Institute of Genetics (IG)

GENOME CANADA &
INSTITUTE OF GENETICS &
INSTITUTE OF POPULATION & PUBLIC HEALTH
CANADIAN INSTITUTES OF HEALTH RESEARCH

Human Population Genetics/Genomics Workshop

REPORT OF THE PROCEEDINGS
September 11th, 2001

BACKGROUND

Purpose
The Human Population Genetics/Genomics Workshop was jointly sponsored by Genome Canada and the CIHR Institutes of Genetics (IG) and Population & Public Health (IPPH). This strategic planning workshop was held in Aylmer, Québec at the Château Cartier, on September 11th, 2001. Approximately 30 individuals from a variety of institutions and organizations in the Human Population Genomics/Genetics community were assembled to participate in this workshop with the following two objectives:

1. To develop a long-term strategy for moving Canadian research forward in this field, taking into consideration mutual opportunities (national and international), needs, and challenges for stakeholders.
2. To devise a strategy to ensure there are proposals in this field ready to submit to Genome Canada for the December 2001 competition and to the CIHR Institutes of Genetics and of Population and Public Health for the 2002 competition.

Steering Committee
Leaders in the field of human population genomics/ genetics were asked to be part of a steering committee to lead the planning process towards the workshop over the summer months of July and August 2001. During the two month planning period the steering committee held weekly teleconferences focused on the following issues:

• Where will the next breakthrough be required in human population genomics/ genetics to move forward?
• If we could ignore current limitations (time, money, personnel, knowledge and skills) what questions/ issues would we like to work on?
• Who and where are the mavericks, the "way outside the box" thinkers in this field or related fields?
• What are the unique skills, research issues, challenges and opportunities that we have, or lack but should have in Canada?

Stimulated by the Steering Committee process, three members began work on ideas that could be developed into large-scale proposals suitable for funding by Genome Canada. B. Rannala & K. Morgan articulated ideas toward a Canadian Complex Genetic Disease Initiative and G. Eyssen outlined a Canadian Gene-Environment Interaction Initiative. Drafts of both proposals were circulated during the Steering Committee process, provided to Workshop participants and presented at the Workshop.

Characteristics Necessary for World-Class Contribution
During the course of their deliberations the Steering Committee described the characteristics necessary for world-class contribution in human population genomics/ genetics. Seven necessary characteristics were identified.

1. Large-scale databases are essential when the critical genetic variation is subtle and/ or interactive in the context of genetic heterogeneity. In these circumstances large sample sizes are required to detect, test and confirm findings.
2. When a putative genetic variant is identified, the next critical step is to validate that insight and confirm causality through reference within a large, diverse database that includes environmental factors beyond the genetic variant.
3. In the case of genetically complex diseases, whole population data sources will be useful in addition to more focused studies of high risk or otherwise specific target groups.
4. Clear research designs must be identified and communicated. Support capability must be developed and deployed appropriately.
5. Data archives must be established to allow quick access for confirmation studies and other data mining efforts once gene candidates are suggested by other research.
6. Specific points of contribution might be negotiated with global partners (i.e. the international haplotype study being organized).

Critical Issues Requiring Resolution
The Steering Committee identified a number of barriers that presently impede human population genetics/ genomics researchers.

1. At present, there is no organizing national structure that supports internal awareness and informal exchange in the human population genetics/genomics research sector. Therefore, there is low interest in cooperative involvement among PIs and/ or custodians with current and planned databases.
2. There is a range of intellectual property (IP) issues that arise with the growing capability of human population genetics/ genomics research. These IP issues are at present not properly addressed by existing IP agreements (i.e. for the creation of novel molecules). This unclear legal position steers researchers to simpler topics and well-understood procedures, and actively dissuades researchers from real creativity in research design and methodological innovation.
3. Because human population genetics/ genomics research requires the cooperative effort of a range of different professionals, the attendant issues of academic credit and advancement must be resolved. Research teams will not likely be entirely resident at one institution or one geographic location.
4. To be fully effective human population genetics/ genomics research must include information on health status in addition to genotype information, environmental information and demographic information. Access to public health data and anonymized individual clinical records on patients, cohorts and populations will be necessary to secure the needed data. Historically the provinces and territories have been reluctant to make this access available due to privacy concerns.
5. Most of the privacy concerns in accessing clinical records have been resolved, through the past decade, in a series of data linkage studies that have been carried out by university researchers (i.e. by the Centre for Health Services and Policy Research at the University of British Columbia). Human population genetics/ genomics research would be more rapidly advanced with access to these data linkage methods (links within and across individual clinical health records) and existing results.

