cGEM - the Center for Genomics, Evolution and Medicine
01.09.2018 – 31.08.2023
The proposed ERA Chair – the Center for Genomics, Evolution and Medicine (cGEM) aims to apply advancements in genomic medicine in an evolutionarily-aware framework to account for different evolutionary pathways of populations which have led to differences in susceptibility to common diseases. This requires the knowledge about the genetic risk factors for diverse ethnic groups and the tools to highlight the underlying genetic predisposition to diseases in complex human populations. For this reason, we will bring together the scientific expertise in three institutions: the Estonian Biocentre (EBC) and the Estonian Genome Center (EGC) which will be consolidated to form the Institute of Genomics at University of Tartu (IGUT) in January 2018, and the Institute of Clinical Medicine (ICM). The synergy between the three scientific hubs will create the research capacity for tackling the abovementioned aim. This capacity will be built to apply a holistic approach to understand the evolutionary driving forces that have led to common diseases; develop disease risk prediction models applicable in different populations, and explore the means for translating these findings into suitable input for everyday clinical practice. For these purposes, we shall estimate the mutation rate across molecular pathways during the evolution, migration and mixing of the human populations, and study the roles of demographic history and local adaptation in the global patterns of mutation processes in humans exploring regional differences in the accumulation of mutations predisposing individuals to common complex diseases. the cGEM will utilize its international collaborations and in-house biobanks to advance the personalized medicine solutions for admixed populations for predicting risk of certain complex diseases, including metabolic and cardiovascular diseases, and cancers.
PRESICE4Q - Personalised Medicine by Predictive Modelling in Stroke for better Quality of Life
01.05.2018 – 30.04.2022
With PRECISE4Q we set out to minimise the burden of stroke both for the individual and for society. To that end we will create multi-dimensional data-driven predictive simulation computer models. This will - for the first time - enable personalised stroke treatment and address the needs of the patient in the stage of the disease (1. Prevention, 2. Acute treatment, 3. Rehabilitation, 4. Reintegration). Stroke is one of the most severe medical problems with far-reaching public health and socio-economic impact and will gather momentum in an ageing society. We will integrate heterogeneous input data from multidisciplinary sources: genomics/microbiomics, biochemical data; imaging data including mechanistic biophysiological models of brain perfusion/function; social, lifestyle and gender data; economic and worklife data. Data will be collected over a patient’s life and the models will enable the patient to report wellbeing, outcome and quality of life. PRECISE4Q will output different decision support systems depending on the life stage the patient is in. We will enable the user to optimise prevention and treatment strategies over time. We will provide coping strategies and support well-being and reintegration into social life and work. The predictive capability and clinical precision of PRECISE4Q will be validated with real clinical data generated by 1. prospective clinical studies and by 2. retrospective analyses of big data-sets such as health registries, cohort studies, health insurance data and electronic health records. PRECISE4Q will have a clinically measurable and sustainable impact and will lead to better understanding of risk, health and resilience factors. It will allow to measure impact of interventions on different scales and in different stages in a patient’s life. In contrast to current schematic therapy guidelines, PRECISE4Q will support the patient throughout his life-long journey by personalised strategies for his or her individual and specific needs.
PRG243 - Natural selection and migrations in shaping human genetic diversity in East European Plain. An ancient DNA study
Recent developments in the field of ancient DNA are revolutionizing our understanding of the evolutionary and demographic processes that have shaped modern human genetic diversity and relationships between genes and phenotypic traits including disease. However, there is a big gap in aDNA sampling in the vast area of the East European Plain. Here we shall fill this gap by sequencing >400 aDNA samples together with relevant stable isotope analyses. This will enable us to reconstruct the complex population history not only from the genetic ancestry point of view but also shedding light on social structure and mobility, diet and health condition through the Mesolithic to Iron Age. We shall reveal the evolutionary paths of genetic variants associated with increased or decreased disease risk. These results will have direct impact on the theoretical basis of the developing Personalized Medicine in Estonia and the openness of the society as a whole.
druggable-MI-genes - Utilising myocardial infarction genes for better treatment
01.09.2018 – 31.08.2021
Andres Metspalu, Tarmo Annilo
Only one-third of the 90 loci identified for coronary artery disease (CAD) through genome-wide association studies (GWAS) are associated with traditional cardiovascular risk factors indicating that our understanding of mechanisms leading to atherosclerosis is substantially incomplete. Our consortium aims to unravel molecular alterations of loci shown by GWAS to increase CAD risk, but are currently not addressed for prevention and therapy. By integrating multi-tissue gene expression and RNA-sequence from several studies (e.g., STARNET) with the globally leading consortium of GWAS on CAD (CARDIoGRAM), we will first identify genes/transcripts underlying genetic risk variants of both myocardial infarction (i.e., unstable plaques) and stable CAD. Next, we will identify molecular contexts of these genes/transcripts in target tissues/cell-types, gene-networks and pathways within these; aiming to identify so-called key disease drivers. Furthermore, molecular mechanisms of plaque stability/instability already partly characterized by the applicants will be further scrutinized for options of therapeutic interventions. Finally, translation to human pathophysiology will be achieved by interrogating unique biobanks of human atherosclerotic plaque material as well as population-based samples of up to 500,000 individuals with genome-wide data and in-depth phenotypic characterization for better recognition of individuals at risk. The overall aim of druggable-MI-genes is to lay the foundation for a more precise and genomics-based prevention of coronary atherosclerosis and plaque stability.
M2T2D - The interplay between gut microbiota and metformin treatment in type 2 diabetes
01.09.2018 – 31.08.2021
European Molecular Biology Organization grant
Gut microbiome have clear impact on modern metabolic diseases such as type 2 diabetes (T2D), obesity and metabolic syndrome. The gut microbiome is shaped by several factors arising from the host (genetics) and environment (diet, lifestyle, drug treatments etc), which in turn has a huge impact on our health. During the last years, I have explored host- gut microbiota interactions in cardio-metabolic traits in mice and human and showed how dietary and host genetic interactions control gut microbiome and influence host phenotypes. I will expand my previous research by exploring how the gut microbiome influences drug metabolism and nutrition. I will focus on pharmacology of metformin, commonly used drug for T2D treatment and study how the gut microbiota interaction with bile acid metabolism influences metformin metabolism and commonly observed side effect – gastrointestinal problems. To do so, I will utilize two human cohorts in this project. First is the METSIM population cohort collected by Dr. Markku Laakso, University of Kuopio, Finland, which consists of 10,000 men, that have been characterized in great detail for metabolic syndrome traits as well as for gut microbiota, metabolites, sequence variation and gene expression in adipose. Second is the Estonian Biobank cohort (around 52,000 participants) with detailed clinical and molecular datasets. In order to gain more comprehensive view of host-microbial interactions, I will employ systems-genetics approach by integrating microbiome data with available metabolomics and genomics datasets.
EnGage - Enhancing Psychiatric Genetic Counselling, Testing, and Training in Europe
17.09.2018 – 16.09.2022
COST- action grant no CA17130
Andres Metspalu, Eero Vasar
The Action Enhancing Psychiatric Genetic Counselling, Testing, and Training in Europe (EnGagE) aims to strengthen pan-European research into the newly emerging disciplines of Psychiatric Genetic Counselling (PsyGC) and Psychiatric Genetic Testing (PsyGT); and to develop a framework to facilitate the implementation of both disciplines into routine clinical care.
Psychiatric disorders are common, with estimated life-time risks of around 1-3 % for schizophrenia, bipolar disorder, and major depressive disorder. The last decade has witnessed major advances in psychiatric genetics. Currently, no form of valid, high certainty diagnostic PsyGT is available in routine clinical practice. However, in view of recent genetic findings (particularly the identification of pathogenic copy number variants that are associated with high risks for schizophrenia), major efforts to establish such testing are now underway. The publication of the major advances in psychiatric genetics have received wide media coverage and awareness among patients and their family members of the role of genetics in psychiatric disorders is growing. An increased demand for high-quality information on psychiatric genetics likely provided in the form of PsyGC, is anticipated.
EnGagE is a knowledge-sharing and expertise-enhancing network comprising preclinical and clinical researchers from the fields of neuroscience, psychiatric genetics, psychosocial research, and ethics; clinicians from the fields of psychiatry, psychology, and medical genetics; genetic counsellors, and scientists from diagnostic genetic testing laboratories from Europe and beyond. EnGagE will establish a framework for PsyGC and PsyGT; develop standardised guidelines, practice recommendations and research protocols; share scientific knowledge and data and provide standardized training in PsyGC and PsyGT.
NIH – GIANT - Biological Insights from Genetic Investigation of ANthropometric Traits (GIANT) Across the Allelic Spectrum
15.08.2017 - 31.07.2022
Boston Childrens Hospital
We focus on deciphering the genetic basis of obesity and of adult height. Obesity is an enormous public health problem with no safe and effective therapies that foretells a future epidemic of diabetes, cardiovascular disease, cancer, and early death. Understanding the specific genetic and biological factors that control susceptibility or resistance to obesity will provide crucial clues that can guide the design of new, critically-needed interventions and therapies. Adult height is the endpoint of childhood growth, a fundamental developmental process and marker of childhood health, but is also the classic model polygenic trait because it is highly heritable and easily measured. As such, studying height has facilitated the development (by us and others) of genetic and computational methods that have been applied broadly to other polygenic traits and diseases.
