Transcript Slide 1

Nordic Center of Excellence
in Disease Genetics
2004-2009
To capitalize the unique Nordic
resources in research of disease
genetics
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
www.ncoedg.org
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
New knowledge and
understanding of biological
processes
Bioinformatics Biocomputing
Genome-wide data collected from well
characterized study samples and
cohorts (across species)
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
NCoEDG: 24 million Nordic population
Helsinki,
Stockholm,
Lund
Uppsala
Århus
National health care system
Reliable healthcare
registers
Accurate population
registers
Traditions in genetic
research
Some isolated
populations
Traditions in
epidemiology and
mathematics
Expertise in
information technology
Equal, high quality education
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
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
QTLs within the Center bridging across species and three
clinical entities
Human QTL1
Disease2
Animal model QTL3
Disease/Trait4
1q
T2DM,FCHL
F344.C2-GK (Rat chr 2)
Pig FAT1 locus
(chromosome 4)
GK T2DM and fat
induced hyperglycemia
Fat deposition
1q31-32
RA
SLE
Mouse Cia10 (mouse chr 1)
Arthritis
1p
Colon Cancer
Mouse Mom1 (chr 4)
Modifier of Intestinal
neoplasia
1p20 – p21
T1DM,
SLE
iddm3 (rat chr 2),
Cia5b and Cia5c (mouse chr
3)
BB rat
diabetes
Arthritis
EAE
2q
Obesity
F344.C9-GK (Rat Chr 9)
Insulin conc. and body
weight
2q
T1DM
Iidm4 (Rat chr 15)
BB rat
diabetes
2q
T1DM
Idd6 (Mouse chr 2)
Autoimmune diabetes
4q11-q12
Gastrointestinal
tumor
Piebaldism
MS?
RA?
Rat Pia6 (rat chromosome 14)
cloned cluster of
Pig PDGF/cKit/VEGF),
Pig cKIT/Dominant white
(chromosome 8)
Chronic arthritis
Chronic EAE
Fur/skin color
Malignancy
Anemia
RA,
autoimmune
autoimmune
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
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)
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
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)
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..
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)
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
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
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)
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
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
EU Partnerships with NCoEDG
partners
•
•
•
•
•
•
•
•
GenomEUtwin and ENGAGE
Geha
Eurohead
Euroclot
Euraps
DiOGenes
Eurodisc
European dog project
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
www.ncoedg.org
Progress: Key Joint Activities
•
2005
2006
2007
Workshops
--
4
1
Practical Courses
(EMBO,EU,local)
3
2
1
Joint Coordination
meeting
1
3
2
Other Key Events
1
1
(Kick-Off Meeting)
(Scientific
Symposium,
Junior Scientist
Meeting)
EMBO course in
SNP mapping
Progess: Across species approach:
Translating findings in farm animals to humans?
X
Same Gene?
Gene Expression
Gene in Syntenic region in Man
(8 MZ Twinpairs discordant for BMI)
QTLs for visceral and subcutaneous Fat
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
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
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
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
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
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
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)
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