Nordic Center of Excellence in Disease Genetics 2004-2009

1. Nordic Center of Excellence in Disease Genetics 2004-2009 To capitalize the unique Nordic resources in research of disease genetics

2. Helsinki, Finland: Helsinki University, National Public Health Institute, Folkhälsan Leena Peltonen (coordinator), Lauri Aaltonen, Anu Jalanko, Juha Kere, Anna-Elina Lehesjoki, Jussi Taipale Focus: Genetics and Molecular basis of neuropsychiatric and cardiovascular diseases and cancer Stockholm, Sweden: Karolinska Institutet Juha Kere (coordinator), Jan-Erik Litton, Juni Palmgren Focus area: Bioinformatics and biostatistics development and integrative database management. Uppsala, Sweden: Uppsala University Leif Andersson, Ulf Landegren, Ann/Christine Syvänen, Ulf Gyllensten, Marta Alarcon Focus area: Technology development of genome-wide strategies, Farm animal families Malmö, Sweden: University of Lund Leif Groop (coordinator), Rikard Holmdahl, Holger Luthman Focus area: Molecular basis of type II diabetes Århus, Denmark: Århus University Hospital Torben F. Orntoft (coordinator) Focus area: Microarray technology, molecular basis of cancer

3. www.ncoedg.org

4. Challenges of complex disease genetics • The effects of disease-associated variants unpredictable • Poorly characterized pathways involved • The impact of disease alleles unknown • Modelling of joint effects of genes and life style risk factors problematic

5. New knowledge and understanding of biological processes Bioinformatics Biocomputing Genome-wide data collected from well characterized study samples and cohorts (across species)

6. Why this Center? • Expensive & demanding genome analyses (laboratory plaforms, biocomputing) • Evolving needs in comprehensive training of new generation of experts in molecular medicine • Nordic countries have a special competitive niche in this field • World-wide competition of top experts Necessity of critical mass & harmonization of study samples

7. NCoEDG: 24 million Nordic population Helsinki, Stockholm, Lund Uppsala Århus National health care system Accurate population registers Reliable healthcare registers Traditions in genetic research Some isolated populations Traditions in epidemiology and mathematics Expertise in information technology Equal, high quality education

8. We represent a large research community • 29 Professors and associate professors • 37 Senior researchers • 63 Postdoctoral fellows • 117 PhD-students • 24 Other academic staff • 70 Auxiliary staff

9. Unique strengths of NCoEDG • Established expertise in critical fields of postgenome genetics • Infrastructure of core facilities • Internationally unique study samples: Families ascertained for disease phenotype Population-based cohorts Deep phenotyping of quantitative traits and follow up of decades • Geneological information to link cases • Linking to records of the health care system

10. QTLs within the Center bridging across species and three clinical entities

11. Scientific Goals of NCoEDG • Construction of databases: • 1) Human: detailed information of families with deep phenotyping in metabolic syndrome,autoimmune diseases and subtypes of colon Ca; • 2) Animal: corresponding data of farm animals and rodent strains parallel and complementing human diseases • Pooled statistical analyses of primary data of already performed genome scans and transcript profiles in these traits • Across species strategies and new system biology based approaches for more efficient analyses of polygenic traits

12. Scientific Goals Pooled data analyses for selected diseases, Comprehensive analyses of genome geography of identified candidate regions: gene content,homologies, LD intervals, haploblocks Characterization of functionally relevant DNA regions identified through cross species genomic comparisons and systematic evaluation of structural and functional variants Biocomputational analyses to combine quantitative phenotype, ganotype and expression data in animals (and humans) Harmonize the operations of genotyping and sequencing sites (KI,Uppsala,Helsinki)

13. Scientific Goals • Biocomputing based pathway predictions to identify genome-wide networks of interactive partners of identified disease or trait genes. This should identify novel candidate genes for further analyses • Establishment of and training in advanced high throughput genome technologies

14. Five intellectual cores:pooled expertise across the sites • Core for molecular technologies (Landegren) • Core for medical expertise (Groop) • Core for human genetics (Peltonen) • Core for animal genetics (Andersson) • Core for databases and biocomputing (Litton and Palmgren)

15. Progress: Data integration in NCoEDG • Data federation system • Based on database federation system developed for the GenomEUtwin (EU project) • Phenotypes ( 8 centres, data from over 250 000 individuals) • Genotypes (600M, in a federated data warehouse ) • Simple to implement • Hub-and-spoke network • Complemented by data warehousing • Using existing software • Data standards • On study basis. Collaborations: P3G..

