The liver plays a central role in the maintenance of homeostasis and health in general. However, there is substantial inter-individual variation in hepatic gene expression, and although numerous genetic factors have been identified, less is known about the epigenetic factors. By analyzing the methylomes and transcriptomes of 14 fetal and 181 adult livers, we identified 657 differentially methylated genes with adult-specific expression, these genes were enriched for transcription factor binding sites of HNF1A and HNF4A. We also identified 1,000 genes specific to fetal liver, which were enriched for GATA1, STAT5A, STAT5B and YY1 binding sites. We saw strong liver-specific effects of single nucleotide polymorphisms on both methylation levels (28,447 unique CpG sites (meQTL)) and gene expression levels (526 unique genes (eQTL)), at a false discovery rate (FDR) < 0.05. Of the 526 unique eQTL associated genes, 293 correlated significantly not only with genetic variation but also with methylation levels. The tissue-specificities of these associations were analyzed in muscle, subcutaneous adipose tissue and visceral adipose tissue. We observed that meQTL were more stable between tissues than eQTL and a very strong tissue-specificity for the identified associations between CpG methylation and gene expression. Our analyses generated a comprehensive resource of factors involved in the regulation of hepatic gene expression, and allowed us to estimate the proportion of variation in gene expression that could be attributed to genetic and epigenetic variation, both crucial to understanding differences in drug response and the etiology of liver diseases.

Large biobanks have set a new standard for research and innovation in human genomics and implementation of personalized medicine. The Estonian Biobank was founded a quarter of a century ago, and its biological specimens, clinical, health, omics, and lifestyle data have been included in over 800 publications to date. What makes the biobank unique internationally is its translational focus, with active efforts to conduct clinical studies based on genetic findings, and to explore the effects of return of results on participants. In this review, we provide an overview of the Estonian Biobank, highlight its strengths for studying the effects of genetic variation and quantitative phenotypes on health-related traits, development of methods and frameworks for bringing genomics into the clinic, and its role as a driving force for implementing personalized medicine on a national level and beyond.

Background: Interindividual differences in liver functions such as protein synthesis, lipid and carbohydrate metabolism and drug metabolism are influenced by epigenetic factors. The role of the epigenetic machinery in such processes has, however, been barely investigated. 5-hydroxymethylcytosine (5hmC) is a recently re-discovered epigenetic DNA modification that plays an important role in the control of gene expression. Results: In this study, we investigate 5hmC occurrence and genomic distribution in 8 fetal and 7 adult human liver samples in relation to ontogeny and function. LC-MS analysis shows that in the adult liver samples 5hmC comprises up to 1% of the total cytosine content, whereas in all fetal livers it is below 0.125%. Immunohistostaining of liver sections with a polyclonal anti-5hmC antibody shows that 5hmC is detected in most of the hepatocytes. Genome-wide mapping of the distribution of 5hmC in human liver samples by next-generation sequencing shows significant differences between fetal and adult livers. In adult livers, 5hmC occupancy is overrepresented in genes involved in active catabolic and metabolic processes, whereas 5hmC elements which are found in genes exclusively in fetal livers and disappear in the adult state, are more specific to pathways for differentiation and development. Conclusions: Our findings suggest that 5-hydroxymethylcytosine plays an important role in the development and function of the human liver and might be an important determinant for development of liver diseases as well as of the interindividual differences in drug metabolism and toxicity.

