P3G: an international consortium in Human Genome Epidemiology

Ultimate Goals:For the understanding of gene-environment causes of chronic diseasesFor better public health strategies

The Causal Complexity of Chronic Diseases

Social Structure

Diet & Lifestyle

Genetics

Environment

“webs of causation”

DiabetesAsthmaHeart DiseaseSchizophreniaCancerMultiple SclerosisObesityArthritis

Why Study Gene-Environment Interactions?

• Obtain a better estimate of the population attributable risk for genetic and environmental risk factors by accounting for their joint interactions

• Strengthen the associations between environmental factors and diseases by examining these in genetically susceptible individuals

• Help dissect disease mechanisms by focusing on biological pathways most relevant to that disease, and environmental factors most relevant to the pathway.

• Determine which specific compounds in a complex mixture of chemicals (from pollution, diet, etc.) cause disease.

• Use the information to design new preventative and therapeutic strategies

• Offer tailored preventive advice that is based on the knowledge of the genetic profile of an individual.

Hunter, Nature Reviews/Genetics 2005

Resources needed for identifying genetic risk factors and gene-environment interactions affecting the predisposition to

chronic diseases

Comprehensive knowledge of genetic variation

Genotyping Technologies

Cohorts - Phenotypes- Exposures- Large Size

Analytical Tools

HapMap

P3G

Example of Sample Size Issue for detecting ONE interaction for a

dichotomous trait and a 10% exposure

Hunter, Nature Reviews/Genetics 2005

What 10,000 incident cases in a gene-environment study can provide:

Paul Burton, UK BioBank Technical Report 2005

(with power calculations that that take into account considerations of misclassification of exposure and outcome data, and realistic data collection scenarios)

1. For genotypic and environmental prevalences of 10% and above, 10,000 cases will provide adequate power for interaction effects with an MDOR greater than 2.

Genotype Prevalence

0.1 0.2 0.33 0.5

0.1 3.03 2.36 2.11 2.05 0.2 2.32 1.95 1.87 1.78

0.33 2.15 1.80 1.68 1.64

Prevale nce o f Env ironme ntal

Expos ure 0.5 2.16 1.86 1.70 1.70

(MDORs; defined as the smallest odds ratio that can be detected at p=10-4 and power=80%).

Paul Burton, UK BioBank Technical Report 2005

(with power calculations that that take into account considerations of misclassification of exposure and outcome data, and realistic data collection scenarios)

2. For a genotypic prevalence as low as 1% there will be adequate power to detect substantial (OR between 2 and 3) direct genetic effects. For this low genotype prevalence, gene-environment interactions will only be detectable for very large interaction effects (e.g. OR > 7).

3. 10,000 cases will provide a powerful platform for genome-wide indirect association studies (requiring rigorous definition of statistical significance of p<10-7).

What 10,000 incident cases in a gene-environment study can provide:

Paul Burton, UK BioBank Technical Report 2005

How long does it take to reach 10,000 cases in a cohort with 500,000 cases?

Breast cancer (F) 17 yrs

Colorectal cancer 22 yrs

Prostate cancer (M) 22 yrs

Lung cancer 34 yrs

Stroke 18 yrs

MI and coronary death 8 yrs

Diabetes mellitus 6 yrs

COPD 13 yrs

Hip fracture 21 yrs

Alzheimer’s disease 18 yrs

Parkinson’s disease 23 yrs

Public Population Project in Genomics

A consortium dedicated to fostering international collaboration between

researchers and projects in the field of

population genomics

P3G: History and Launching Phase (2003-2005)

• International meetings leading to the creation of P3G:

• 2003: London, Montreal, Manchester• 2004: Helsinki, Tallinn, Toronto• Supported by: Wellcome Trust, European Union

Genome Canada and Genome Quebec

• Non-for-profit organization incorporated in 2004

• Secretariat and Observatory created February 2005

• Seed money from Genome Quebec and Genome Canada for the launching phase

P3G mandate

• create a network in population genomics that will comprise over 3 million participants for epidemiological studies

• provide statistical power for analysing complex genetic and environmental determinants of health and disease

• leverage the combined expertise of hundreds of researchers around the world

• promote communication among national and international organizations

• increase the ability to share and generate new knowledge dedicated to improve public health and welfare.