16. Progress: Databases • Two brainstrorming workshops of the best database structure • Federated setting for human phenotypes and genotypes • A separate shared data warehouse for animal phenotypes and genotypes • Standard BASE format for array data (more comprehensive solution in collaboration with EBI)

17. Progress: databases • Nordic Centrer concept attracted funding from the Wallenberg Foundation for databases, total of 5 M Skr • Database expert recruited for each site • Federated database concept designed • Proof of principle constructed for metabolic syndrome-related traits: phenotypes and genotypes • Database produced for expression array data, proof of principle: cancer

18. Database and informatics • Human data: • Database federation hub installed between the sites • Based on system developed for the GenomEUtwin • VPN gateway installed • VPN network pilot implemented • Data warehouse applications installed on hub • Current data imported: Metabolic syndrome and MS data “control” genotypes from Nordic populations • Animal data: • 3 workshops

19. Progress: Molecular technologies • QC and dataflow issues harmonized across genotyping centers, common database structure (Syvänen) • A website format established for detailed protocols of advanced molecular analyses (Landegren) • Three courses and hands on training sessions organized for students (Syvänen, Palotie)

20. Research training within the Centre • Mission: to train new generation of scientists, fluent in new strategic thinking and methodology of genetic research after genome projects • special emphasis on novel genome-wide strategies, • including statistical analyses and biocomputing • integration with the training programs of Institutes

21. Research training of the Centre • Rotating of students and experts (databases, statistics) • between the NCoEDG groups • Postdoctoral scientists recruited for joint projects • Joint graduate program founded in Biomedicine • between Helsinki University and Karolinska Institutet, • to be extended across the other institutes of NCoE:s • Hands-on training in core facilities in different • centers, multiple NCoEDG funded courses • Co-ordination with training programs&events • with EU projects and EMBL

22. EU Partnerships with NCoEDG partners • GenomEUtwin and ENGAGE • Geha • Eurohead • Euroclot • Euraps • DiOGenes • Eurodisc • European dog project

23. Recruitments and Mobility • Two open calls for research fellowships : • www.ncoedg.org: Research Projects with Nordic Component described • 25 Applications received • Evaluation Criteria: • Scientific excellence • Nordic collaboration • Nordic competence building • 2 Awarded : 4 postdocs; 1 PhD student

24. www.ncoedg.org

25. Progress: Key Joint Activities

26. Gene Expression Progess: Across species approach: Translating findings in farm animals to humans? X Same Gene? Gene in Syntenic region in Man QTLs for visceral and subcutaneous Fat (8 MZ Twinpairs discordant for BMI)

27. Scientific Outputs • 42 Scientific papers published (collaboration between at least two Nordic countries) • 5 manuscrips submitted from NCoEDG projects • The first pooled data analyses of genome scans have been completed for lipid traits and the manuscript reporting a new QTL gene for HDL is submitted • Over 30 review articles • 19 PhD Degrees supervised in 2005-2007

28. New international projects with critical partnership of NCoEDG investigators • CoEDG investigators are critical partners in in the harmonisation effort of European biobanks, Assist, and lead the ENGAGE, an integrated project application for FP7 • CoEDG investigators key partners in ERFRI insfrastructure calls: BBMRI for biobanks, EBI extension bid • CoEDG investigators leading the dog genome project for FP7 call • P3G: The critical role of center investigators, the database concept is based on the federation concept ”dress rehearsed” by our center

29. Future challenges • Nordic joined efforts are critical to guarantee the visibility of Nordic research in large molecular epidemiological efforts • Nordic countries would provide an ideal setting for research: in molecular medicine in biobank-based initiatives in translational research

30. Threats • Nordic scientists have not operated very efficiently as a community • Several decisions on funding in each country are made ”in silos”, integration or harmonization of national efforts across Nordic countries non-exiting • We can only succeed if we show better integration in molecular medicine within Nordic countries

31. Critical actions • Nordic molecular medicine deserves more national and Nordic funding • Top ranked programs should become an integral element of the Nordic EMBL node in molecular medicine • Joined training programs in molecular medicine in graduate and postgraduate levels should be initiated as soon as possible

32. Intensified intecactions between three NCoE:s • Joint training program in molecular medicine: Immediatelly cross acceptance of workhops and courses by all universities, plans at place for joint graduate and postgraduate training programs • Joint meeting of P.I:s in August 2007, including two hours panel with Nordic decision makers and representatives of reseach councils

33. Joint efforts between Nordic centers in education • Links between websites: information of courses and educational events • Joint funding of training events and courses • Joint graduate program in molecular medicine • Joining forces to influence the funding agencies and governments • Joining forces in the educational use of research infrastructures (call by Nordforsk)

34. Critical value of Nordic collaboration in biomedical research • Integration and joint analyses of study samples • Nordic funding would be for critical large projects • Nordic evaluation would be better than national • ESFRI structures need Nordic nodes (BBMRI, EATRIS,ELIXIR,Mouse effort…) • New technologies need Nordic competence centers • New EU projects – intensified Nordic links • Nordic pool of talent