Aim 1. Perform the largest GWAS to date, using >1.5 million deeply imputed samples from multiple ancestries, focused on measures of obesity and height. Within the GIANT framework, we will coordinate the generation of and perform the meta-analysis of deeply imputed GWAS data, to find associated variants not discoverable in previous GWAS. We will provide infrastructure for imputation to deep reference panels (including the haplotype reference consortium panel), and perform QC and meta-analysis of association data.
Aim 2. Assemble and analyze data from >100,000 exome and whole genome sequences to discover low frequency and rare variants, coding and noncoding, that influence measures of obesity and height. We will make available infrastructure/software for sequence processing, variant calling and analysis. We will QC and perform meta-analysis of single variant associations and gene-based tests of rarer coding variants.
Aim 3. Integrate the association results from common and rare/low-frequency variants, and use complementary data sets to implicate causal genes and biological processes. We will use the GWAS results to guide association tests of aggregations of rare noncoding variants from sequence data. We will also use integrative computational methods – developed, tested and/or refined using height – to interpret the association results for obesity. We will use expression, metabolite, epigenetic, and other genomic data to prioritize genes, gene sets, regulatory elements and metabolites as likely causal contributors to obesity.
MOBTT53 - Unravelling the Estonian genome: the whole is greater than the sum of its parts
Mobilitas Pluss top researcher grant
Recent advances in the field of ancient human genetics showed that the gene pool of Estonians, as elsewhere in Europe, is the sum of various evolutionary histories that met in the region after the Ice Age. Each of these human groups, however, carried different genetic variants with potentially different consequences on the physiology and genetic makeup of modern Estonians. With the present project the whole genome sequences of 2500 modern Estonians recently generated at the Estonian Genome Centre will be subdivided into their ancestral components. These components will be screened for their burden of genetically causative variants (from a catalog of GWAS and literature hits). Given the uniqueness of modern Estonian genomes, this approach will shed light on the evolutionary basis that form the present disease burden in the region. The proposed approach will also be extended to other European populations and the demography history of the various ancestral components traced.
GEIGHEI - Gene-Environment Interplay in the Generation of Health and Education Inequalities
01.03.2018 – 28.02.2021
NORFACE, Estonian Research Council
We will examine how Genes and the Environment (GxE) interact to generate inequalities in education and health over the life course. We will go beyond the old nature versus nurture debate by testing two novel hypotheses: (i) children born into advantaged environments are better able to reach their genetically conditioned education potential, and (ii) a privileged environment protects against genetic susceptibility to risky health behaviour. Both hypotheses propose a GxE interplay that influences the transition from early childhood (theme 1) to adulthood (theme 2, 3) in periods that are critical to the generation of inequalities. We innovate by combining methods from genetics and social science. Building on the discovery of genetic variants that exhibit robust associations with behavioural outcomes and the recent availability of large datasets with information on both environments and genes, we will grasp unprecedented opportunities to fill the gap in knowledge about the combined role of genes and environments in causing inequality. By taking account of the endogenous, multifaceted and dynamic nature of the environment, the research promises a sustained impact by identifying policy interventions that ameliorate inequalities. For example, we will test whether high-quality child care can overcome genetic disadvantage in educational attainment. Four young core researchers with emerging track records in advancing understanding of inequalities in education and health will supervise junior researchers, and benefit from the committed support of world-leading experts in (i) the genetics of education, (ii) genetic epidemiology, (iii) (neuro-)biological psychology, (iv) socioeconomic health inequalities and (v) econometrics.
PRG184 - Role of Rare and Common Genetic Variants in Adverse Drug Reactions
Lili Azin Milani
Despite recent advances in pharmacogenomic research, interindividual variability in drug metabolism and sensitivity for drug toxicity persists as a major problem for drug treatment. Recent research has highlighted the large extent of rare variants in genes with importance for drug metabolism. The aim of this study is to create a catalogue of common and rare genetic variants related to suboptimal drug metabolism and adverse drug reactions (ADRs) in the Estonian and Swedish populations. This will be achieved using genome sequences of 5000 and genotype data of 50,000 individuals combined with extensive health records regarding drug prescriptions and ADR diagnoses. The identified gene-ADR associations will be tested using functional studies. The results will serve as a basis for variants that can be included for pre-emptive pharmacogenomic testing, which could ultimately reduce the health and economic burden of low drug efficacy and unnecessary side effects caused by genetic variants.
Point Lab - Population Intelligence Lab
01.01.2018 – 31.12.2018
It is difficult for entrepreneurs to get reliable and valid information on potential users of their innovation. The data captured in large citizen and patient population cohorts and accompanying biorepositories could be very useful in this perspective. These rich bigdatasets contain business intelligence in all of EIT Health’s challenges. However, not (yet) in formats accessible, or useable for the business development oriented questions of entrepreneurs and business developers. To promote the use of data from these cohorts and biorepositories we will develop procedures, methods and apply techniques to make this intelligence available in compliance to rules of using such privacy sensitive data, and tailored to the type of questions raised in innovative business. Point-lab hereby addresses the cross challenges of EIT Health, namely, removing barriers to innovation and leveraging enabling technologies and exploiting big data, by making this service available for SMEs and startups.
i-Days - Innovation Days
01.01.2018 – 31.12.2018
Merike Leego/ Merit Kreitsberg
Innovation Days will encourage and promote health innovation amongst students. Students will receive an introduction to practical health innovation tools and work in multidisciplinary teams to tackle real life health challenges in healthy living and active ageing. The 2016 and 2017 i-Days provided training and inspiration to hundreds of students in three CLCs. In 2018 we wish to scale these i-Days to include students from all EIT Health CLCs and strengthen the i-Days network across Europe.
EIT Health Product/Market Fit
01.01.2018 – 31.12.2018
The Product/Market Fit program is intended to support European digital health and medtech start-ups that are ready to launch their solutions in other European countries outside of their home market. Start-ups get customized guidance upon market entry barriers in the country of their choice being Belgium, France, Germany, Estonia, Spain, Sweden, The Netherlands or United Kingdom.
estPerMed I - Clinical pilot projects of personalised medicine in the precise prevention of breast cancer and cardiovascular diseases
01.01.2018 – 31.12.2020
Estonian Research Council
We propose to carry out a pilot project with two types of diseases using principles of personalised medicine. One project is the implementation of a model for personalised risk-based breast cancer screening, early detection and prevention. The study is aimed to demonstrate the usability of personalised approach for adjusting screening recommendations, based on predicted genetic and cumulative risk estimates for breast cancer including both the detection of moderate and high hereditary breast cancer risk carriers as well as high risk polygenic risk score carriers among healthy individuals. The other project is the implementation of a model for personalised prevention of cardiovascular diseases (CVD) and mortality.
The project is aimed to demonstrate the usability of personalised approach for stratification, adjusting screening recommendations, based on predicted genetic and cumulative risk estimates for CVD among healthy individuals by risk factors calculation and genetic testing.
PUT1701 - Elucidation of the role of Tribbles homolog 3 (TRIB3) in the cellular stress response and normal physiology
TRIB3 is a mammalian gene that is strongly upregulated in response to several types of cellular stress, such as endoplasmic reticulum stress, oxidative stress and nutrient deprivation. TRIB3 functions by forming protein–protein interactions that affect the activity of its binding partner, and through such interactions, TRIB3 is involved in the regulation of cell death, differentiation, inflammation and metabolism. We have previously shown that TRIB3 acts as a negative feedback regulator of ATF4, a central stress response transcription factor. To further understand co-repressor action of TRIB3, we propose to investigate the regulatory interplay between transcriptional activators and TRIB3 during cellular stress, including analysis of chromatin binding sites of TRIB3-containing complexes at a genome-wide level. Our group and others have recently unveiled a role for TRIB3 in blood cell development, and in the current project we will also continue to study TRIB3 in hematopoietic cells.
ESKO - PUT1660 - Utilizing special human populations to quantify the impact of rare DNA sequence variants in human health
01.01.2017 – 31.12.2020
Project aims to build a unique resource for the study of human genetics by focusing on a country with special advantages for the genetic study of common diseases. Estonia has semi-isolated population features and a large biobanks linked to medical information that together enable unique approaches. Most of the genetic discoveries so far has been limited on common DNA variants, which have revealed novel insights to human biology but only explain a fraction of trait variance in a population. It is proposed that rare alleles, both coding and noncoding, could close the cap of missing heritability. Profiling of rare alleles requires whole genome sequencing, which still proves to be too expensive to achieve necessary power for association testing. Current project proposes to develop long range haplotyping based imputation framework which allows cost efficient imputation of whole sequence data into array based genotyped endogamous cohort, and rare variant analysis in a large sample.
NB! Acknowledging grant support in research papers: "This research was supported by the Estonian Research Council personal research grant PUT1660"
FISCHER - PUT1665P - Genetic and epidemiological predictors for all-cause and cause-specific mortality in the Estonian population
01.01.2017 – 31.12.2020
Estonia ranks high among other EU countries with respect to mortality before the age of 70, especially in males. There is a need for in-depth analysis of the determinants of early mortality, to identify the potential public health measures that could efficiently increase life expectancy in this country. The population-based cohort of the Estonian Genome Centre, University of Tartu (52000 individuals) is one of the best available databases for such study due to detailed recruitment questionnaire and follow-up information from electronic databases, with 8.2 years of median follow-up time by the beginning of 2017. The primary objective of this study is to identify main risk factors for all-cause mortality and their effect sizes. To understand the causal pathways leading to mortality, the effects of genetic risk scores for known complex diseases and behavioral risk factors on mortality will be estimated. In addition, other molecular biomarkers will be asessed for the effect on mortality.
