disease or NAFLD. Incident NAFLD was estimated using the biomarker-based algorithms, fatty liver index (FLI) and hepatic steatosis index (HSI). Odds ratios (ORs) (95% confidence intervals) for NAFLD were assessed. The genetic variant rs6742078 located in the UDP-glucuronosyltransferase (UGT1A1) locus was used as an instrumental variable. Participants were followed up for a mean duration of 4.2 years. The multivariable adjusted OR (95% CIs) for NAFLD as estimated by FLI (434 cases) was 0.82 (0.73–0.92; p  = 0.001) per 1 standard deviation (SD) change in log e total bilirubin. The corresponding adjusted OR (95% CIs) for NAFLD as estimated by HSI (452 cases) was 0.87 (0.78–0.97; p  = 0.012). The rs6742078 variant explained 20% of bilirubin variation. The ORs (95% CIs) for a 1 SD genetically elevated total bilirubin level was 0.98 (0.69–1.38; p  = 0.900) for FLI and 1.14 (0.81–1.59; p  = 0.451) for HSI. Elevated levels of total bilirubin were not causally associated with decreased risk of NAFLD based on MR analysis. The observational association may be driven by biases such as unmeasured confounding and/or reverse causation. However, due to low statistical power, larger-scale investigations are necessary to draw definitive conclusions.

Recent studies have revealed a role for zinc in insulin secretion and glucose homeostasis. Randomized placebo-controlled zinc supplementation trials have demonstrated improved glycemic traits in patients with type II diabetes (T2D). Moreover, rare loss-of-function variants in the zinc efflux transporter SLC30A8 reduce T2D risk. Despite this accumulated evidence, a mechanistic understanding of how zinc influences systemic glucose homeostasis and consequently T2D risk remains unclear. To further explore the relationship between zinc and metabolic traits, we searched the exome database of the Regeneron Genetics Center-Geisinger Health System DiscovEHR cohort for genes that regulate zinc levels and associate with changes in metabolic traits. We then explored our main finding using in vitro and in vivo models. We identified rare loss-of-function (LOF) variants (MAF <1%) in Solute Carrier Family 39, Member 5 ( SLC39A5 ) associated with increased circulating zinc (p=4.9 × 10 -4 ). Trans-ancestry meta-analysis across four studies exhibited a nominal association of SLC39A5 LOF variants with decreased T2D risk. To explore the mechanisms underlying these associations, we generated mice lacking Slc39a5. Slc39a5 -/- mice display improved liver function and reduced hyperglycemia when challenged with congenital or diet-induced obesity. These improvements result from elevated hepatic zinc levels and concomitant activation of hepatic AMPK and AKT signaling, in part due to zinc-mediated inhibition of hepatic protein phosphatase activity. Furthermore, under conditions of diet-induced non-alcoholic steatohepatitis (NASH), Slc39a5 -/- mice display significantly attenuated fibrosis and inflammation. Taken together, these results suggest SLC39A5 as a potential therapeutic target for non-alcoholic fatty liver disease (NAFLD) due to metabolic derangements including T2D.

Although erythropoietin has been used for decades in the treatment of anemia, data regarding endogenous levels in the general population are scarce. Therefore, we determined erythropoietin reference ranges and its clinical, biochemical and genetic associations in the general population. We used data from 6,777 subjects enrolled in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study. Fasting venous blood samples were obtained in the morning from all participants from 2001-2003. Serum erythropoietin concentrations were measured using a fully automated chemiluminescent enzyme-labeled immunometric assay. A genome-wide association study was performed to identify genetic determinants. Mean age (± SD) was 53 ± 12 years and 50% were female. Median (IQR) erythropoietin concentrations were 7.6 (5.8-9.9) IU/L in men and 7.9 (6.0-10.6) IU/L in women. A strong positive correlation was found between erythropoietin and waist circumference, glucose and systolic blood pressure (all P < 0.05). In subjects with normal renal function there was a strong exponential relation between hemoglobin and erythropoietin, whereas in renal impairment (eGFR < 60 mL/min/1.73m²) this relation was linear (men) or absent (women) (P < 0.001 for interaction). Single-nucleotide polymorphisms at the HBS1L-MYB locus were shown to be related to erythropoietin levels (P < 9x10-21), more significantly than other erythrocyte parameters. We provide age-specific reference ranges for endogenous serum erythropoietin. Erythropoietin levels are positively associated with the components of the metabolic syndrome, except cholesterol. We show that even mild renal failure blunts erythropoietin production and propose the HBS1L-MYB locus as a regulator of erythropoietin.