Factors such as age, pre-injury health, and injury severity, account for less than 35% of outcome variability in traumatic brain injury (TBI). While some residual outcome variability may be attributable to genetic factors, published candidate gene association studies have often been underpowered and subject to publication bias. We performed the first genome- and transcriptome-wide association studies (GWAS, TWAS) of genetic effects on outcome in TBI. The study population consisted of 5268 patients from prospective European and US studies, who attended hospital within 24 h of TBI, and satisfied local protocols for computed tomography. The estimated heritability of TBI outcome was 0·26. GWAS revealed no genetic variants with genome-wide significance (p < 5 × 10⁻⁸), but identified 83 variants in 13 independent loci which met a lower pre-specified sub-genomic statistical threshold (p < 10⁻⁵). Similarly, none of the genes tested in TWAS met tissue-wide significance. An exploratory analysis of 75 published candidate variants associated with 28 genes revealed one replicable variant (rs1800450 in the MBL2 gene) which retained significance after correction for multiple comparison (p = 5·24 × 10⁻⁴). While multiple novel loci reached less stringent thresholds, none achieved genome-wide significance. The overall heritability estimate, however, is consistent with the hypothesis that common genetic variation substantially contributes to inter-individual variability in TBI outcome. The meta-analytic approach to the GWAS and the availability of summary data allows for a continuous extension with additional cohorts as data becomes available. A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Acne vulgaris is a common chronic skin disorder presenting with comedones, cystic structures forming within the distal hair follicle, and in most cases additionally with inflammatory skin lesions on the face and upper torso. We performed a genome-wide association study and meta-analysis of data from 34,422 individuals with acne and 364,991 controls from three independent European-ancestry cohorts. We replicated 19 previously implicated genome-wide significant risk loci and identified four novel loci [11q12.2 (FADS2), 12q21.1 (LGR5), 17q25.3 (FASN), and 22q12.1 (ZNRF3-KREMEN1)], bringing the total number of reported acne risk loci to 50. Our meta-analysis results explain 9.4% of the phenotypic variance of acne. A polygenic model of acne risk variants showed that individuals in the top 5% of the risk percentiles had a 1.62-fold (95% CI 1.47–1.78) increased acne risk relative to individuals with average risk (20–80% on the polygenic risk score distribution). Our findings highlight the Wnt and MAPK pathways as key factors in the genetic predisposition to acne vulgaris, together with the effects of genetic variation on the structure and maintenance of the hair follicle and pilosebaceous unit. Two novel loci, 11q12.2 and 17q25.3, contain genes encoding key enzymes involved in lipid biosynthesis pathways.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in clinical practice. The pathogenesis of AF is linked to inflammatory reaction and oxidative stress, which leads to fibrosis of the atria and progression of the disease. The purpose of this study was to define the role of several biomarkers of inflammation, fibrosis, and oxidative stress (OxS). We included 75 patients with paroxysmal/persistent AF, who were admitted for electrical cardioversion or pulmonary vein isolation (PVI). High‐sensitivity C‐reactive protein (hsCRP), galectin‐3 (Gal‐3), myeloperoxidase (MPO), oxidized low‐density lipoprotein (oxLDL), and N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) were measured before the procedures. We compared the results with those of 75 healthy age‐, sex‐, and blood pressure‐matched individuals. The patients were followed up for 1 year after the intervention to establish the recurrence of AF and its association with the measured markers. Patients with AF had higher MPO (52.6 vs. 36.2 ng/ml, p < 0.001) and NT‐proBNP (209.0 vs. 28.0 pg/ml, p < 0.001) compared to healthy subjects. Also, they showed significantly higher levels of hsCRP (1.5 vs. 1.1 mg/l, p = 0.001) and Gal‐3 (11.4 vs. 9.7 mg/l, p = 0.003), while there was no difference found in oxLDL (71.5 vs. 71.7 U/l, p = 0.449). MPO (OR = 1.012, p = 0.014), hsCRP (OR = 1.265, p = 0.026), and weight (OR = 1.029, p = 0.013) were independently associated with AF in a multivariable logistic regression analysis. Patients with successful maintenance of sinus rhythm (SR) for one year had lower baseline MPO (40.5 vs. 84.3 ng/ml, p = 0.005) and NT‐proBNP (127.5 vs. 694.0 pg/ml, p < 0.001) compared to patients with recurrent AF episodes, but there was no difference in hsCRP, Gal‐3, or oxLDL between them. MPO (OR = 0.985, p = 0.010) was independently associated with AF recurrence during the follow‐up period when adjusted for cofounders. Patients with AF had increased markers of inflammation and fibrosis, while there was no increase detected in the OxS marker oxLDL. MPO was independently associated with AF in a multivariate model. Inflammatory and fibrotic mechanisms are important factors in electrical and structural remodelling progress in the atria of patients with AF.