The present proposal seeks support for a consortium arrangement between the University of Western Australia (Australia) and the University of Bristol (UK) toconduct genetic epidemiological analyses of a unique prospective longitudinal birth cohort in order to evaluate the etiological pathways underlying the childhood precursors of T2D - obesity and metabolic factors such as IR and GI. Whilst the principal consortium members include Australian and British researchers, collaborative arrangements have also been arranged at an "as required" basis with researchers from McGill University, University of Leicester, University of Oxford, University of Cambridge and the NIDDK.

As a result of these arrangements, there is a substantial foreign component present in this proposal. As described in the Research Plan, the ALSPAC group at Bristol University will contribute their epidemiological expertise and the rich ALSPAC cohort resource, the group at the University of Western Australia will contribute their expertise in genetic epidemiology and informatics, and the groups at McGill University/Genome Quebec Innovation Center and Oxford will contribute their expertise and knowledge of high-throughput genotyping.

Over the preceding 12 months, UWA (Palmer) has coordinated the formation of the new consortium between Bristol and Perth. This role arose out collaborations and interactions between these two groups, and because of the self-evident synergies and mutually complementary skills and knowledge. Dr Palmer spent a 4 month sabbatical as a Leverhulme Trust visiting Professor with the ASLPAC group in 2005, and Dr Ness will be visiting Perth later in 2006.

The prime rationale for the involvement of the senior collaborators at Oxford (McCarthy), Cambridge (Wareham) and the NIDDK (Knowler) is their capacity to provide DNA samples from well-phenotyped studies for replication of positive signals from this study. As set out in the Research Plan, our ability to confirm positive signals by replication in multiple independent datasets is an essential part of strategy (although funding for the replication comes from each group and non-NIH sources, and no funds for this part of the project are requested in this application). In addition to supplying replication samples, these senior collaborators also provide intimate knowledge of their samples and the phenotypic characteristics relevant to T2D in their respective populations, along with specific clinical, epidemiological and genetic expertise related to T2D.

The analytic team from Bristol (Green), Oxford (Cardon), Leicester (Burton) and Perth (Palmer) represent an experienced team of senior statistical geneticists and mathematicians who collectively have a substantial amount of experience in the applied analysis of complex datasets and in methods development in biostatistics. These senior investigators and collaborators have complementary experience and interests, and a long history of collaboration and interaction on a number of projects. Current collaborations include an ongoing activity and obesity study undertaken by Dr Ness and Dr Wareham, whilst Professor Smith, Professor Burton, Dr Ness and Professor Palmer are involved in the ALSPAC programme. Based on the relevant expertise of these investigators and the high standard of current and past collaborative efforts, we believe that this is an ideal team to guide the analysis of large amounts of SNP data in the complex ALSPAC datasets.

To maximize efficiency, the project will utilize a centralized high-throughput genotyping approach. For this purpose, the Genome Quebec Innovation Centre (Montreal, Canada) has been closely involved with the development of this proposal. In addition, Dr Hudson has a long-term interest in the genetics of T2D and obesity and close collaborative links to a number of senior investigators and collaborators involved in this proposal. This made the Innovation Centre the logical partners in the development of this proposal. As their contribution to the HapMap demonstrates, the Innovation Center remains at the forefront of efforts to develop high-throughput genotyping and related analysis tools, and the commitment of their expertise and technological capacity to this project is a valuable component of our plans. All equipment and maintenance costs are covered by internal Innovation Center funds. The consequence is a cost price that is below that available from any comparable commercial or academic source. In addition to their commitment to genotyping of the ALSPAC resource, the Innovation Center will also support the genotyping and resequencing needs of our replication and follow-up studies (for which funding is not sought in this application). Finally, existing strong 3-way links between Tom Hudson's group at the Genome Quebec Innovation Center, George Davies-Smith's group at Bristol University, and Lyle Palmer's group at the University of Western Australia will facilitate information exchange between the 3 groups, enabling us to maximize the efficiency of the project. Prof Hudson will be a Visiting Professor with Prof Palmer's group in Perth in August 2006.