Search

Non-alcoholic fatty liver disease (NAFLD) is a complex cardiometabolic disease associated with premature mortality. The diagnosis of NAFLD is challenging and the identification of biomarkers causally influenced by NAFLD may be clinically useful. We aimed at identifying blood metabolites causally impacted by NAFLD using two-sample Mendelian randomization (MR) with validation in a population-based biobank and a cohort of patients undergoing bariatric surgery. Our instrument for genetically-predicted NAFLD (the study exposure) included all independent genetic variants (n=7 SNPs) from a recent genome-wide association study on NAFLD. The study outcomes included 123 blood lipids, lipoproteins and metabolites measured in 24,925 individuals from 10 European cohorts. After correction for multiple testing, we identified a positive effect of NAFLD on plasma tyrosine levels but not on other metabolites. The association between NAFLD and tyrosine levels was consistent across MR methods and robust to outliers and pleiotropy. In observational analyses performed in the Estonian Biobank (10,809 individuals including 359 patients with NAFLD), after multivariable adjustment, tyrosine levels were positively associated with the presence of NAFLD (odds ratio per 1-SD increment = 1.23 (95% confidence interval = 1.12-1.36, p = 2.19e-05). In a sample of 138 patients undergoing bariatric surgery, compared to patients without NAFLD, blood tyrosine levels were higher in those with NAFLD, but were comparable among patients with or without non-alcoholic steatohepatitis. This analysis revealed a potentially causal effect of NAFLD on blood tyrosine levels, suggesting that blood tyrosine levels may represent a new biomarker of NAFLD.Graphical abstract

Objectives This study aimed to determine short- and long-term mortality, clinical determinants and causes of death in young patients with ischaemic stroke. Materials and methods We performed a hospital-based study of 18- to 54-year-old consecutive patients with ischaemic stroke, who were treated in the two largest hospitals in Estonia from 2003 to 2012. All cases were reviewed by the authors. Survival data and causes of death were obtained from the Estonian Population Registry and the Causes of Death Registry, respectively. Logistic regression and Cox proportional hazard models with backwards stepwise analysis were used to identify determinants of mortality. Results We identified 738 patients, of whom 124 died during the 5-year follow-up. Cumulative mortality rates at 30 days and 5 years were 4.5% (95% confidence interval [CI], 3.0%-6.0%) and 16.8% (95% CI, 14.1%-19.5%), respectively. The proportion of deaths due to vascular causes was 87.9% at 1 month and 54.6% at 5 years. Thirty-day mortality was independently associated with severe stroke, with a National Institutes of Health Stroke Scale (NIHSS) score >15, and post-stroke infections. The determinants of 5-year mortality were post-stroke infections, structural cardiac diseases and moderate stroke severity with NIHSS score of 7-15. Conclusion The mortality rate among young patients with ischaemic stroke in Estonia is higher than that reported in previous studies and is associated with increased stroke severity, post-stroke infections and structural cardiac diseases. These results emphasize the need for more effective preventive strategies in these patient groups.

Background: Observational studies have linked obesity and especially abdominal obesity to non-alcoholic fatty liver disease (NAFLD). These traits are also associated with type 2 diabetes (T2D) and coronary artery disease (CAD) but the causal factor(s) underlying these associations remain unexplored. Multivariable Mendelian randomization (MVMR) is a method that uses multiple genetic variants associated with traits of interest to simultaneously estimate the causal effect of each of these traits on outcomes of interest. Methods: We used a MVMR study design to determine whether obesity (defined using body mass index [BMI]) and abdominal obesity (defined using waist circumference) were causally associated with NAFLD using publicly available genome-wide association study (GWAS) summary statistics of the UK Biobank (n>450,000) and a GWAS meta-analysis of NAFLD (8434 cases and 770,180 control). A MVMR study design was also used to determine the respective causal contributions of waist circumference and NAFLD to T2D and CAD using GWAS summary statistics of the DIAGRAM (74,124 cases and 824,006 controls) and CARDIoGRAMplusC4D (122,733 cases and 424,528 controls) consortia.Results: In univariable Mendelian randomization analyses, both BMI and waist circumference were associated with NAFLD. NAFLD was not associated with obesity or abdominal obesity. In MVMR analyses, waist circumference was associated with NAFLD when accounting for BMI (OR per 1-standard deviation increase = 2.35 95% CI=1.31-4.22, p=4.1e-03) and BMI was not associated with NAFLD when accounting for waist circumference (0.87 95% CI=0.54-1.38, p=5.5e-01). In MVMR analyses accounting for NAFLD, waist circumference remained strongly associated with both T2D (2.65 95% CI=2.32-3.04, p=5.7e-45) and CAD (1.49 95% CI=1.37-1.62, p=8.3e-21).Conclusions: These results identified abdominal obesity as a strong, independent and causal contributor to NAFLD, T2D and CAD, thereby highlighting the importance of assessing body fat distribution for the prediction and prevention of cardiometabolic diseases.