NB! Acknowledging grant support in research papers: "This research was supported by the Estonian Research Council personal research grant PUT1665P"
ORG - PUT1371 - The interplay between gut microbiota and metformin treatment in type 2 diabetes through bile acid metabolism
01.01.2017 – 31.12.2020
The mechanisms of action of metformin, the most commonly used anti-diabetic drug, are still poorly understood. Recent studies have shown altered gut microbiota in type 2 diabetes patients as well as changes of gut microbiota and bile acid pool upon metformin treatment. These findings implicate that our gut microbiota could have profound impact on metformin pharmacology and efficiency. During my postdoctoral studies we showed that common gut anaerobe, Akkermansia muciniphila, was associated with both metabolic effects as well as with changes in bile acids. Interestingly, metformin treatment also increases A. muciniphila frequency. The current proposal aims to investigate the impact of A. muciniphila and other gut microbial communities on pharmacology of metformin and its possible mechanism through bile acid metabolism. In addition, we will explore the role of gut microbiota in some of the commonly observed metformin's side effects.
NB! Acknowledging grant support in research papers: "This research was supported by the Estonian Research Council personal research grant PUT1371"
Detectin-HF - DETERMINING THE ROLE OF CLINICAL AND EPI-GENETIC RISK MARKERS IN DILATED CARDIOMYOPATHIES AND HEART FAILURE
ERA-CVD grant (Joint transnational call 2016)
Andres Metspalu, Maris Alver
Dilated cardiomyopathies (DCM) represent a major cause for heart failure (HF), especially in the young. Although it is estimated that 30-50% of all DCM cases are caused by a genetic predisposition, the precise mechanisms that underlie the variations in disease susceptibility and phenotype presentation including risk for HF development or sudden cardiac death (SCD) are virtually unknown.
To improve treatment and prognosis of DCM as a major cause for HF, there is an urgent need to improve early disease detection, to establish common standards for phenotyping and to adequately predict risk in patients and their relatives. Efforts thus far, however, have concentrated mostly on smaller studies, single centers or national efforts at best.
The DETECTIN-HF consortium aims to improve this situation by applying selected clinical and molecular markers in a multi-center, multi-national cohort. To enable true translation in the field, the consortium aims at three major tasks: 1) Harmonization of existing national registries to foster trans-national research on DCM. 2) To investigate the clinical value of selected IP-protected biomarker candidates, genotypes and gender in this large-scale cohort and 3) to develop and validate a personalized risk model for development of HF and SCD in DCM patients.
By creating a single data portal and harmonization of clinical workflows, a facility arises that is unprecedented in scale and setup and that is invaluable for research and improved clinical practice. The here established resources shall be available early for other research consortia within the ERA-CVD framework.
CliniMARK - 'Good biomarker practice' to increase the number of clinically validated biomarkers.
H2020 COST action grant no CA16113 (call: OC-2016-1)
Krista Fischer, Toomas Haller
Thousands of circulating proteins have been shown to be hallmarks of emerging disease, response to treatment, or a patients’ prognosis. The identification of these small molecule biomarkers holds a great promise for significant improvement of personalized medicine based on simple blood tests. For instance, diagnosis and prognosis with biomarkers (e.g. carcinoembryonic antigen (CEA)) has significantly improved patient survival and decreased healthcare costs in colorectal cancer patients. Unfortunately, despite significant investments to increase the number of biomarker studies, only ~150 out of thousands of identified biomarkers have currently been implemented in clinical practice. This is mainly caused by the time-consuming process of reliably detecting biomarkers, the irreproducibility of studies that determine a biomarkers’ clinical value, and by a mismatch in studies that are performed by academia and what is required for regulatory and market approval. To increase the number of clinically validated biomarkers, rather than further increasing the number of biomarker discovery studies, CliniMARK will improve the quality and reproducibility of studies and establish a coherent biomarker development pipeline from discovery to market introduction.
CliniMARK aims to achieve said goal by creating a BestBiomarker Practice (BBP) community, which will provide guidance to:
Classify biomarkers according to their characteristics, anticipated clinical use, and their phase of development, Select and validate appropriate research-grade biomarker detection tests, Select appropriately designed studies and biological samples to reliably and reproducibly validate biomarkers clinically, and Select and report on appropriate clinical data storage, biomarker data storage, data analysis protocols, privacy concerns, ethical issues, and statistical analysis methods.
CliniMARK, will establish a high-quality collaborative pan-European network consisting of multidisciplinary experts active in protein biomarker discovery, biomarker feasibility studies, and biomarker assay development and clinical validation. The experts in CliniMARK will establish ‘good biomarker practice’ guidelines for biomarker measurement and clinical feasibility studies, and apply these guidelines to biomarkers of COPD.
ASTRA - Tartu Ülikooli ASTRA projekt PER ASPERA
November 2016 – August 2022
Andres Metspalu, Maris Väli-Täht, Allen Kaasik
The project focusses on strengthening the core laboratories of University of Tartu through further development and modernization of equipment base and furnishing possible laboratory workspaces for cooperation opportunities with businesses.
The wider aim of the project is to develop uniform competence centre on the basis of existing core laboratories, which would ensure the sustainable development of existing technologies. The action therefore unites upgrading of infrastructure, databases and development of operational competence. The ultimate goal is to provide the highest level of know-how for businesses and health care sectors.
Roadmap ELIXIR Estonia - A Distributed Infrastructure for Life-Science Information
ELIXIR is a component of the European infrastructure roadmap concerning different life science data and IT infrastructure. http://www.elixir-europe.org/ ELIXIR Eesti is a full member of this infrastructure which also provides services as part of the ELIXIR infrastructure (www.elixir.ut.ee). Two components of the roadmap of Estonian research infrastructures are directly or indirectly connected to the project: the Estonian Scientific Computing Infrastructure and the Estonian Genome Centre (BBMRI). The lead partner of the project is the University of Tartu (UT) and the main partner is the Tallinn University of Technology (TUT). Additional partners of ELIXIR Eesti are the Estonian Biocentre, NICPB, the Competence Centre for Cancer Research, the Software Technology and Applications Competence Centre, the University of Tallinn and other institutions producing and using biological data (regarding DNA, RNA, other molecules, biological pathways etc.) ELIXIR is intended for use by all life scientists (in molecular biology, medicine, green, red and white biotechnology, genetics etc.). The use of ELIXIR is global, not bioinformatics-centred. ELIXIR Eesti is currently in the development phase, i.e. the first basic services are available, but ELIXIR Eesti is responsible for bringing them into accordance with the rules of the infrastructure. ELIXIR is planned as an international consortium. A draft of the international consortium agreement has been drawn up, applications for the partner nodes of ELIXIR have been submitted. ELIXIR Eesti is prepared to initiate a hiring process for maintaining and developing the infrastructure services (the main tools are already finished and made public, they are in regular use).
ASTRA Ultrasensitiivne biomolekulide labor ja moodne populatsioonigeneetika
Projekti on kaasrahastatud Euroopa Liidu Regionaalaregnu Fondist
Projektile eraldatud toetus on 1 404 974 eurot
Projekti eesmärk on EBK ja Eesti teaduse rahvusvahelise konkurentsivõime tõstmine geenitehnoloogia alal. Loome ülikõrge sensitiivsusega biomolekulide analüüsi labori ning kaks uut teadusgruppi. Esimene neist keskendub vanadest proovidest DNA eraldamise, rikastamise ja sekveneerimise tehnoloogiate arendamisele.Teise teadusgrupi fookuses on moodsate populatsioonigeneetika meetodite väljatöötamine ja rakendamine. Paranevad nii õppe- kui teadustöö kvaliteet ning tõuseb koostöö maht ettevõtlusega.
PUT1217 - Temporal dynamics of population structure in the territory of present Estonia - synthesis of data from ancient and contemporary genomes
This project takes a qualitative step in our interdisciplinary effort to shed light on the demographic history of Estonians, making use of ancient DNA (aDNA) studies that are in the state of revolution at the moment. Based on our experience in human population genomics and archaeogenetics in general, and on our preliminary results in the planned work in particular, we will study aDNA of Estonian Neolithic human remains with a focus on Combed Ceramics and Corded Ware cultures, hopefully including Mesolithic as a baseline. We aim for genetic documentation of putative long-distance movements of humans in this part of Europe, their directionality and extent and role in shaping the present-day genetic variation. By sequencing even a few archaeologically well-characterized samples and comparing the results to our in-house extensive reference base of extant genetic variation in Eurasia, we will be able to reveal key moments in the genetic aspects of ethnogenesis of the Estonians.
PUT1339 - Deciphering the human past across East European populations
European region holds its important position in our understanding of how humans have spread across the globe and shaped the observed today genotypic, phenotypic and cultural diversity. In this project we will generate new and use available empirical data on uniparental and whole genome sequence variation in modern and published ancient West Eurasians to address key problems in the demographic history of Europeans: early stages of peopling of Europe with the focus on its eastern region; Neolithic in East Europe (extent of its effect on the genetic architecture); region-scale patterns of admixture, their temporal and spatial characteristics.
