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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

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 Children who consistently withdraw from social situations face increased risk for later socioemotional difficulties. Twin studies indicate that genetic factors substantially account for the persistence of social withdrawal over time. However, the molecular genetic etiology of chronic courses of social wariness and preference for solitude, two dimensions of social withdrawal, remains undocumented. The objectives of the present study were (a) to identify high-risk trajectories for social wariness and preference for solitude in childhood and (b) to examine whether falling on these high-risk trajectories can be predicted by specific polygenic scores for mental health traits and disorders and by a general polygenic predisposition to these traits. Methods Teachers evaluated 971 genotyped children at five occasions (age 6 to 12 years) from two prospective longitudinal studies, the Quebec Newborn Twin Study and the Quebec Longitudinal Study of Child Development. Developmental trajectories for social wariness and preference for solitude were identified. We tested whether polygenic scores for attention deficit hyperactivity disorder, autism spectrum disorder, depression, loneliness, and subjective well-being, as well as a general mental health genetic risk score derived across these traits, were associated with the developmental trajectories. Results Polygenic scores differentially predicted social wariness and preference for solitude. Only the loneliness polygenic score significantly predicted the high trajectory for social wariness. By contrast, the general mental health genetic risk score factor was associated with the trajectory depicting high-chronic preference for solitude. Conclusions Distinct associations were uncovered between the polygenic scores, social wariness, and preference for solitude.

Background. Children who consistently withdraw from social situations face increased risk for later socioemotional difficulties. Twin studies indicate that genetic factors account for a substantial share in the persistence of social withdrawal over time. However, the molecular genetic etiology of chronic courses of social wariness and preference for solitude, two dimensions of social withdrawal, remain unexplored. The objectives were 1) to identify high-risk trajectories for social wariness and preference for solitude in the childhood years, and 2) to examine whether the assignment to these high-risk trajectories can be predicted by polygenic scores for mostly adult mental health traits and disorders and by a general polygenic predisposition to these traits. Methods. Teachers evaluated 1133 genotyped children at five occasions (age 6 to 12 years) from two prospective longitudinal studies, the Quebec Newborn Twin Study and the Quebec Longitudinal Study of Child Development. Developmental trajectories for social wariness and preference for solitude were identified. We tested whether polygenic scores for attention deficit hyperactivity disorder, autism spectrum disorder, depression, loneliness and subjective well-being, as well as a general mental health genetic risk score derived across these traits were associated with the developmental trajectories. Results. Polygenic scores differently predicted social wariness and preference for solitude. Only the loneliness polygenic score significantly predicted the elevated trajectory for social wariness. By contrast, the general mental health genetic risk score factor was associated with the trajectory depicting high and chronic preference for solitude. Conclusion. Distinct associations were uncovered between the polygenic scores, social wariness, and preference for solitude. These results point to multiple genetic processes underlying the development of social withdrawal, as well as the potential value of preference for solitude as an endophenotype for the later onset and persistence of mental health difficulties in adulthood.

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).

Few studies have examined the genetic and environmental pathways through which formal daycare attendance and school readiness are associated. The purpose of this study was to explore if daycare attendance could moderate genetic and environmental contributions to school readiness. A sample of 648 (85% White; 50% Female) pairs of twins was used to compute a GxE, CxE and ExE interaction analyses. Each standard deviation of formal daycare intensity (high number of hours per week), but not age of onset decreased the contribution of shared environment (-0.13) but not genes or unique environment to school readiness. The results support the hypothesis that daycare acts as a normalizing environment, possibly buffering the negative effects from low-quality home environments on cognitive abilities.

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).