Alterations of the gut microbiota, often referred to as gut dysbiosis, have been associated with several chronic diseases and longevity in pre-clinical models as well as in observational studies. Whether these relationships underlie causal associations in humans remains to be established. We aimed to determine whether gut dysbiosis influences the risk of chronic diseases and longevity using a comprehensive 2-Sample Mendelian randomization (2SMR) approach. We included as exposures inflammatory bowel disease (IBD) as a human model of gut dysbiosis, 11 gut-associated metabolites and pathways and 48 microbial taxa. Study outcomes included eight chronic diseases previously linked with gut dysbiosis using observational studies (Alzheimer’s disease, depression, type 2 diabetes, non-alcoholic fatty liver disease, coronary artery disease (CAD), stroke, osteoporosis and chronic kidney disease) as well as parental longevity and life expectancy. Neither IBD, nor gut-associated metabolites were causally associated with chronic disease or lifespan. After multiple testing correction for 582 tests, no microbial taxa-chronic disease associations remained significant. After robustness analyses and multivariate MR to correct for body mass index and alcohol intake on all 42 nominally significant causal relationships, four associations remained. Altogether, results of this multidimensional Mendelian randomization study suggest that gut dysbiosis has little impact on chronic diseases and human longevity and that previous documented associations may not underly causal relationships. Studies with larger sample sizes and more optimal taxonomic discrimination may ultimately be required to determine whether the human gut microbiota plays a causal role in the etiology of chronic diseases and longevity.

Background: Food neophobia is considered a behavioral trait closely linked to adverse eating patterns and reduced dietary quality, which have been associated with increased risk of obesity and noncommunicable diseases. Objectives: In a cross-sectional and prospective study, we examined how food neophobia is associated with dietary quality, health-related biomarkers, and disease outcome incidence in Finnish and Estonian adult populations. Methods: The study was conducted based on subsamples of the Finnish DIetary, Lifestyle, and Genetic determinants of Obesity and Metabolic syndrome (DILGOM) cohort (n = 2982; age range: 25-74 y) and the Estonian Biobank cohort (n = 1109; age range: 18-83 y). The level of food neophobia was assessed using the Food Neophobia Scale, dietary quality was evaluated using the Baltic Sea Diet Score (BSDS), and biomarker profiles were determined using an NMR metabolomics platform. Disease outcome information was gathered from national health registries. Follow-up data on the NMR-based metabolomic profiles and disease outcomes were available in both populations. Results: Food neophobia associated significantly (adjusted P

Background: There is lack of data on the incidence of Parkinson’s disease (PD) based on repeat studies. Mortality rates of PD in Estonia have never been studied before. Objectives: To estimate the incidence and mortality rates of PD in ­Estonia, to compare current incidence rates with those of the prior epidemiological study in Estonia, and to examine the reported causes of death of the study population. Methods: Eligible subjects were identified from multiple case-finding sources. Subjects were subsequently tracked on the Electronic-Health Record until either the end of the study, or their death. Incidence rates and standardized mortality ratios (SMR) were calculated. Causes of death were identified, based on the data from death certificates. Results: In the current study, the overall age-adjusted incidence rate was 28.0/100,000 person-years (95% CI 25.2–30.8). Compared with the previous study, the age-adjusted incidence rate inEstonia has not significantly changed (rate ratio 1.11; p = 0.19). Overall SMR for the inception cohort of PD cases with a median follow-up time of 5 years was 1.12 (95% CI 0.88–1.36; p = 0.3). For those deceased subjects known to have had clinically diagnosed PD, this was mentioned on 46.8% of death certificates. Conclusions: Over the last 20 years, the overall incidence of PD in Estonia has remained comparatively stable. The data did not show an excess mortality in PD patients (vs. general population) in the first 5 years of the disease.

