A phenome-wide comparative analysis of genetic discordance between obesity and type 2 diabetes

Obesity and type 2 diabetes are causally related, yet there is considerable heterogeneity in the consequences of both conditions and the mechanisms of action are poorly defined. Here we show a genetic-driven approach defining two obesity profiles that convey highly concordant and discordant diabetogenic effects. We annotate and then compare association signals for these profiles across clinical and molecular phenotypic layers. Key differences are identified in a wide range of traits, including cardiovascular mortality, fat distribution, liver metabolism, blood pressure, specific lipid fractions and blood levels of proteins involved in extracellular matrix remodelling. We find marginal differences in abundance of Bacteroidetes and Firmicutes bacteria in the gut. Instrumental analyses reveal prominent causal roles for waist-to-hip ratio, blood pressure and cholesterol content of high-density lipoprotein particles in the development of diabetes in obesity. We prioritize 17 genes from the discordant signature that convey protection against type 2 diabetes in obesity, which may represent logical targets for precision medicine approaches.</p

Genome-Wide and Abdominal MRI-Imaging Data Provides Evidence that a Genetically Determined Favourable Adiposity Phenotype is Characterized by Lower Ectopic Liver Fat and Lower Risk of Type 2 Diabetes, Heart Disease and Hypertension

Recent genetic studies have identified alleles associated with opposite effects on adiposity and risk of type 2 diabetes. We aimed to identify more of these variants and test the hypothesis that such favorable adiposity alleles are associated with higher subcutaneous fat and lower ectopic fat. We combined MRI data with genome-wide association studies of body fat percentage (%) and metabolic traits. We report 14 alleles, including 7 newly characterized alleles, associated with higher adiposity but a favorable metabolic profile. Consistent with previous studies, individuals carrying more favorable adiposity alleles had higher body fat % and higher BMI but lower risk of type 2 diabetes, heart disease, and hypertension. These individuals also had higher subcutaneous fat but lower liver fat and a lower visceral-to-subcutaneous adipose tissue ratio. Individual alleles associated with higher body fat % but lower liver fat and lower risk of type 2 diabetes included those in PPARG, GRB14, and IRS1, whereas the allele in ANKRD55 was paradoxically associated with higher visceral fat but lower risk of type 2 diabetes. Most identified favorable adiposity alleles are associated with higher subcutaneous and lower liver fat, a mechanism consistent with the beneficial effects of storing excess triglycerides in metabolically low-risk depots.</p

Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration

Background & Aims: Excess liver iron content is common and is linked to hepatic and extrahepatic disease risk. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. Methods: First, we performed a genome-wide association study (GWAS) in 8,289 individuals in UK Biobank with MRI quantified liver iron, and validated our findings in an independent cohort (n=1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 29 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 anthropometric traits and diseases. Results: We identified three independent genetic variants (rs1800562 (C282Y) and rs1799945 (H63D) in HFE and rs855791 (V736A) in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p<5x10-8). The two HFE variants account for ~85% of all cases of hereditary haemochromatosis. Mendelian randomisation analysis provided evidence that higher central obesity plays a causal role in increased liver iron content. Phenome-wide association analysis demonstrated shared aetiopathogenic mechanisms for elevated liver iron, high blood pressure, cirrhosis, malignancies, neuropsychiatric and rheumatological conditions, while also highlighting inverse associations with anaemias, lipidaemias and ischaemic heart disease. Conclusion: Our study provides genetic evidence that mechanisms underlying higher liver iron content are likely systemic rather than organ specific, that higher central obesity is causally associated with higher liver iron, and that liver iron shares common aetiology with multiple metabolic and non-metabolic diseases