Eesti Genoomikakeskus II /Estonian Center of Genomics/Roadmap II (project No. 2014-2020.4.01.16-0125)
January 2016- August 2022
Andres Metspalu, Maris Väli-Täht
As a result of the project, the infrastructure of the Estonian Center of Genomics will be fully developed. The project will be carried out by the Estonian Genome Center of the University of Tartu (EGCUT) and Estonian Biocentre. The EGCUT will participate in the activities of BBMRI-ERIC infrastructure (the European Consortia of Biobanks) fulfilling the obligations of the Estonian node.
GENTRANSMED - Genoomika-ja siirdemeditsiini TIPPKESKUS – Centre of Excellence for Genomics and Translational Medicine
January 2016 – March 2023
Funding from the European Regional Development Fund (ERDF) for the development of CoEs
Head of the CoE: Andres Metspalu
Project Manager: Maris Väli-Täht
The CoE for Genomics and Translational Medicine aims to translate discoveries in the field of genomics into improved understanding of molecular mechanisms of disease. The new interdisciplinary environment of the CoE makes it possible to interpret and rapidly utilize data produced by cutting edge omics technologies. The Centre will explore genetic and biolological mechanisms of disease by 1) investigating DNA sequence variants that contribute to disease through large scale genomic screens, and 2) using molecular and cellular bology techniques complemented by the use of animal models to study their role in disease. This offers an exciting platform for discovering important biological mechanisms that contribute to disease. The outputs of the project are anticipated to unravel processes underlying complex disease, identify new therapeutic targets and enable development of new approaches for disease prevention and precision medicine that will have a major impact in Europe and globally.
NB! Acknowledging grant support in research papers: "This research was supported by the European Union through the European Regional Development Fund (Project No. 2014-2020.4.01.15-0012)".
ePerMed - Rise of scientific excellence and collaboration for implementing personalised medicine in Estonia
January 2016 – December 2018
EU H2020 grant no. 692145
Andres Metspalu, Merike Leego, Merit Kreitsberg
Emerging personalised medicine initiatives have the perspective to cut healthcare costs and improve the overall health of the population. Taking into account the individual’s molecular characteristics complemented by environmental and lifestyle factors, will allow to develop more precise and improved disease prevention and treatment programs compared to conventional methods. As an example of potential for personalised medicine, an estimated 90% of drugs are effective in only 30-50% of the population, which means that more than a third of all money spent on drugs has been ineffective. Research opportunities provided by the unique sources of EGC-UT Biobank, nation-wide Electronic Medical Records systems and the Estonian National Personal Medicine Pilot project can be effectively translated into improved understanding of disease etiopathologies and clinical benefit through early diagnosis, risk stratification, treatment and management. The ePerMed project is aimed at increasing the scientific excellence of EGC-UT in the fields of functional and statistical genomics of common and rare diseases by capitalising on knowledge transfer from two internationally renowned partners in the field of human and medical genomics – UNIL-CIG in Switzerland and UH-FIMM in Finland. As a foreseen result of the ePerMed project, EGC-UT will have the capacity to move from the current research on the genome-wide association studies to advanced research of disease mechanisms and to public health benefits through early diagnosis, reliable risk stratification and improved treatment strategies. Ultimately, this will enable EGC-UT to deliver effective personalised medicine across several clinically relevant phenotypic traits and diseases.
NB! Acknowledging grant support in research papers: "This research was supported by the European Union through Horizon 2020 grant no. 692145"
EIT – Health EIT Knowledge and Innovation Community (KIC) grant
January 2016 – December 2018
Andres Mestpalu, Merike Leego
Mission of EIT Health is to promote entrepreneurship and develop innovations in healthy living and active ageing, providing Europe with new opportunities and resources. EIT Health will enable citizens to lead healthier and more productive lives by delivering products, services and concepts that will improve quality of life and contribute to the sustainability of healthcare across Europe. EIT Health is a strong, diverse and balanced partnership of best-in-class organisations in education, research, technology, business creation and corporate and social innovation. InnoStars – a unique concept for widening participation and outreach across Europe – will establish new ties for innovation and growth. EIT Health will foster cooperation and unlock Europe’s innovation and growth potential – developing and retaining the best talents, creating high-quality jobs and boosting the global competitiveness of European industry.
NB! Acknowledging grant support in research papers: “The activities were funded from EU grant EIT-Health by European Institute of Innovation & Technology”
ADOPT BBMRI-ERIC - implementAtion anD OPeration of the gateway for healTh into BBMRI-ERIC
August 2015 – Decembre 2018
EU H2020 grant no 676550
BBMRI-ERIC: the Biobanking and BioMolecular resources Research Infrastructure - European Research Infrastructure Consortium, aims to establish, operate and develop a Pan-European distributed research infrastructure in order to facilitate the access to biological resources as well as facilities and to support high quality biomolecular and biomedical research. The ADOPT BBMRI-ERIC proposal aims at boosting and accelerating implementation of BBMRI-ERIC and its services. Its main deliverables are designed to complete or launch the construction of key Common Services of the Research Infrastructure as required for ESFRI-projects "under implementation", reflecting the targets of the European Research Area (ERA). One of the challenges in the post-genomic era is the research on common complex diseases, such as cancer, diabetes and Alzheimer’s disease. Revealing these diseases will depend critically on the study of human biological samples and data from large numbers of patients and healthy individuals. The EU’s ageing population is will result in an increase in many of those diseases and consequently an increased healthcare expenditure for senior citizens. BBMRI-ERIC is a specific European asset having become a fundamental component in addressing the ongoing and future requirements particularly of Europe's health service frameworks, including competitiveness and innovativeness of healthrelated industries. Its implementation is essential for the understanding of the diversity of human diseases, biological samples and corresponding data, which are required for the development of any new drug or diagnostic assay and are, therefore, critical for the dvancement in health research, ultimately leading to personalised medicine. BBMRI-ERIC will provide a gateway access to the collections of the European research community, expertise and services building on the outcome of ADOPT BBMRI-ERIC.
NB! Acknowledging grant support in research papers: "This research was supported by the European Union through Horizon 2020 grant no. 676550"
CORBEL - Coordinated Research Infrastructures Building Enduring Life-science services
August 2015 – July 2019
EU H2020 grant 654248
The social and economic challenges of ageing populations and chronic disease can only be met by translation of biomedical discoveries to new, innovative and cost effective treatments. The ESFRI Biological and Medical Research Infrastructures (BMS RI) underpin every step in this process; effectively joining scientific capabilities and shared services will transform the understanding of biological mechanisms and accelerate its translation into medical care. Biological and medical research that addresses the grand challenges of health and ageing span a broad range of scientific disciplines and user communities. The BMS RIs play a central, facilitating role in this groundbreaking research: interdisciplinary biomedical and translational research requires resources from multiple research infrastructures such as biobank samples, and resources from multiple research infrastructures such as biobank samples, imaging facilities, molecular screening centres or animal models. Through a user-led approach CORBEL will develop the tools, services and data management required by cutting-edge European research projects: collectively the BMS RIs will establish a sustained foundation of collaborative scientific services for biomedical research in Europe and embed the combined infrastructure capabilities into the scientific workflow of advanced users. Furthermore CORBEL will enable the BMS RIs to support users throughout the execution of a scientific project: from planning and grant applications through to the long-term sustainable management and exploitation of research data. By harmonising user access, unifying data management, creating common ethical and legal services, and offering joint innovation support CORBEL will establish and support a new model for biological and medical research in Europe. The BMS RI joint platform will visibly reduce redundancy and simplify project management and transform the ability of users to deliver advanced, cross-disciplinary research.
NB! Acknowledging grant support in research papers: "This research was supported by the European Union through Horizon 2020 grant no. 654248"
Ageing with elegans - Validating C. elegans healthspan model for better understanding factors causing health and disease, to develop evidence based prevention, diagnostic, therapeutic and other strategies
May 2015 – Aprill 2020
EU H2020 grant no 633589
Healthspan (the life period when one is generally healthy and free from serious disease) depends on nature (genetic makeup) and nurture (environmental influences, from the earliest stages of development throughout life). Genetic studies increasingly reveal mutations and polymorphisms that may affect healthspan. Similarly, claims abound about lifestyle modifications or treatments improving healthspan. In both cases, rigorous testing is hampered by the long lifespan of model organisms like mice (let alone humans) and the difficulty of introducing genetic changes to examine the phenotype of the altered genome. We will develop C. elegans as a healthspan model. Already validated extensively as an ageing model, this organism can be readily modified genetically, and effects of environmental manipulations on healthspan can be measured in days or weeks. Once validated as a healthspan model, it can be used for an initial assessment of preventive and therapeutic measures for humans, as well as for risk identification and the initial evaluation of potential biomarkers. It will also prove useful to study interactions between genetic and various environmental factors.
NB! Acknowledging grant support in research papers: "This research was supported by the European Union through Horizon 2020 grant no. 633589"
TÕNISSON – PUT736 - Circulating DNA as a biomarker of lung cancer/Tsirkuleeriv DNA kopsuvähi biomarkerina
Jaanuar 2015 – detsember 2018
Personal Research grant from Ministry of Education and Research
This translational genomics project is planned for the analysis of mutations and DNA epimutations in the circulating cell-free DNA (cfDNA) of non-small cell lung cancer (NSCLC) patients. In perspective, the developed methods can be further utilised in other types of malignancies. It is known that the blood plasma of cancer patients contains cfDNA originating from tumour that may be detected already in its early stages. At first, the project includes cfDNA analysis of actionable and potentially actionable mutations, hopefully in genome-wide scale. We will also validate in the cfDNA of lung cancer patients the methylation biomarkers with a potential diagnostic and prognostic utility that were discovered in our previous study. In addition, we will perform a genome-wide study for the potential early biomarkers from the cfDNA of the blood donors in the Estonian Genome Cente biobank, who were later diagnosed with lung cancer.