ObjectiveTo conduct a comprehensive analysis of circulating metabolites and incident stroke in large prospective population-based settings.MethodsWe investigated the association of metabolites with risk of stroke in 7 prospective cohort studies including 1,791 incident stroke events among 38,797 participants in whom circulating metabolites were measured by nuclear magnetic resonance technology. The relationship between metabolites and stroke was assessed with Cox proportional hazards regression models. The analyses were performed considering all incident stroke events and ischemic and hemorrhagic events separately.ResultsThe analyses revealed 10 significant metabolite associations. Amino acid histidine (hazard ratio [HR] per SD 0.90, 95% confidence interval [CI] 0.85, 0.94; p = 4.45 × 10−5), glycolysis-related metabolite pyruvate (HR per SD 1.09, 95% CI 1.04, 1.14; p = 7.45 × 10−4), acute-phase reaction marker glycoprotein acetyls (HR per SD 1.09, 95% CI 1.03, 1.15; p = 1.27 × 10−3), cholesterol in high-density lipoprotein (HDL) 2, and several other lipoprotein particles were associated with risk of stroke. When focused on incident ischemic stroke, a significant association was observed with phenylalanine (HR per SD 1.12, 95% CI 1.05, 1.19; p = 4.13 × 10−4) and total and free cholesterol in large HDL particles.ConclusionsWe found association of amino acids, glycolysis-related metabolites, acute-phase reaction markers, and several lipoprotein subfractions with the risk of stroke. These findings support the potential of metabolomics to provide new insights into the metabolic changes preceding stroke.

Biological age (BA), a measure of functional capacity and prognostic of health outcomes that discriminates between individuals of the same chronological age (chronAge), has been estimated using a variety of biomarkers. Previous comparative studies have mainly used epigenetic models (clocks), we use ~1000 participants to create eleven omics ageing clocks, with correlations of 0.45-0.97 with chronAge, even with substantial sub-setting of biomarkers. These clocks track common aspects of ageing with 94% of the variance in chronAge being shared among clocks. The difference between BA and chronAge - omics clock age acceleration (OCAA) - often associates with health measures. One year’s OCAA typically has the same effect on risk factors/10-year disease incidence as 0.46/0.45 years of chronAge. Epigenetic and IgG glycomics clocks appeared to track generalised ageing while others capture specific risks. We conclude BA is measurable and prognostic and that future work should prioritise health outcomes over chronAge.

Non-alcoholic fatty liver disease (NAFLD) is a complex disease linked with several chronic diseases. We aimed at identifying genetic variants associated with NAFLD and evaluate their functional consequences. We performed a genome-wide meta-analysis of four cohorts of electronic health record-documented NAFLD in participants of European ancestry (8434 cases and 770,180 controls). We identified five potential susceptibility loci for NAFLD (located at or near GCKR, TR1B1, MAU2/TM6SF2, APOE, and PNPLA3). We also report a potentially causal effect of lower LPL expression in adipose tissue on NAFLD susceptibility and an effect of the FTO genotype on NAFLD that is likely explained by obesity. Positive genetic correlations between NAFLD and cardiometabolic diseases and risk factors such as body fat accumulation/distribution, lipoprotein-lipid levels, insulin resistance and coronary artery disease and negative genetic correlations with parental lifespan, socio-economic status and acetoacetate levels were observed. Altogether, this large GWAS meta-analysis revealed new insights into the genetic architecture of NAFLD. Funding: Part of this study was supported by the European Union through the European Regional Development fund. The work of Estonian Genome Center, Univ. of Tartu has been supported by the European Regional Development Fund and grants No. GENTRANSMED (2014-2020.4.01.15-0012), MOBERA5 (Norface Network project no 462.16.107) and 2014-2020.4.01.16-0125. This study was also funded by the European Union through Horizon 2020 research and innovation programme under grant no 810645 and through the European Regional Development Fund project no. MOBEC008 and Estonian Research Council Grant PUT1660. Ethical Approval: This study and the use of data from 4119 cases and 190,120 controls was approved by the Research Ethics Committee of the University of Tartu (Approval number 288/M-18).