Enhancing prediction and causal inference in metabolic dyshomeostasis

This thesis is focused on two globally prevalent diseases: i) non-alcoholic fatty liver disease (NAFLD) and ii) type 2 diabetes (T2D), with an overall aim of improving prediction and causal inference in the context of these conditions. Our projects were mainly conducted using IMI DIRECT and UK Biobank datasets including multi-omics data, extensive environmental exposures, and biological intermediates.In paper I, we utilized structural equation modeling to test the 'twin-cycle' hypothesis concerning interactions between the liver and the pancreas in the etiology of T2D. Furthermore, the association of physical activity with glycemic control was investigated within the twin-cycle hypothesis. Our results showed the association of physical activity with several metabolic traits and factors. Moreover, the mediation effect of basal insulin secretion rate, insulin sensitivity and liver fat was identified from physical activity towards glucose regulation.In paper II, we developed a series of machine learning-based models for the diagnosis of fatty liver, using different combinations of complex clinical and omics input data, to screen at-risk populations for NAFLD. Beta-cell function and insulin sensitivity appeared to be the most informative predictors in the developed diagnostic models. Furthermore, the derived importance lists of each data set (clinical, genetic, transcriptomic, proteomic, and metabolomic) were highlighting previous findings and suggesting potential molecular features of the NAFLD etiology.In paper III, Bayesian network and Mendelian randomization approaches were deployed to examine a range of putative causal associations underlying the development of fatty liver. Our analyses identified basal insulin secretion rate and visceral fat as two key drivers. In addition, the sensitivity analysis on diabetes and non-diabetes strata identified a network mostly dominated by dysglycemia in presence of T2D, whereas, it was mainly controlled by excess adiposity in the absence of T2D. In paper IV, genotype-based recall (GBR) clinical trials, in which the genetic burden of individuals is used in recruiting two groups of participants with a high and low genetic risk score, were simulated and compared with the conventional randomized controlled trials (RCTs) in terms of their statistical power and the required sample sizes. The analysis showed that GBR trials are, under several diverse scenarios, more powerful than conventional RCTs for testing gene-treatment interactions

Association of Established Blood Pressure Loci With 10-Year Change in Blood Pressure and Their Ability to Predict Incident Hypertension

Background: Genome‐wide association studies have identified &gt;1000 genetic variants cross‐sectionally associated with blood pressure variation and prevalent hypertension. These discoveries might aid the early identification of subpopulations at risk of developing hypertension or provide targets for drug development, amongst other applications. The aim of the present study was to analyze the association of blood pressure‐associated variants with long‐term changes (10 years) in blood pressure and also to assess their ability to predict hypertension incidence compared with traditional risk variables in a Swedish population. Methods and Results: We constructed 6 genetic risk scores (GRSs) by summing the dosage of the effect allele at each locus of genetic variants previously associated with blood pressure traits (systolic blood pressure GRS (GRSSBP): 554 variants; diastolic blood pressure GRS (GRSDBP): 481 variants; mean arterial pressure GRS (GRSMAP): 20 variants; pulse pressure GRS (GRSPP): 478 variants; hypertension GRS (GRSHTN): 22 variants; combined GRS (GRScomb): 1152 variants). Each GRS was longitudinally associated with its corresponding blood pressure trait, with estimated effects per GRS SD unit of 0.50 to 1.21 mm Hg for quantitative traits and odds ratios (ORs) of 1.10 to 1.35 for hypertension incidence traits. The GRScomb was also significantly associated with hypertension incidence defined according to European guidelines (OR, 1.22 per SD; 95% CI, 1.10‒1.35) but not US guidelines (OR, 1.11 per SD; 95% CI, 0.99‒1.25) while controlling for traditional risk factors. The addition of GRScomb to a model containing traditional risk factors only marginally improved discrimination (Δarea under the ROC curve = 0.001–0.002). Conclusions: GRSs based on discovered blood pressure‐associated variants are associated with long‐term changes in blood pressure traits and hypertension incidence, but the inclusion of genetic factors in a model composed of conventional hypertension risk factors did not yield a material increase in predictive ability

Predicting Sensitivity to Adverse Lifestyle Risk Factors for Cardiometabolic Morbidity and Mortality