Needed Partnerships
The Steering Committee identified a number of partnerships that must be initiated or fostered in order to efficiently achieve the potential of human population genetics/ genomics research in Canada. Currently existing data sets should be brought together, and those currently in design phases (i.e. the next Canada Community Health Survey) should be coordinated to contribute to a maximally useful and available archive to facilitate data mining studies.

A wide range of partnerships will be necessary to support a significant endeavor in human population genetics/ genomics research over the time span required in this type of research. The other necessary partners would include various levels of governments and government agencies (of particular note is the new agency the Canadian Health Infoway Inc.), other funding sources (national and international); voluntary health associations (i.e. Heart and Stroke); industry sectors (biotechnology, pharmaceutical).

A close relationship with the emerging discipline of bioinformatics is also required. The intention must be to build the bioinformatics discipline integrally into the design, conduct and analysis of human population genomics/genetics research.

Advantages for Canadian Researchers in Human Population Genomics/Genetics
Canadian scientists have already developed significant scientific expertise in this area. A large-scale Canadian cohort study in human population genetics/ genomics research could be established based on a combination of existing data sets, augmented by targeted new data acquisition to address gaps among the databases. An inventory of relevant existing data sets suitable for continued follow-up must be assembled, and additional data sets must be established.

A number of well-defined Canadian populations have already been characterized through genetic studies, demographic studies, personal and family histories. Examples of data sets that are presently in place, or under development include:

• National Population Health Survey
• Cohort(s) being assembled by Heather Bryant of the Alberta Cancer Board
• Toronto Urban Health Initiative being developed jointly by St Michael's Hospital and the Department of Public Health Sciences in Toronto
• The Ontario Familial Registries for Breast and Colon Cancer
• The Newfoundland Colon Cancer Familial Registry
• The Quebec-based CARTaGENE project
• Previous studies of other well-defined populations (i.e. the Hutterite of Alberta/ Saskatchewan).

The entire Canadian population is 'well-defined' due to the existence of individual clinical records of significant depth and duration in all provinces and territories. These records are accessible through the existence of unique identifiers for all citizens already attached to clinical health records. Most of these records exist in hard copy only and reside in dispersed locations (hospitals, physicians' offices, the public health units). Increasingly however the records, even the archived records, are becoming electronic and centrally available from secure servers (i.e. all the units funded through the Canada Health Infostructure Partnerships Program (CHIPP) program, and the unified health information systems in a number of provinces, notably British Columbia, Manitoba, Quebec and Saskatchewan).

Another advantage that Canadian researchers in human population genetics/ genomics have is Canada's publicly funded health care system with strong public health components. The existence of these systems directly support the health needs of study participants making it more likely that participants will seek help by contact with these systems throughout their lives. This ease of access generates more continuous health records, current contact information and more likelihood that whole families will access healthcare through a single access point. All these factors produce more accurate, more continuous data for researchers in human population genetics/ genomics with less likelihood of participants lost to the studies.

The positive experiences with clinical record linkage studies over the past decade have reduced the barriers to these studies at federal, provincial and local levels. Interest and support for studies requiring even more complex data linkages, as will be required for significant research in human population genetics/ genomics, is more likely as a result. A new federally funded agency, the Canadian Health Infoway Inc. (CHII), has been established with the express purpose of facilitating use of the country's extensive health records systems for the public good. In addition to health systems research, research in human population genetics/ genomics should be well served by this new agency.

Canada has an international reputation for stewardship and good government policy across a range of sensitive issues (i.e. privacy, data protection, community recruitment). Experience and precedent in these areas will help researchers overcome initial barriers and negative reactions to human population genomics/genetics research.

Canadian researchers are more advanced in our model approaches to DNA sampling for clinical studies than are other international colleagues. We have developed social/ ethical/ legal models for DNA sampling and consent and we are developing a code of ethics for those working in genomics at the population level.

