FP6

“Molecular Phenotyping to Accelerate Genomic Epidemiology”

Concept of MolPAGE

MolPAGE

MolPAGE

“GENOMIC EPIDEMIOLOGY”

measurement, manipulation and analysis of “omics” scale data in thousands of subjects

MolPAGE ConsortiumEuropean Consortium

• 11 Universities/Research Institutes• 2 Pharma• 5 Biotech/SME

• 4 Year programme (Oct 04-08)• 12 million Euro

Coordinated by the University of Oxford

Professor John BellProfessor Mark McCarthy

PharmaSMEPublic Body

Programme Goals

“The application of genomic, metabonomic and proteomic tools to develop novel technical, data analysis and integration

protocols that will enable disease biomarker typing and discovery

projects on an epidemiological scale”

“The identification and validation of biomarkers for use as

pre-clinical predictors of metabolic disease”

Programme Overview

1. The evaluation of sample collection and storage methodology;

• to optimally reduce sample variation and maximise analyte stability2. The development of genomic, metabonomic and proteomic tools;

• to prepare for molecular phenotyping on an epidemiologic scale • relevant to both biomarker discovery and subsequent biomarker

measurement in large sample sets• Includes proof of principle biomarker discovery (medium-scale)

3. The development of project specific tools to support data warehousing, data interrogation and statistical analysis

• integrated approaches to data analysis across multiple platforms

• integrated approach to data storage and dissemination

MolPAGE

….with a clinical focus on diabetes and cardiovascular disease

Work Package Overview

StandardizationAssessing variability in omics measuresMedium scale biomarker discoveryApplication to large cohortsData management

Some vignettes

1. Standardisation

• Contribute to efforts to standardise sample collection strategies for genomic epidemiology: “future-proofing” biobank collections for future analysis. Build on UK Biobank efforts in this respect….

• Contribute to efforts to generate standards and norms for genomic epidemiology * study design and analysis * sample collection, processing and storage * measurement of exposure and clinical phenotypes * data formats, management, manipulation and storage * analyte measurement (-omics scale) * ethics, data privacy, material transfer * meta-data • To ensure that in 5 years from now, it will be much easier to work across multipleEuropean biobanks than currently….

2. Sources of variation in omics data

• UK TWIN STUDY• Twin volunteers recruited through

media campaigns• Healthy adult population 18+• Representative of UK pop• 500 MZ and 1,500 DZ pairs seen

clinically in detail• Body comp DEXA fat total and

central, fasting glucose,insulin,leptins, lipids

• >10000 twins on database with questionnaire data

• All will have fresh DNA & fasting blood by 2007

Decomposing variance

MZ

40 pairs

MZ female Representative for BMI

DZ

20 pairs

DZ female Representative for BMI

From each twin collect;

Blood For RNA

Urine

Blood For EBV

Serum Plasma

Adipose

MZ

Variance

Technical

Biological

Genetic

Me-DNARNAProteomePeptidomeMetabonome

Power studies

Fig 2b. Total sample size required (MZs +/- DZs) to detect combined 'familiality' (h2+c2) when common environment c2 = 0.3

Measurement scenarios: 2 in MZs and DZs (smooth lines) vs. 2 in MZs and 1 in DZs (small dash) vs. 2 in MZs only (large dash)

0

10

20

30

40

50

60

70

80

0.3 0.35 0.4 0.45 0.5

h2 (heritability)

To

tal n

um

ber

of

twin

pa

irs

(MZ

s +

/- D

Zs

)

r2=0.5, DZ=2

r2=0.6, DZ=2

r2=0.7, DZ=2

r2=0.8, DZ=2

r2=0.9, DZ=2

r2=0.5, DZ=1

r2=0.6, DZ=1

r2=0.7, DZ=1

r2=0.8, DZ=1

r2=0.9, DZ=1

r2=0.5, 2 MZ only

r2=0.6, 2 MZ only

r2=0.7, 2 MZ only

r2=0.8, 2 MZ only

r2=0.9, 2 MZ only

Lon Cardon, Krina Zondervan Oxford (WP9)

MolPAGE

3. Biomarker discoverydiscordantMZ twins

healthy individualsstratified for future

disease disk

legacy samplesfrom prospective

cohorts

new samplesfrom prospective

cohorts

plasma

serum

urine

subcutaneous fat

omental fat

muscle

samplesgathered at

surgery

proteomics

MetabonomicsLC-MS & NMR

peptidomics

epigenomics

Twins discordant for BMI

Plasma

Peptide display

Peptide display heat map

Putative biomarker

4. Evaluation of biomarkers

Need for high throughput methods based on affinity reagents

Tissue micro array, Metabolic array

Serum affibodies Biomarker affibodies

Serum depletion Protocols,

Antibody arrays

pREST antibodies

(HPR)

Serum arrays,Antibody arrays

Candidate gene-list

Microfluidics CD

Large scale Ab generation

http://www.proteinatlas.org/

Serum array performance

Insulin Pancreas

http://www.proteinatlas.org/

Thyroglobulin precusorThyroid

http://www.proteinatlas.org/

Sample Mgnt

Assay Mgnt

DB

Patient Mgnt

Data Warehouse

TRANSCRIPTOMICS

NovoNordiskOGT

Proteomics

BioVisioN

Peptides(Sequence)

Roche

KTH

Proteins(UNIPROT)

Protein Arrays

DNA methylation & SNP

Epigenomics, CNG

Measurement types

Gene

Pepti

des

Assay

Repository

METABONOMICS

NovoNordisk

ICL

NMR

LCMS

TRANSCRIPTOMICS

NovoNordiskOGT

DNA Methylation & SNP

Epigenomics, CNG

Raw/ data files

WP11 - Training

1) Annual training courses • Statistical genetics training (Pavia, 4-8th July 2005)• Transcriptomics workshop (Pavia, 20-24th March 2006)• Data reduction techniques in metabonomics & proteomics (2007)

2) Mobility awards• Competitive awards to support inter-partner training visits

3) Science Workshops (technology/analysis)• Data Warehousing workshop (September 2006)• Proteomics workshop (March 2007)

Dissemination Activities1) Project events open to wider scientific community• Training courses in Pavia• Public Technology Workshop (Paris May 8-10th 2005)• Follow up Technology Workshop (autumn 2008)

4) Interaction with other projects• EU projects; e.g. MolTOOLS, GenomeEUtwin, GA2LEN• SystemsX consortium interaction

3) Publicity• Project overview presentations, Press release, case studies etc..• Project web pages (www.molpage.org)

2) Contribution to standards• Standard setting workshop (October 2006) • Publication of SOPs

MolPAGE Project CoordinatorMark McCarthy, John BellLon Cardon, Peter Donnelly

Mark LathropIvo Gut

Esper BoelJan Fleckner

Mathius Uhlen

Luisa Bernardinelli

Vladimir Stich

Hanno LangenEverson Nogoceke

Fredrik Ponten

Stephan Hoffmann

Commission Project Officer; Dr. Shahid Baig

Ed SouthernSpiros Servos

Peter Schulz-Knappe

Kurt BerlinFlorian Eckhardt

Thomas Bergman

Jeremy Nicholson

Alvis BrazmaUgis Sarkans

Juris Viksna

Dominique Langin

Tim Spector

• MolPAGE: developing approaches to enable large scale genomic epidemiology

• Contributing to standardisation methods development informatics, and analysis• Medium-scale biomarker discovery• Long term: application to existing/future

European biobanking initiatives

Summary