Non-alcoholic fatty liver disease (NAFLD) has been associated with several blood biomarkers and chronic diseases. Whether these associations underlie causal effects remains to be determined. We aimed at identifying blood metabolites, blood proteins and human diseases that are causally impacted by the presence of NAFLD using Mendelian randomization. We created a NAFLD genetic instrument from NAFLD loci (MTARC1, GCKR, LPL, TRIB1, LMO3, FTO, TM6SF2, APOE and PNPLA3) identified in a new electronic health record based-GWAS meta-analysis (6715 cases and 682,748 controls). We found a potentially causal effect of NAFLD on tyrosine metabolism as well as on blood levels of eight proteins that could potentially represent new early biomarkers of NAFLD. Using results from the UK Biobank, FinnGen and the COVID-19 Host Genetics Initiative, we found that NAFLD was not causally associated with diseases outside the spectrum of liver diseases, suggesting that the resolution of NAFLD might not prevent other diseases.

Nutrition plays an important role in the development and progress of several health conditions, but the exact mechanism is often still unclear. Blood metabolites are likely candidates to be mediating these relationships, as their levels are strongly dependent on the frequency of consumption of several foods/drinks. Understanding the causal effect of food on metabolites is thus of extreme importance. To establish these effects we utilized Two-sample Mendelian randomization using the genetic variants associated with dietary traits as instrumental variables. The estimates of single-nucleotide polymorphisms’ effects on exposures were obtained from a recent genome-wide association study (GWAS) of 25 individual and 15 principal-component dietary traits, whereas the ones for outcomes were obtained from a GWAS of 123 blood metabolites measured by nuclear magnetic resonance spectroscopy. We identified 417 potentially causal links between food and metabolites, replicating previous findings, such as the association between increased oily fish consumption and higher DHA, and highlighting several novel associations. Most of the associations were related to very-low-density, intermediate-density (IDL) and low-density lipoproteins (LDL). For example, we found that constituents of IDL particles and large LDL particles were raised by coffee and alcohol while lowered by an overall healthier diet and fruit consumption. Our results represent one of the first examples of the estimates of long-term causal effects of diet on metabolites and start bridging the gap in the mechanistic understanding linking food consumption to its health consequences.

This study aimed to assess long-term, health-related quality of life (HRQOL) in a young ischemic stroke cohort, and to identify factors associated with poor HRQOL.We conducted a survey with ischemic stroke survivors in Estonia aged 18-54 years at the time of stroke, measuring HRQOL with the three-level version of the five-dimension EuroQol (EQ-5D-3L). The control group comprised the participants of the Health Behavior among Estonian Adult Population study. A tobit regression model with a backward stepwise analysis was used to identify factors associated with low EQ-5D-3L utility scores.In total, 352 patients with a mean follow-up time from the qualifying event of 5.7 years and 2304 controls were included. The mean EQ-5D-3L utility score in stroke survivors was significantly lower compared with that in the general population (0.71 vs. 0.87, respectively, p0.001). However, the subgroup with excellent functional outcome had a significantly higher mean EQ-5D-3L utility score compared with non-stroke counterparts (0.91 v 0.87, respectively, p0.001). The largest differences between stroke survivors and the general population were in the physical domains. Coronary heart disease at the index event, and higher follow-up duration, functional disability, depressive symptoms, recurrent stroke, and not being fully employed at follow-up, were independently associated with lower HRQOL.Young ischemic stroke survivors have long-term decreased HRQOL, except for those with excellent functional recovery. Our results prioritize motor rehabilitation and highlight the importance of secondary prevention, treatment of depression, and career counselling as potential ways of increasing HRQOL.