An international resource for the coordination and exchange of ideas and data that will be generated by the various population biobanks

P3G Consortium Model

Estonian Genome Project

CartaGeneGenomEutwin P3G

CIGMR

Kora-Gen LifeGene(Sweden)

Danubian Biobank Foundation

WAGHP(Australia)

(Canada)

(Germany)

(Europe)

(Europe)(UK)

NHLBI(USA)

Generations(Scotland)

Genoma Espana(Spain)

NIGM(Mexico)

LifeLines(Netherlands)

ALSPAC(UK)

3

Regular MemberAssociate MemberIndividual Member

P3G Membership

3

NEED FOR HARMONIZATION

Analogie: Bill Ollier

HARMONIZATION IS NOT REGIMENTATION

P3G General Assembly

P3G Board of Directors

P3G Steering Committee

IWG 1(Social/Clinical/Environmental)

P3G Secretariat

Core

IWG 2Informatics

IWG 3Ethics and Governance

IWG 4Epidemiology/Biostatistics

CoreCoreCore

Core Core Core

Core

Core Core Core Core

FundersAuditors

P3G OBSERVATORY

P3G Operational Chart

International Working Groups (IWGs), leaders and early outcomes

Social, Environmental andBiochemical Investigations

Leader: H. Erich Wichmann (KORA-Gen, Germany)

-Common Core Variables for Population Based Studies-Common DNA Quality and Quantity Control-Conceptual model for harmonization of physiologic and biochemical measures

Knowledge CurationAnd Information Technology

Leader: Jan-Eric Litton (LifeGene, Sweden)

-Nomenclature Working Group -Protocols for Data Sharing-Biobank lexicon

Ethics, Governance and Public Engagement

Leader: Alastair Kent (Genetic Interest Group, UK)

-Intellectual Property Policy-Consent form Inter-operability

Epidemiology and Biostatistics

Leader:Muin Khoury and Julian Little (CDC)

-Leader was just appointed: first meeting in September

P3G Cores

• Principal work units of P3G, • Self-funded,• Focused on specific issues related to biobanks,

• Cores activities are reported to IWG regularly

• 2006 goals to create cores in areas such as:

Questionnaires and Clinical Measures

Laboratory Phenotypes

DNA/SNPs andGenotyping

Statistics and Epidemiology

Environmental Assessment

Population GeneticsAnd Policymaking

Impact ofCommercialization

Participation: GenderAge, Ethnic Differences

Nomenclature

Federated Databases

The P3G Observatory: a web-site describing

Biobanks and Population Genetic

Studies

Isabel Fortier, Ph.D.

Vincent Ferretti, Ph.D.

Denis Legault, MPA

McGill University and Genome Quebec,

Innovation Center740 Dr. Penfield

AvenueMontreal (Qc) H3A

1A4

The P3G Observatory

The Observatory contains:

• a description of studies (57 as of May 29, 2006)

• a catalog of questionnaires, consent forms, etc.

• a search tool using key words for common variables used in genetic epidemiology

• a companion tool for questionnaire development and harmonization between studies

www.p3gobservatory.org

Catalogue of Studies

A standard way to describe population studies in genomics

General Information Background Objectives Methods Status Ethics and Governance Available Documents Publications

57 large population-based studies(P3G members and non-members)

22 studies with complete information

35 studies with summary information

DESIGN OF STUDIES

INFORMATION COLLECTION/ TREATMENT

ETHICS AND GOVERNANCE

INFORMATION TECHNOLOGY

DATA ANALYSIS

BioBank lexicon

Ethics and governance “good practices” guidance documents

General reference procedures for: • Questionnaires development/collection; • Physiological measures collection; • Samples collection, manipulation, storage or analysis

Open source information management system for Biobanks

Reference tools for statistical analysis and power calculation

General Tools in Development

From Biobanks to improving health and preventing disease:

P3G Future Research

P3G Portofolio of Studies: Examples

Biobanks Sample Sizes AtherosclerosisArthritisColon CancerSchizophhreniaObesity100 otherGenomeuTwin 100,000 x x x xEstonian Genome Project 100,000 x x x x xCartagene (Quebec) 50,000 x x x x xGenerations Scotland 50,000 x x xLifeGene (Sweden) 500,000 x x xWAGHP (Australia) 2,000,000 x x x xNHLBI, NIH, etc. 500,000 x x x x xKora-Gen 20,000 x x xDanubian Biobank 50,000 x x x xEPIC 500,000 x x xOthers: UK Biobank, Spain, Mexico, Korea, China, etc. 2,000,000 x x x x x

P3G 2020With the synergy of P3G:•The scientific community will benefit from having a powerful international resource for gene-environment studies of complex diseases• Return of investment will be quicker, more efficient and of higher quality through international harmonization• Health Care Systems will benefit from accurate information for designing and implementing population health strategies

MERCI

Bartha Knoppers, Leena Peltonen, Andres Metspalu, Bill Ollier,

Eric Wichmann, Jan-Eric Litton, Julian Little, Muin Khoury, Alistair Kent, Lyle

Palmer, Thomas Hudson, Paul Burton,Claude Laberge, Isabel Fortier and Mylene

Deschenes,