WORKSHOP PROCESS

Participants were provided with a stimulus document, On Defining a Canadian Niche in Human Population Genomics/Genetics, prepared by Lynn Curry of CurryCorp, prior to the workshop.

After welcoming words from the two sponsors (M. Godbout for Genome Canada and R. McInnes from the CIHR Institutes of Genetics and Population & Population Health), overviews of current large-scale research ideas in human population genomics/ genetics were presented.

Areas of Possible Cooperative Effort for Large-Scale Research

1. CARTaGENE presented by Claude Laberge
2. NIH Coordinated Haplotype Mapping Project (Shared Inheritance for Medicine MAP [SIMMAP]) presented by Tom Hudson
3. Ideas for a Human Population Genomics Initiative presented by Bruce Rannala and Ken Morgan
4. Population Genomics and the Public Health Impact presented by John McLaughlin
5. Canadian Gene-Environment Interaction Initiative (GenI) presented by Gail Eyssen

Workshop participants were invited to outline a preferred course for the development of large-scale human population genomics/ genetics research in Canada. Divided into three groups to enhance opportunity for discussion, the groups independently developed responses to the question of vision, by focusing their discussion on the following series of stimulus questions:

1. What is the "big vision" and how do we get there?
2. What are the necessary short and long term mechanisms to achieve this vision?
3. What are the priorities or immediate next steps?

WORKSHOP RESULTS

After hearing the results from each group, the plenary of all participants developed the following sense of direction:

Vision for Human Population Genomics/Genetics in Canada
No focal support emerged among workshop participants for a cooperative effort toward any of the five suggested possible research directions. Workshop participants preferred to characterize their preferred vision for human population genomics/ genetics research in Canada in more general terms.

The preferred Vision was described as using population genomics/ genetics to improve public health, prevent disease and enhance the well being of Canadians.

• This vision would require the 'marrying' of population epidemiologists and population geneticists.
• It would also highlight the necessity of gene-environment studies and gene-gene interaction studies.
• Possible pilot examples could be built on demonstrated Canadian strengths in studying cancers and neurological diseases.

Goals that must be accomplished to achieve the Vision
In order to achieve the above vision, Workshop participants identified two component goals:

• characterize the genetic structure of populations
• characterize functional genetic variation

Realizing these goals will require simultaneous development in a number of areas.

• Necessary epidemiology research tools must be developed and tested to characterize environmental factors, social factors, lifestyles and health outcomes. Technology must be developed to assist in the necessary data collection, extraction and storage. Informatics must be further developed as a science to assist in the design, linkage and analysis of data. Further work on the NIH haplotype study may generate some of these needed components.
• The quality, linkability and accessibility of existing, planned and potential cohort databases must be confirmed. Already available information and resources must be evaluated for quality, linkability and accessibility (i.e. current information on founding populations, currently available health records).
• Common functional genetic variation must be characterized.
• Resource capacity in human population genomics/ genetics research must be built in Canada. Capacity for theory development and modeling in human population genomics/ genetics must be enhanced within this community of researchers.
• Funding partners must be identified for this new range of comprehensive human population genomics/ genetics research.
• Public stewardship/ leadership, participation must be developed (including communication, education, development of needed public policy and regulation)
• Legal and ethical issues must be addressed (i.e. tissue sampling; access to clinical information).

Priorities
Workshop participants identified the following immediate priorities, if Canada is to develop world-class contributions in human population genomics/ genetics:

1. Match needs and potentials for development in human population genomics/ genetics to possible funding sources and constraints including timing requirements.
2. Build capacity in human population genomics/ genetics research
3. Continue to develop vision and long-term plan for human population genomics/ genetics
4. Develop an action plan for communication within the human population genomics/ genetics research community.
5. Continue community building and collaboration development for human population genomics/ genetics research.

WORKSHOP FOLLOW-UP

CIHR Institutes
Since the workshop, a joint committee with representatives from the CIHR Institutes, IPPH and IG will facilitate the development of a collaborative project in the area of population level investigations of gene-environment interactions. The primary objective is to facilitate the interdisciplinary design and execution of large epidemiological (e.g. cohort) studies of the joint genetic and environmental determinants of common multi-factorial, genetically "complex" diseases, in Canada.