NB! Acknowledging grant support in research papers: "This research was supported by the Estonian Research Council personal research grant PUT735"
IUT24-1 - The dawn of whole genomic era in archaeogenetics
The research planned under this proposal is best classified as archaeogenetics: we wish to understand the genesis of the extant human genetic diversity. The “event horizon” of our research lies beyond the birth of anatomically modern humans (AMH) as a species, yet our main aim is to contribute to the genetic reconstruction, in space and time, of the colonization of the world by AMH by serial expansions and recessions, adaptations and admixture events. Our study draws ideas from, and we trust that also contributes to, archaeology and history in general, ethnology and linguistics, palaeoclimate research etc. It thus develops in an essentially trans-disciplinary environment, though remains methodologically a branch of population genetics. As such, it is tightly linked to the current trends in human genomics. We have been active in this field since late 90-ies. Here we plan a profound step ahead by establishing our archaeogenetic research on the basis of whole genome analysis.
IUT20-60 Omics for health: an integrated approach to understand and predict human disease
January 2014 – December 2019
EU Social Fund support through Estonian Research Council
The Estonian Biobank (EBB) was developed to study how genomics together with transcriptomics, epigenomics, metabolomics, environmental factors and lifestyle influence human health, and how this knowledge can be applied in precision medicine. We have divided the work of 23 researchers into 5 workpackages which all aim to apply OMICS information to human health questions from different angles. In WP1 we will assay and evaluate the impact of rare genetic variation in the Estonian population. WP2 uses a systems-genomics approach to understand biological pathways that lead to disease by combining SNP, gene expression and metabolomics data. WP3 focuses on application of OMICS in obesity by studying constitutionally thin individuals from the EBB. WP4 studies normal epigenetic variation and its application for early non-invasive detection of disease. WP5 will use the information generated by WP1-4 combined with available literature for personalized risk prediction of common complex diseases. NB! Acknowledging grant support in research papers: "This research was supported by the EU Social Fund through Estonian Research Council research grant IUT20-60 "
IUT24-6 Tuumiktaristu: Estonian Centre for Genomics
January 2014 - December 2019
EU Social Fund support for core facilities through Estonian Research Council
The Estonian Genomics Centre was established on 15 June 2010, incorporating the core laboratory of the Estonian Biocentre and the Estonian Genome Centre of the University of Tartu. The aim of the project is to bring the field of genomics in Estonia to a qualitatively new level in a technological, computational and infrastructural sense. The core infrastructure of the Estonian Genomics Centre is open to both the academic and private sector in Estonia and abroad. It is aimed to offer possibilities of application for scientists from diverse fields, incl. genetics and medicine, and guaranteeing access to quality data and offering world class sequencing and genotyping services. The Estonian Genome Centre of the University of Tartu is a research and development institution whose infrastructure includes the following complexes: the biobank and the unit for the release of biological material; the genotyping and sequencing core facility; the IT department with servers and databases.
NB! Acknowledging grant support in research papers: "This research was supported by the EU Social Fund support for core facilities through Estonian Research Council research grant IUT24-6"
STACC EU48684 - Technologies for Information Extraction, data integration and management
The aim of STACC is to engage in research and development in the field of software technologies and applications, in cooperation with the Research Partners and the Business Partners, as well as other scientific research establishments and companies.
The aim of sub-project 4.1 is
Q1 Achieve better natural language processing of medical free texts
Q2 Automating information extraction processes
Q3 Develop methods for medical data storage and analysis
Q4 Develop future Business opportunities
NIASC - The Nordic Information for Action eScience Center
January 2014 – December 2018
Nordic Centres of Excellence, NeGI NCoE eScience in Health and social preconditions for health grant no. 62721
There is a need to develop computer-based tools to manage and analyse data from the health registries and biobanks. Such eScience tools would enhance the ability to calculate disease risk and provide a basis for customising health care services while increasing the efficiency and precision of both diagnostics and treatment. The objective of the Nordic Information for Action eScience Centre is to develop computer-based tools that allow easier tracking of Nordic biobank samples and data and enhance the capability to use data from national health registries and biobanks in the health care sector. The new tools are to be put into practice via a pilot project for improved, more cost-effective cancer screening programmes. The centre emphasises the importance of ethical aspects of these tools and will engage in widespread dissemination to the public in order to increase the transparency of research that draws upon biobanks and registries. NB! Acknowledging grant support in research papers: "This research was supported by the Nordic Centres of Excellence grant no. 62721"
ECHC - Estonian Connected Health Cluster
September 2015 - August 2018
EAS grant no EU49305
Call: Klastrite arendamise programm
Estonian Connected Health Cluster (ECHC) is committed to accelerate the adoption of connected health solutions, at scale on commercial terms. ECHC is part of the European Connected Health Alliance and ScanBalt network which helps to accelerate global access for the Estonian cluster members. ECHC involves 40+ health companies (startups, health IT, medtech, biotech and pharma), R&D partners and user groups (hospitals, GPs, sportsmen, spas, quantified self people). Cluster focus on the following competence fields: products and connected services improving healthier lifestyle, sports, wellness, prevention, prognostics, diagnostics, cure and rehabilitation.
BioAge Labs - Understanding molecular signatures for human aging and all-cause mortality
March 2016 – February 2018
Collaboration agreement with BioAge Labs Inc., USA
Goal of the project is identification of biomarkers of healthy aging, mortality, and age-related diseases. After completion of the Research, BioAge intends to use the Results to profile metabolomes of Estonian Biobank subjects, and to use various statistical and machine learning approaches to determine which individual biomarkers, and combinations of individual biomarkers, associate significantly with various outcomes relevant to healthy aging using follow-up data for the profiled subjects.
DocuMental - digital support system for mental health
01.03.2017 – 30.11.2017
Connected Health Cluster
Andres Metspalu, Eduard Maron
Estonian Genome Center is a partner of Connected Health Cluster (CH) - a permanent, mutually beneficial partnership between stakeholders in Estonia, who are committed to accelerating the adoption of connected health solutions, at scale on commercial terms. The aim of the Connected Health Cluster is:
• to impact healthier life and improve patient care
• to provide economic growth through the adoption of connected health solutions
• to accelerate global access for the Estonian cluster members
Our vision is to transform healthcare services through the implementation of connected health solutions. By encouraging innovation through entrepreneurship and providing a collective forum for connected health advocates, CH brokers solutions for these challenges, thereby creating financial efficiencies for Estonian government and ultimately helping healthcare providers to deliver quality care for people, patients and families in Estonia and internationally. Connected Health Cluster has got 60+ partners, which includes 43 companies (startups, health IT, biotech), R&D partners and need partners, i.e. hospitals, GPs, big Pharma, spas, sportsmen, etc.
Within Connected Health cluster, Estonian Genome Center is a partner in a joint development project „DocuMental“. The activities of the project are carried out in cooperation with North Estonia Medical Center, lead partner Documental and Tallinn University of Technology. The Project is co-financed by the European Regional Development Fund in total amount of 29 900€.
The project will develop a documental electronic support system, which is a decision-making support system for mental health diagnosis and treatment services. The support system will help reduce medical errors, improve mental health management, reduce the time spent by the specialist for initial assessment of condition and to improve the correct implementation of clinical guidelines in clinical practice. The support system also allows to raise the quality of the patient consultation and the time spent. The system will help to improve the patient's involvement in the treatment process, enabling a better exchange of information between the patient and the medical team and allowing the patient to monitor their treatment plan, and psychiatric status.
Best Ageing - Biomarker Research Alliance for Diagnosing Heart Disease in the Ageing European Population
February 2012 – 1st of February 2018
EU FP7 grant no 306031
Andres Metspalu, Tarmo Annilo
The ageing of the European population represents a growing health care problem. In particular, cardiovascular diseases show a marked increase with age and have remained the leading cause of morbidity and mortality in the elderly. Unfortunately, cardiovascular disorders and their associated risks are often difficult to diagnose in the elderly due to many age-related confounders and co-morbidities, leading to substantial uncertainties in diagnostic classification and therapeutic decision making with huge impact on patients’ outcomes. Hence, there is an unmet need for novel biomarkers to enable a more accurate diagnosis, sub-classification, risk assessment, and treatment guidance for both acute and chronic cardiovascular diseases in the elderly. The BestAgeing consortium aims to improve this unsatisfactory situation by developing and validating novel omics-based biomarkers that may complement or substitute traditional biomarkers for more accurate or earlier diagnosis, better risk assessment, and appropriate guidance of therapies, overcoming limitations inherent with traditional biomarkers – supporting healthy ageing in Europe. www.bestageing.eu
BBMRI-LPC - Bio banking and Biomolecular Resources Research Infrastructure-Large Prospective Cohorts
February 2013 – November 2017
EU FP7, grant no 313010
Andres Metspalu; Merike Leego, Annely Allik
This project unites the large study sets of the European Biobanking and Biomolecular Research Infrastructure (BBMRI) and the International Agency for Research on Cancer (IARC), thus achieving a worldwide unique scale of integration. Specifically, we aim to: 1) Evaluate/improve the harmonization of individual data on health, lifestyle and other exposures; 2) Develop/implement harmonized definitions of diseases; 3) Improve biobanking and research technologies and develop innovative solutions facilitating high-quality, fair access to samples and data; 4) Provide free transnational access by users, through study proposals selected by an open, pan-European call; 5) In the framework of these studies, generate and provide access to whole genome sequences, transcriptome, proteome, metabolome and methylome data; 6) Build new public-private partnerships involving large-scale prospective cohorts, and strengthening existing ones, allowing transparent industrial access to academic expertise; 7) Build a network transferring the expertise of established European large-scale biobanks to new biobank initiatives under development in other countries.