People appear to vary in their susceptibility to lifestyle risk factors for cardiometabolic disease; determining a priori who is most sensitive may help optimize the timing, design, and delivery of preventative interventions. We aimed to ascertain a person's degree of resilience or sensitivity to adverse lifestyle exposures and determine whether these classifications help predict cardiometabolic disease later in life; we pooled data from two population-based Swedish prospective cohort studies (n = 53,507), and we contrasted an individual's cardiometabolic biomarker profile with the profile predicted for them given their lifestyle exposure characteristics using a quantile random forest approach. People who were classed as 'sensitive' to hypertension- and dyslipidemia-related lifestyle exposures were at higher risk of developing cardiovascular disease (CVD, hazards ratio 1.6 (95% CI: 1.3, 1.91)), compared with the general population. No differences were observed for type 2 diabetes (T2D) risk. Here, we report a novel approach to identify individuals who are especially sensitive to adverse lifestyle exposures and who are at higher risk of subsequent cardiovascular events. Early preventive interventions may be needed in this subgroup

Estimating the Direct Effect between Dietary Macronutrients and Cardiometabolic Disease, Accounting for Mediation by Adiposity and Physical Activity

Assessing the causal effects of individual dietary macronutrients and cardiometabolic disease is challenging owing to the complexity to distinguish direct effects from those mediated or confounded by other factors. To estimate these effects, intake of protein, carbohydrate, sugar, fat, and its subtypes were obtained using food frequency data derived from a Swedish population-based cohort (n~60,000). Data on clinical outcomes (i.e., type 2 diabetes (T2D) and cardiovascular disease (CVD) incidence) were obtained by linking health registry data. We assessed the magnitude of direct and mediated effects of diet, adiposity and physical activity on T2D and CVD using structural equation modelling (SEM). To strengthen causal inference, we used Mendelian randomization (MR) to model macronutrient intake exposures against clinical outcomes. We identified likely causal effects of genetically predicted carbohydrate intake (including sugar intake) and T2D, independent of adiposity and physical activity. Pairwise, serial-and parallel-mediational configurations yielded similar results. In the integrative genomic analyses, the candidate causal variant localized to the established type 2 diabetes gene TCF7L2. These findings may be informative when considering which dietary modifications included in nutritional guidelines are most likely to elicit health-promoting effects

Investigating the causal relationships between excess adiposity and cardiometabolic health in men and women

AIMS/HYPOTHESIS: Excess adiposity is differentially associated with increased risk of cardiometabolic disease in men and women, according to observational studies. Causal inference studies largely assume a linear relationship between BMI and cardiometabolic outcomes, which may not be the case. In this study, we investigated the shapes of the causal relationships between BMI and cardiometabolic diseases and risk factors. We further investigated sex differences within the causal framework.METHODS: To assess causal relationships between BMI and the outcomes, we used two-stage least-squares Mendelian randomisation (MR), with a polygenic risk score for BMI as the instrumental variable. To elucidate the shapes of the causal relationships, we used a non-linear MR fractional polynomial method, and used piecewise MR to investigate threshold relationships and confirm the shapes.RESULTS: BMI was associated with type 2 diabetes (OR 3.10; 95% CI 2.73, 3.53), hypertension (OR 1.53; 95% CI 1.44, 1.62) and coronary artery disease (OR 1.20; 95% CI 1.08, 1.33), but not chronic kidney disease (OR 1.08; 95% CI 0.67, 1.72) or stroke (OR 1.08; 95% CI 0.92, 1.28). The data suggest that these relationships are non-linear. For cardiometabolic risk factors, BMI was positively associated with glucose, HbA1c, triacylglycerol levels and both systolic and diastolic BP. BMI had an inverse causal relationship with total cholesterol, LDL-cholesterol and HDL-cholesterol. The data suggest a non-linear causal relationship between BMI and BP and other biomarkers (p<0.001) except lipoprotein A. The piecewise MR results were consistent with the fractional polynomial results. The causal effect of BMI on coronary artery disease, total cholesterol and LDL-cholesterol was different in men and women, but this sex difference was only significant for LDL-cholesterol after controlling for multiple testing (p<0.001). Further, the causal effect of BMI on coronary artery disease varied by menopause status in women.CONCLUSIONS/INTERPRETATION: We describe the shapes of causal effects of BMI on cardiometabolic diseases and risk factors, and report sex differences in the causal effects of BMI on LDL-cholesterol. We found evidence of non-linearity in the causal effect of BMI on diseases and risk factor biomarkers. Reducing excess adiposity is highly beneficial for health, but there is greater need to consider biological sex in the management of adiposity