Objectives A previous epidemiological study of Parkinson's disease (PD) in the county of Tartu, Estonia, found an adjusted prevalence rate of 152/100 000 persons. We aimed to determine PD prevalence almost 20 years later, as well as evaluate any dynamic changes in disease frequency compared to the first study. Methods A cross-sectional, community-based study was conducted over 2010-2016 in the county of Tartu, Estonia. Multiple case-finding sources, including information from neurologists, family doctors, the local PD Society, nursing institutions, and the database of the Estonian Health Insurance Fund were used to identify patients with PD of all ages. Results Total crude PD prevalence was 283 and age-adjusted prevalence (standardized to the 2014 age structure of the Estonian population) 314/100 000. No significant differences in age-adjusted prevalence rates were found between men and women, nor people living in urban and rural areas. After adjustment to the same standard population used in the previous prevalence study, the overall age-adjusted prevalence rate was 197/100 000. Patients in the current study were older and often had a more severe form of PD and a longer disease duration, compared to those reported in the first epidemiological study 20 years ago. Conclusions The age-specific crude rates in oldest age-groups have risen substantially, and the age-adjusted prevalence has moderately increased compared to 20 years ago in Estonia. We hypothesize that the increased life expectancy of the Estonian population and improved diagnosis of PD contributed most to the increase in disease frequency.

Summary Non-alcoholic fatty liver disease (NAFLD) is a complex disease linked to several chronic diseases. We aimed at identifying genetic variants associated with NAFLD and evaluating their functional consequences. We performed a genome-wide meta-analysis of 4 cohorts of electronic health record-documented NAFLD in participants of European ancestry (8,434 cases and 770,180 controls). We identify 5 potential susceptibility loci for NAFLD (located at or near GCKR, TR1B1, MAU2/TM6SF2, APOE, and PNPLA3). We also report a potentially causal effect of lower LPL expression in adipose tissue on NAFLD susceptibility and an effect of the FTO genotype on NAFLD. Positive genetic correlations between NAFLD and cardiometabolic diseases and risk factors such as body fat accumulation/distribution, lipoprotein-lipid levels, insulin resistance, and coronary artery disease and negative genetic correlations with parental lifespan, socio-economic status, and acetoacetate levels are observed. This large GWAS meta-analysis reveals insights into the genetic architecture of NAFLD., Graphical abstract, Highlights This analysis identifies 5 genetic loci for non-alcoholic fatty liver disease Non-alcoholic fatty liver disease loci are GCKR, TR1B1, TM6SF2, APOE, and PNPLA3 Adipose tissue LPL expression may influence non-alcoholic fatty liver disease The FTO genotype may affect non-alcoholic fatty liver disease susceptibility, To gain insight into the genetic architecture of non-alcoholic fatty liver disease (NAFLD), Ghodsian et al. performed a genome-wide meta-analysis of electronic health record-documented NAFLD and identify 7 potential susceptibility loci for this disease (located at or near GCKR, TR1B1, LPL, FTO, MAU2/TM6SF2, APOE, and PNPLA3).

Objective To conduct a comprehensive analysis of circulating metabolites and incident stroke in large prospective population-based settings. Methods We investigated the association of metabolites with risk of stroke in 7 prospective cohort studies including 1,791 incident stroke events among 38,797 participants in whom circulating metabolites were measured by nuclear magnetic resonance technology. The relationship between metabolites and stroke was assessed with Cox proportional hazards regression models. The analyses were performed considering all incident stroke events and ischemic and hemorrhagic events separately. Results The analyses revealed 10 significant metabolite associations. Amino acid histidine (hazard ratio [HR] per SD 0.90, 95% confidence interval [CI] 0.85, 0.94; p = 4.45 × 10−5), glycolysis-related metabolite pyruvate (HR per SD 1.09, 95% CI 1.04, 1.14; p = 7.45 × 10−4), acute-phase reaction marker glycoprotein acetyls (HR per SD 1.09, 95% CI 1.03, 1.15; p = 1.27 × 10−3), cholesterol in high-density lipoprotein (HDL) 2, and several other lipoprotein particles were associated with risk of stroke. When focused on incident ischemic stroke, a significant association was observed with phenylalanine (HR per SD 1.12, 95% CI 1.05, 1.19; p = 4.13 × 10−4) and total and free cholesterol in large HDL particles. Conclusions We found association of amino acids, glycolysis-related metabolites, acute-phase reaction markers, and several lipoprotein subfractions with the risk of stroke. These findings support the potential of metabolomics to provide new insights into the metabolic changes preceding stroke.