Context Multiple observational studies have reported an inverse relationship between 25-hydroxyvitamin D concentrations (25(OH)D) and type 2 diabetes (T2D). However, the results of short- and long-term interventional trials concerning the relationship between 25(OH)D and T2D risk have been inconsistent. Objectives and methods To evaluate the causal role of reduced blood 25(OH)D in T2D, here we have performed a bidirectional Mendelian randomization study using 59,890 individuals (5,862 T2D cases and 54,028 controls) from European and Asian Indian ancestries. We used six known SNPs, including three T2D SNPs and three vitamin D pathway SNPs, as a genetic instrument to evaluate the causality and direction of the association between T2D and circulating 25(OH)D concentration. Results Results of the combined meta-analysis of eight participating studies showed that a composite score of three T2D SNPs would significantly increase T2D risk by an odds ratio (OR) of 1.24, p = 1.82 × 10 –32 ; Z score 11.86, which, however, had no significant association with 25(OH)D status (Beta -0.02nmol/L ± SE 0.01nmol/L; p = 0.83; Z score -0.21). Likewise, the genetically instrumented composite score of 25(OH)D lowering alleles significantly decreased 25(OH)D concentrations (-2.1nmol/L ± SE 0.1nmol/L, p = 7.92 × 10 –78 ; Z score -18.68) but was not associated with increased risk for T2D (OR 1.00, p = 0.12; Z score 1.54). However, using 25(OH)D synthesis SNP (DHCR7; rs12785878) as an individual genetic instrument, a per allele reduction of 25(OH)D concentration (-4.2nmol/L ± SE 0.3nmol/L) was predicted to increase T2D risk by 5%, p = 0.004; Z score 2.84. This effect, however, was not seen in other 25(OH)D SNPs (GC rs2282679, CYP2R1 rs12794714) when used as an individual instrument. Conclusion Our new data on this bidirectional Mendelian randomization study suggests that genetically instrumented T2D risk does not cause changes in 25(OH)D levels. However, genetically regulated 25(OH)D deficiency due to vitamin D synthesis gene (DHCR7) may influence the risk of T2D.

Abnormal QRS duration and amplitudes on the electrocardiogram are indicative of cardiac pathology and are associated with adverse outcomes. The causal nature of these associations remains uncertain and could be due to QRS abnormalities being a symptom of cardiac damage rather than a factor on the causal pathway. By performing Mendelian randomization (MR) analyses using summary statistics of genome wide association study consortia with sample sizes between 20,687 and 339,224 individuals, we aimed to determine which cardiovascular risk factors causally lead to changes in QRS duration and amplitude (Sokolow-Lyon, Cornell and 12-leadsum products). Additionally, we aimed to determine whether QRS traits have a causal relationship with mortality and longevity. We performed inverse-variance weighted MR as main analyses and MR-Egger regression and weighted median estimation as sensitivity analyses. We found evidence for a causal relationship between higher blood pressure and larger QRS amplitudes (systolic blood pressure on Cornell: 55SNPs, causal effect estimate per 1 mmHg = 9.77 millimeters·milliseconds (SE = 1.38, P  = 1.20 × 10 −12 ) and diastolic blood pressure on Cornell: 57SNPs, causal effect estimate per 1 mmHg = 14.89 millimeters·milliseconds (SE = 1.82, P  = 3.08 × 10 −16 ), but not QRS duration. Genetically predicted QRS traits were not associated with longevity, suggesting a more prominent role of acquired factors in explaining the well-known link between QRS abnormalities and outcome.