An investigation of causal relationships between prediabetes and vascular complications

Prediabetes is a state of glycaemic dysregulation below the diagnostic threshold of type 2 diabetes (T2D). Globally, ~352 million people have prediabetes, of which 35–50% develop full-blown diabetes within five years. T2D and its complications are costly to treat, causing considerable morbidity and early mortality. Whether prediabetes is causally related to diabetes complications is unclear. Here we report a causal inference analysis investigating the effects of prediabetes in coronary artery disease, stroke and chronic kidney disease, complemented by a systematic review of relevant observational studies. Although the observational studies suggest that prediabetes is broadly associated with diabetes complications, the causal inference analysis revealed that prediabetes is only causally related with coronary artery disease, with no evidence of causal effects on other diabetes complications. In conclusion, prediabetes likely causes coronary artery disease and its prevention is likely to be most effective if initiated prior to the onset of diabetes.Errata: Mutie, P.M., Pomares-Millan, H., Atabaki-Pasdar, N. et al. Author Correction: An investigation of causal relationships between prediabetes and vascular complications. Nat Commun 12, 202 (2021). DOI: 10.1038/s41467-020-20663-6</p

Glucose-dependent insulinotropic peptide and risk of cardiovascular events and mortality: a prospective study

Aims/hypothesis Evidence that glucose-dependent insulinotropic peptide (GIP) and/or the GIP receptor (GIPR) are involved in cardiovascular biology is emerging. We hypothesised that GIP has untoward effects on cardiovascular biology, in contrast to glucagon-like peptide 1 (GLP-1), and therefore investigated the effects of GIP and GLP-1 concentrations on cardiovascular disease (CVD) and mortality risk. Methods GIP concentrations were successfully measured during OGTTs in two independent populations (Malmo Diet Cancer-Cardiovascular Cohort [MDC-CC] and Prevalence, Prediction and Prevention of Diabetes in Botnia [PPP-Botnia]) in a total of 8044 subjects. GLP-1 (n = 3625) was measured in MDC-CC. The incidence of CVD and mortality was assessed via national/regional registers or questionnaires. Further, a two-sample Mendelian randomisation (2SMR) analysis between the GIP pathway and outcomes (coronary artery disease [CAD] and myocardial infarction) was carried out using a GIP-associated genetic variant, rs1800437, as instrumental variable. An additional reverse 2SMR was performed with CAD as exposure variable and GIP as outcome variable, with the instrumental variables constructed from 114 known genetic risk variants for CAD. Results In meta-analyses, higher fasting levels of GIP were associated with risk of higher total mortality (HR[95% CI] = 1.22 [1.11, 1.35]; p = 4.5 x 10(-5)) and death from CVD (HR[95% CI] 1.30 [1.11, 1.52]; p = 0.001). In accordance, 2SMR analysis revealed that increasing GIP concentrations were associated with CAD and myocardial infarction, and an additional reverse 2SMR revealed no significant effect of CAD on GIP levels, thus confirming a possible effect solely of GIP on CAD. Conclusions/interpretation In two prospective, community-based studies, elevated levels of GIP were associated with greater risk of all-cause and cardiovascular mortality within 5-9 years of follow-up, whereas GLP-1 levels were not associated with excess risk. Further studies are warranted to determine the cardiovascular effects of GIP per se.Peer reviewe