NB! Acknowledging grant support in research papers: "This research was supported by the European Union through FP7 grant no 313010"
CHIP ME - Citizen's Health through public-private Initiatives: Public health, Market and Ethical perspectives
November 2013 - November 2017
FP7 ISCH COST Action grant no IS1303-271113-07872
Andres Metspalu, Merike Leego
The falling cost of genome sequencing is making genetic information more easily accessible to the ordinary citizen. The proliferation of different actors in COST countries and beyond, engaging with the generation and interpretation of genetic data represents a tremendous opportunity but also a new challenge for society. The public health care system will increasingly be asked to provide interpretation and counselling relating to genetic information that has been generated privately and to satisfy the legitimate curiosity of participants in large-scale population genetic research. Existing ethical and regulatory frameworks may not be suitable to allow an efficient and ethical meeting of demand and supply of genetic knowledge and health, as well as a virtuous interaction between public and private actors. This Action aims to improve the state of the art by creating a community of researchers and stakeholders and linking existing initiatives which bring critical expertise in bioethics, social studies of science and technology, genetic technology, information and communication technology (ICT Information and Communication Technologies - A COST Domain), stakeholder deliberation, and patient centred initiatives (PCI). www.chipme.eu. NB! Acknowledging grant support in research papers: "This research was supported by the European Union through FP7 ISCH COST Action grant no IS1303-271113-07872"
NIH-BMI - Candidate Gene Studies of Obesity Guided by Whole Genome Association Data
July 2012 – July 2017
NIH, Department of Health and Human Services, Public Health Services, USA, grant no. 2R01DK075787-06A1
Andres Metspalu, Tõnu Esko
Aim of the project is to investigating the genetic basis of obesity by applying the data from genome wide association analyses in a candidate gene approach. Over the five years, the University of Tartu investigators will select, plate and transfer 1,000 samples to Boston, including 250 samples each from the top and bottom 1% of the BMI (which is the proxy to obesity), stratified by gender. University of Tartu investigators will assemble, curate and share phenotype data on these samples with the Boston group, receive sequencing and genotyping data, and participate in the analysis of the genotype and phenotype data. University of Tartu investigators will also provide expert input on the Estonia Biobank cohort phenotype data and epidemiologic considerations relevant to analysis of these data. NB! Acknowledging grant support in research papers: "This research was supported by the USA Department of Health and Human Services, Public Health Services grant no. 2R01DK075787-06A1"
BroadNext10 - Towards Genomic-Based Prevention of Sudden Cardiac Death
NIH, Department of Health and Human Services, Public Health Services, USA
January 2016 – March 2017
Andres Metspalu, Tõnu Esko
More than 8 million individuals worldwide die suddenly from cardiac causes each year. For a substantial fraction, including 50% of those with myocardial infarction, the initial presenting symptom is death. Four diseases - myocardial infarction, heritable arrhythmias, cardiomyopathies, and aortic dissection - mainly contribute to premature sudden cardiac death (SCD), and more than 50 genes have been identified with high penetrance mutations in them. Moreover, each of these four diseases has an associated preventive therapy for prospectively identified patients. As such, genome-based risk prediction is particularly attractive for this condition, as the outcome is lethal, effective interventions are available, and there is uncertainty about who should receive them.
The proposed study is specifically focused on Familial Hypercholesterolemia (FH) as a cause of premature sudden cardiac death within the Estonian population. We envision that it will serve as the pilot for downstream philanthropic and NIH funding that would expand this effort to both other etiologies of SCD, as well as other populations. In this proposal, we seek to construct a systematic framework for FH proband screening, molecular diagnosis, and family cascade screening within the Estonian population. Estonia has a nationwide healthcare system that utilizes a single EHR system. It has also established a national Biobank that currently contains ~50,000 patients and growing, and it is interested in utilizing this resource to enable translational work in clinical genomics.
January 2016 – December 2017
Estonian Research Council Mobilitas+ grant
Support grant for EIT Health Knowledge and Innovation Community (KIC) grant
JJ Pilot (VP1GV16402) - Pilot study to obtain an overview of available genotypic and phenotypic information in the biobank database
in collaboration with Janssen Research & Development LLC
The feasibility study will provide a report on data availability and technical requirements for three main objectives: 1) characterize genetic variations associated with Diabetes Mellitus Type 1 (T1D) in the Estonian GeneBank population 2) identify and characterize individuals with or at -risk of T1D; 3) evaluate feasibility of recruiting their siblings and children in potential observatonal or interventional study.
MIBIOandCMD - Gut microbiota, choline metabolites and cardiometabolic diseases
September 2013 – August 2016
FP7 Marie Curie International Outgoing Fellowships (IOF) grant no 330381
Common forms of cardiovascular diseases are exceptionally complex, where several genetic and lifestyle/environmental factors are involved. The discovery of different risk factors will be crucial for prevention of these high mortality diseases. Metabolomic studies have broaden our understanding of cardiovascular phenotypes and have created possibility to find new biomarkers for disease risk prediction. Recently a targeted metabolomic study indentified a novel mechanism through which gut-flora and hepatic-mediated metabolism of dietary choline contributes to the development of cardiovascular disease. This study demonstrated that higher plasma levels of choline and two of its metabolites, trimethylamine N-oxide (TMAO) and betaine, are associated with atherosclerosis in humans and mice. The current proposal aims to study the role of choline metabolites in cardiovascular and metabolic traits and to examine microbial role in this process. The possible role of choline-derived metabolites in perturbation of cardiometabolic phenotypes will be determined using well-characterized metabolic and cardiovascular-targeted samples. The second part of the project aims to study the role of gut flora in choline metabolic pathway. We will use different approaches in order to identify specific group(s) of intestinal bacteria responsible for the formation of TMA(O) from dietary choline. In summary, the results of the study will provide important insights into the mechanism by which novel metabolite-gut flora interplay contributes to the regulation of cardiovascular system.
Nestle – Genomic and Metabolomic study to identify factors implicated in resistance to weight gain
July 2013 – June 2016
Andres Metspalu, Reedik Mägi
Research Agreement between Nestle Institute of Health Sciences SA (NIHS) and Estonian Genome Center of the Tartu University (EGCUT) for Genomic and Metabolomic study to identify factors implicated in resistance to weight gain.
CTG - Center of Translational Genomics
March 2011 – March 2016
Development Fund of the University of Tartu
The activities of the project are focused on discovering the genetic, epigenetic, transcriptomic, proteomic and metabolomic components lying behind common and complex diseases. The project will facilitate a systemic approach to the translation of genetic information from the DNA variations to the metabolic variations including also the RNA, epigenetic and proteomic levels.
PerMed I - Personaalse meditsiini pilootprojekt "Eestlaste genoomivarieeruvuse andmebaasi loomine"
January 2015 – August 2015
Andres Metspalu, Merike Leego
Käesoleva projekti eesmärk on määrata kogu-genoomi järjestus maksimaalsel arvul geenidoonoritel, mis eraldatavad vahendid võimaldavad, et luua esinduslik andmebaas Eesti populatsioonis esinevast geneetilisest varieeruvusest. Projekt on fundamentaalse tähtsusega inimese genoomika valdkonnas ja lisaks sellele on see oluliseks eelduseks personaalse meditsiini pilootprojekti rakendamisele, mis on ka vabariigi valitsuse üheks eesmärgiks.
TAP 48-2- Upgrade of the instrumentation in the pan-university core facility for genotyping and sequencing services
January 2014 - January 2015
EU structural Fund support through Archimedes Foundation, grant no. 3.2.0302.13-0551
Andres Metspalu, Maris Väli-Täht
Projekti eesmärgiks on sekveneerimiskeskuse aparatuuri kaasajastamine, mille raames hangitav aparatuur on TÜ ja teiste teadusasutuste ülese nõudlusega. Laiemaks eesmärgiks on Eesti teadus- ja arendustegevuse koostöö- ja konkurentsivõime tõstmine biotehnoloogia valdkonnas läbi kaasaegse infrastruktuuri arendamise. Projekt toetab kõrge infrastruktuurse ja teadusliku tasemega tuumiklabori edasist arendamist, mis on oluliseks toeks biotehnoloogia arengule ettevõtlussektoris ning selle kasutamisele kliinilises meditsiinis.
Sekveneerimiskeskuse tuumiklabori poolt pakutav kiire ja kompetentne geenianalüüsi teenus andmete tootmiseks ja nende statistiliseks ning bioinformaatiliseks töötlemiseks on avatud nii akadeemilisele kui erasektorile Eestis ja välismaal. Seoses diagnostilise sekveneerimisega mida Eesti Haigekassa planeerib lülitada nende poolt pakutavate teenuste hinnakirja, on tekkinud vajadus soetada pipeteerimisrobot, mis võimaldab automatiseerida tuumiklaboris olemasolevate Illumina sekvenaatorite jaoks proovide ettevalmistamise aeganõudvat ja töömahukat tööprotsessi.