Background: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of liver disease. Observational studies documented associations of NAFLD with several chronic and infectious diseases but whether these associations underlie causal effects is unknown. The molecular mechanisms and genetic architecture of NAFLD are poorly understood. Our objectives were to identify genetic loci associated with NAFLD and determine whether the presence of NAFLD was causally associated with human diseases. Methods: We created a NAFLD genetic instrument through the identification of independent single-nucleotide polymorphisms (SNPs) associated with NAFLD in a meta-analysis of genome-wide association study (GWAS) (6715 cases and 682,748 controls). Using inverse-variance weighted Mendelian Randomization (MR), we investigated the impact of NAFLD on human disease-related phenotypes in the UK Biobank and FinnGen cohorts as well as in the COVID-19 host genetics initiative. Results: We first performed a GWAS meta-analysis of four cohorts and found variants significantly associated with NAFLD (p800 diseases) using a genetic instrument for NAFLD. Results of these analyses suggest that NAFLD was not causally associated with diseases outside the spectrum of liver diseases. We also found no causal association between genetically predicted NAFLD and COVID-19-related outcomes. Conclusions: This study identified several new genetic loci associated with NAFLD. NAFLD was not causally associated with diseases outside those of the spectrum of liver diseases. This finding suggests that the resolution of NAFLD might not prevent other diseases previously associated with NAFLD.

Objectives Levodopa is the most effective therapy for treating Parkinson's disease (PD); however, side effects such as dyskinesias and motor fluctuations may occur after some years of its usage. The aims of this study were to assess the frequency of and factors associated with motor complications among PD patients on levodopa treatment. Methods In a cross-sectional study carried out in 2010–2013, clinical data and treatment details were collected. Logistic regression expressed by odd ratios (OR) and 95% confidence intervals (CI) was conducted to examine the effects of several independent variables on the occurrence of motor complications. Results A total of 455 patients were enrolled, among whom 374 were on levodopa. Analysis was performed in 328 patients whose exact duration of levodopa treatment was known. Among patients included in the analysis, 25.9% experienced motor complications; of these, 21% had dyskinesias and 20.1% had motor fluctuations. Based on logistic regression, statistically significant factors associated with the occurrence of motor complications were younger age at onset of the disease, higher levodopa equivalent daily dose (LEDD), shorter time to levodopa initiation, and akinetic-rigid dominant phenotype of PD. Conclusions This study suggests that postponing the start of levodopa therapy and maintaining low daily doses of levodopa might reduce the risk of motor complications. Our results confirm that due to higher risk of motor complications, effectively treating patients with akinetic-rigid dominant phenotype of PD might be more challenging than for patients whose dominant symptom is tremor.

Introduction. The purpose of this study was to demonstrate the frequency and severity of nonmotor symptoms and their correlations with a wide range of demographic and clinical factors in a large cohort of patients with Parkinson’s disease (PD).Methods. 268 PD patients were assessed using the validated Movement Disorders Society’s Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), the Beck Depression Inventory (BDI), Parkinson’s Disease Questionnaire (PDQ-39), the Hoehn and Yahr scale (HY), the Schwab and England Activities of Daily Living (SE-ADL) Scale, and the Minimental State Examination (MMSE).Results. Nonmotor symptoms had a strong positive relationship with depression and lower quality of life. Also, age, duration and severity of PD, cognitive impairment, daily dose, and duration of levodopa treatment correlated with the burden of nonmotor symptoms. Patients with postural instability and gait disorder (PIGD) dominance or with the presence of motor complications had higher MDS-UPDRS Part I scores expressing the load of nonmotor features, compared to participants with other disease subtypes or without motor complications.Conclusions. Though the severity of individual nonmotor symptoms was generally rated by PD patients as “mild” or less, we found a significant cumulative effect of nonmotor symptoms on patients’ mood, daily activities, and quality of life.