Fischer ETF - Causal inference methodology for studies involving conventional and Mendelian randomization
January 2012 - December 2015
Estonian Research Foundation grant no ETF9353
Randomized Clinical Trial is a standard study design when the aim is to draw causal conclusions. Typically such design is used to assess the effect of medical treatment or another intervention. In the presence of non-adherence (not all randomized individuals receiving their assigned treatment), standard statisticsl tests are not able to produce estimates for the actually received treatment. In such cases, instrumental variables estimation methods are recommended - using the random treatment assignment as an instrument, they are able to estimate parameters with causal interpretation. At the same time they require certain, often untestable, assumptions to be valid. One of the purposes of the proposed project is to compare the underlying assumptions and levels of interpretability and generalizability of different Instrumental Variables estimation approaches (such as Principal Stratification, Structural Mean Models) in the context of practical studies (Estonian Postmenopausal Hormone Therapy Trial, the EVAR/UK trial on comparison of surgical interventions to treat Abdominal Aortic Aneurysm). Another task is to assess existing methodology and develop new methods for instrumental variables estimation when the outcome is measured as a censored time-to-event variable. The second broad research area for the planned project is to study, to what extent are the causal inference methods for randomized controlled trials applicable in studies using "Mendelian randomization". These are cohort or case-control studies where the exposure of interest can be predicted by a certain gene marker. If this gene marker is not knowingly directly associated with the outcome of interest, the data structure will resemble that of a randomized controlled trial and the marker can be used as an instrument. There are also some important differences with the randomized trial - unlike the treatment assignment, the gene marker itself is not a modifiable intervention. We plan to apply the ideas of mendelian randomization on the data of Estonian Genome Center, University of Tartu, assessing the effect of epidemiologic risk factors to incidence of cardiovascular diseases and mortality. In the resulting publications the assumptions and generalizability of the analysis will be formally assessed and new methodology will be developed to analyze time-to-event outcomes. In addition, software packages will be created to implement the methodology.
MILANI ETF - In-depth genetic and epigenetic analyses of genes involved in drug metabolism by next-generation sequencing
January 2012 – December 2015
Estonian Research Foundation grant no ETF9293
Lili Azin Milani
The aim of this research project is to identify genetic and epigenetic signatures that control interindividual variation in drug metabolism and response. We will use ultra high-throughput sequencing technology to identify novel genetic and epigenetic variation in regulatory and protein coding regions of major genes involved in drug absorbtion, distribution, metabolism and excretion. We will study a unique collection of Caucasian liver samples, which have been extensively phenotyped for the activity and expression levels of different drug metabolizing enzymes. The identified variants will be further examined in samples from the Estonian Genome Center to verify their frequency and effect in a wider population. If successful, our approach will reveal previously unknown genetic variants associated with drug metabolism, which can be applied as pharmacogenetic markers to design optimal treatment for patients.
TEEKAART - Estonian Centre for Genomics
April 2011- December 2015
Estonian and European Research (infrastructure) Roadmap grant no 3.2.0304.11-0312
Merike Leego, Ene Mölder, Andres Metspalu
The ability to analyse and understand genomes is one of the key prerequisites for advancement of medicine and biology. To secure sustainable development of genomics in Estonia we create the Estonian Centre for Genomics (ECG). This follows the ESFRI – BBMRI - ERIC development plan of the EC. The ECG aims to provide the growing Estonian R&D with the emerging new tools and a large biobank of 50 000 subjects for genome analyses. This is instrumental both for successful international cooperation in science and applications in the practice of medicine. The three key objectives of the ECG are: a) To upgrade the existing genotyping and sequencing core facilities to the level of European expert centres in the context of ERIC and ensure their sustainable development in future. In doing so we will build comprehensive technological platform for life sciences in general which shall be matched with the respective investment in computational capabilities. b) To ensure the constant development of the EGC biobank as one of the cornerstones of the ECG by regular follow-up of their health status of the gene donors and assembling high density SNP maps and full genome sequences. c) To coordinate and participate in scientific endeavours on Estonian, European and world-wide levels, to contribute into training of young scientists and to participate in projects together with entrepreneurs.
TIPPKESKUS – Centre of Excellence in Genomics
January 2008 – December 2015
Funding from EU European Regional Development Fund for the development of CoEs
Andres Metspalu, Maido Remm
The Centre of Excellence in Genomics is based on three workgroups from Estonian Biocentre and University of Tartu, with its focus on basic and applied research of human as well as other genomes. The main objective of this consortium is to achieve, through dedicated collaboration, an added value, to be materialized and manifested in high-level scientific publications, enhanced international collaboration, creation of intellectual property and promotion of entrepreneurship in biotechnology. A particular goal will lie in applications in healthcare and in enhancement of the value of Estonian Biobank as a valuable national asset. It is an interdisciplinary research consortium with a scope extending from creating tools to analyse genomic, proteomic and metabolomic information and search for "disease genes", to the understanding of the origin of genetic structure variation in humans.
BiomarCaRE - Biomarker for Cardiovascular Risk Assessment in Europe
October 2011 - September 2015
FP7-HEALTH-2011.2.4.2-2, grant no 278913
Andres Metspalu, Maris Alver
Biomarkers are considered as tools to enhance cardiovascular risk estimation. Based on harmonised and standardised European population cohorts we have built significant research collaboration, expertise and infrastructure in the EU to apply highly innovative technologies and perform large-scale biomarker determination to assess the predictive value of existing and emerging biomarkers. Selection of emerging biomarkers will be based on integrated cutting-edge quantitative proteomic, transcriptomic, metabolomic, and miRNomic datasets. Existing biomarkers will be selected based on non-redundancy and their association with cardiovascular risk and phenotypes. The developed assay will be validated to their impact on risk prediction, their association with lifestyle determinants and cardiovascular phenotypes assessed by ultrasound and MRI technique will be evaluated. www.biomarcare.eu
EUSARNAD - Joint European and South African Research Network in Anxiety Disorders
October 2011 – September 2015
FP7-PEOPLE-2010 (Marie Curie Actions—International Research Staff Exchange Scheme IRSES) grant no 269213
The overall aim of our proposal is to build on the strengths of an existing European network for research into causes and maintaining factors in anxiety disorders and to extend these by establishing firmer research collaboration with the University of Cape Town in South Africa. Through establishing this research exchange, we aim to share knowledge and expertise among participating centres, and ensure a comprehensive translational research approach in anxiety disorders, relevant to the needs of developed and developing societies. The exchange scheme has three broad objectives. First, to develop a collaborative international database for the detailed characterisation of large samples of patients, across the range of anxiety disorders. Second, to provide exchange researchers with a range of complementary training opportunities, gaining experience in innovative investigations in anxiety disorders. Third, to establish a firm platform to support subsequent pragmatic randomised effectiveness trials in patients who have not responded to previous treatment interventions.
IndiMed - Implementation of Individualized Medicine: Education, Prediction and Treatment
January 2012 – August 2015
EU structural support through Archimedes Foundation, grant no: 3.2.1001.11-0033
Andres Metspalu, Krista Fischer
The general goal of the project is to assess the impact of the implementation of individualized medicine on disease prevention and treatment outcomes in Estonia.
SOTSMIN - Secure storage of all Estonian Genome Center tissue samples and data, establishing the prerequisites and guarantees for the long-term maintenance and usability of the samples and data
January 2005 – December 2014
Target financing from Estonian Ministry of Education and Science, grant no. SP1GVSO
EuroEPINOMICS - Genetics of rare epilepsy syndromes (RES)
June 2011 - May 2014
ESF grant, EUROCORES program
Andres Metspalu, Tiina Talvik, Eva Reinmaa, Margit Nõukas
This Collaborative Research Project (CRP) aims to decipher the genetic basis of many rare epileptic syndromes(RES )using a multinational large-scale approach, bringing together the expertise of epileptologists with access to large patient cohorts and molecular genetic teams with a vast experience in locus and gene identification. Collectively, this team of researchers will recruit the largest cohort of patients with RES to date and, for the first time, collect comprehensive clinical, electrophysiological and genealogical data in a standardized way. Novel genes for seizure disorders will be identified in 50 large families and 500 sporadic cases using broad range of Technologies including large-scale CNV analysis and next-generation sequencing techniques. These technologies will be applied in a systematic genetic workflow to streamline analysis efficiency. Finally, genotype-phenotype correlation will be performed to identify novel disease entities based on genetic findings. The interdisciplinary character and scale of this initiative comprising 10 European partners and 4 international partners is unprecedented. This CRP has the ambitious goal to identify the genetic basis in a substantial fraction of patients with Rare Epilepsy Syndromes. Therefore, we expect this CRP to represent a milestone in genetic research in seizure disorders.
MILANI MOBILTAS - In-depth Genetic and Epigenetic Analysis of the Cytochrome P450 System by Next-Generation Sequencing
March 2011 – February 2014
MOBILITAS Postdoctoral Research Grant no MJD71
Lili Azin Milani
The aim of this research project is to identify genetic signatures that control interindividual variation in drug metabolism and response. We will use ultra high-throughput sequencing technology to identify novel genetic and epigenetic variation in regulatory and protein coding regions of major genes involved in drug metabolism. We will study a unique collection of Caucasian liver samples, which have been extensively phenotyped for the activity and expression levels of different drug metabolizing enzymes. The identified variants will be further examined in samples from the Estonian genome project to verify their frequency and effect in a wider population. If successful, our approach will reveal previously unknown genetic variants associated with drug metabolism, which can be applied as pharmacogenetic markers to design optimal treatment for patients
TAP 30-1- Modernization of the Genotyping and Sequencing Centre of the University of Tartu
August 2012 – January 2014
EU structural Fund support through Archimedes Foundation, grant no. 3.2.0302.12-0429
Andres Metspalu, Maris Väli-Täht
Targeted Financing - Genetic variations, lifestyle and environmental factors in shaping the human health.
January 2008 – December 2013.
Funding from Estonian Research Council no. SF0180142Cs08
Goal is to study human genetic variation (GV) and correlate it with health status taking into account lifestyle and environmental factors. For GV we’ll study the single nucleotide polymorphisms, gene copy number variations, gene expression and methylation patterns using the whole genome array methods. We will use the health and environmental data together with DNA, plasma and lymphocytes samples from the Estonian Genome Center (Biobank) database, collected by general practitioners, using genetic epidemiological questionnaire. A control cohort based on 1500-2000 gene donors will be assembled and GV data together with biomarkers will be determined. These population-based controls will be used for different genome-wide analyses using 400-1500 cases in case-control or cohort studies. Phenotypes to be studied first will be pharmacogenomics of antidepressants (responders/nonresponders), mental retardation, genotype relation to nicotine addiction, panic disorder, lung cancer.
EFSD - Genomic, metabolomic, and demographic characteristics of type 2 diabetes in the Estonian population
May 2012 - April 2013
European Foundation for the Study of Diabetes (EFSD) grant
Andres Metspalu, Toomas Haller
ENGAGE - European Network for Genetic and Genomic Epidemiology
January 2008 – December 2012
FP7-HEALTH CP Collaborative grant no 201413
The primary aim of ENGAGE is to translate the wealth of data emerging from large-scale research efforts in genetic and genomic epidemiology conducted in well-characterized European (and other) samples into information of relevance to future clinical advances. The practical impacts of the ENGAGE societal WP 8 include policy guidance for ENGAGE members, the development of templates for consent, confidentiality and commercialization templates specific to metabolic syndrome-CVD, and codes of conduct for clinicians. Technology platforms themselves will be a crucial commercial deliverable from this collaborative project. In addition to technology platforms, biomarkers as predictors of disease onset or progression would establish a potentially valuable intellectual property position for commercial exploitation.
Metspalu ETF - Human genome variability and its association with longevity
January 2009 – Detsember 2012
Funding from Estonian Research Council, grant no ETF7859
The ability to survive to extreme old age appears to be the result of a complex combination of genetics, environment, lifestyle and luck. Understanding the genetics of the very old and identifying the molecular mechanisms of longevity is a powerful approach to discovering and targeting the pathways mediating aging and disease susceptibility and developing preventive and therapeutic agents that will allow more of the population to age in good health. Currently, 1 in every 76 individuals in the Estonia is 85 years of age or older. This prevalence is quickly changing and most industrialized nations will soon experience twice that prevalence. Aging is associated with a decline in the frequency of survivors attaining older ages. Given the evidence of genetic basis for longevity, we would expect the prevalence of favorable genotypes in genes contributing to prolonged lifespan-i.e., longevity haplotypes to be significantly higher among centenarians relative to their prevalence in a younger control population. In contrast, deleterious genotypes associated with "aging phenotype" (age-related disease genes) would be expected to decrease as mortality selects out individuals with these deleterious genotypes. These considerations suggest that changes in genotypic frequencies affecting lifespan in different age groups can be detected and used to determine the relevant genes associated with the aging process. In addition, some of the favorable genotypes act as mechanisms that buffer the deleterious effect of age-related disease genes. As a result, the frequency of deleterious genotypes may increase among individuals with extreme lifespan because their protective genotype allows disease-related genes to accumulate. It is important to find targets for longevity genes (gene-gene interactions). As longevity is very complicated process involving molecular mechanisms of the whole organism, it is important to analyze lots of genetic markers to discover the gene-gene interactions and the molecular processes occurring in aging. The aim of the study is to identify genetic markers/haplotypes associated with longevity and such information enables to estimate the expected life expectancy, which provides individuals the choice for appropriate environment/lifestyle in the future. Samples from the Estonian Biobank database and Illumina high density microarrays (370K to 1Million SNPs) will be used for the association study and the functional analysis of the found genes will be performed.
OPENGENE - Opening Estonian Genome Project for European Research Area
Detsember 2009 - November 2012
FP7-REGPOT-2009-1 grant no 245536
Andres Metspalu, Merike Leego
Aim of the project is to open the resources of the Estonian Genome Project of University of Tartu (EGPUT) to European Research Area. 1) The first objective is to increase the research potential of the EGPUT by improving the technological platform for genomic research. For that purposes we purchase the Illumina iScan system. This instrument will be the first in Estonia (and in Baltic region) and will increase the research potential and competitiveness in ERA enormously. 2) The second general objective is strengthening our human capital i) Recruitment of experienced researchers from abroad and ii) Exchange of know-how and researchers of different level with other European (and beyond) universities, institutes and laboratories. This will increase the research potential of the EGPUT by increasing the number of scientists working on the research projects. We assume that both PI will create the teams up to 5 researchers by the end of the project using additional funding. 3) The third general objective of the proposal relates to increasing the visibility of the EGPUT both among scientists, research partners and among the Estonian people. The biobank of the EGPUT is operational for at least 30 years and to maintain a trustful interaction with the general public and scientists is vital for the future success of the research programs of EGPUT.
TAP-2-22 - Establishment of the Genotyping and Sequencing Centre of the University of Tartu
May 2010 – April 2012
EU structural support through Archimedes Foundation, grant no 3.2.0302.10-0190
Andres Metspalu, Merike Leego
EUROCOURSE—Europe against Cancer: Optimisation of the Use of Registries for Scientific Excellence in research
April 2009 – March 2012
FP7-ERANET-2007-RTD grant no 219453
Andres Metspalu, Mati Rahu
EUROCOURSE will tackle fragmentation in the funding and usage of cancer registries in Europe. It will do so by exploring ways to link and integrate national/regional programmes aimed at supporting cancer registries and research carried out using registry data. At the same time EUROCOURSE is seeking to optimize the use of cancer registration data for the amelioration of cancer control and the strengthening of population-based cancer research in Europe.
TAP-2-3 – Upgrade of sample release system in Estonian Genome Center, the University of Tartu
January 2010 – January 2012
EU structural support through Archimedes Foundation, grant no 3.2.0302.10-0189
Andres Metspalu, Krista Liiv
BBMRI - Biobanking and Biomolecular Resources Research Infrastructure
February 2008 – July 2010
FP7-INFRASTRUCTURES-2007 grant no 212111
Key components of BBMRI are comprehensive collections of biological samples from different populations of Europe, which should be linked with continuously updated data on the health status, lifestyle and environmental exposure of the sample donors. BBMRI will build on existing sample collections, resources, technologies, and expertise, which will be specifically complemented with innovative components and will be properly embedded into European ethical, legal and societal frameworks. Sustainability will be achieved by appropriate funding and financing solutions. BBMRI will increase the scientific excellence and efficacy of European research in the biomedical sciences as well as expand and secure competitiveness of European research and industry in a global context. www.bbmri.eu
IDAMES - Innovative Dietary Assessment Methods in Epidemiological Studies and Public Health
April 2007 - September 2009
FP7 Public Health Program, grant no 2006315
Andres Metspalu, Aidula-Taie Kaasik
The aim of this project is to generate Standard Operating Procedures (SOPs) for innovative methods assessing diet in epidemiological studies that allow quantitative and detailed characterization of individuals regarding their dietary intake including alcohol. The expected results are the guidelines for new innovative instruments and methodologies to assess dietary intake including alcohol use will be formulated as SOPs. SOPs are now widely used in life science to communicate the best practice in a field and to increase standardization of approaches across research groups. The overall information of the project results will be communicated by scientific presentations, internet information web sites including documents and SOPs and written material for distribution.
PHOEBE - Harmonising Population-BasedBiobanks and Cohort Studies to Strengthen the Foundation of Biomedical Science in the Post-Genome Era
March 2006 - August 2009
FP6 grant no 518148
The ultimate aim is to harmonise those features that are common to many such studies and that, when harmonised, will help to: (1) promote communication between major biobanking initiatives; (2) enhance the effective sharing and synthesis of information and data; and (3) avoid the expensive mistakes and inefficiencies that can arise when individual initiatives repeatedly “re-invent the wheel”.
HeCaPrev EE LV - Development of Hereditary Cancer Prevention Measures in Estonia and Latvia
March 2005 – November 2007
INTERREG Regional Development Fund INTERREG IIIA grant no NI008
Andres Metspalu, Monika Tuuling, Helene Alavere
ScanBalt Campus - A European Model Case for Transnational Institution Building in Education Research and Development
July 2005 - June 2007
Baltic Sea Region INTERREG IIIB
Andres Metspalu, Helene Alavere
ScanBalt - ScanBalt Clinical Research Network
March 2005 - January 2006
Nordic Innovations Center grant no 04096
Andres Metspalu, Helene Alavere, Estonian Genome Project Foundation