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      Integrating post-genomic approaches as a strategy to advance our understanding of health and disease

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      1 , 2 , 1 , , 2 ,
      Genome Medicine
      BioMed Central

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          Abstract

          Following the publication of the complete human genomic sequence, the post-genomic era is driven by the need to extract useful information from genomic data. Genomics, transcriptomics, proteomics, metabolomics, epidemiological data and microbial data provide different angles to our understanding of gene-environment interactions and the determinants of disease and health. Our goal and our challenge are to integrate these very different types of data and perspectives of disease into a global model suitable for dissecting the mechanisms of disease and for predicting novel therapeutic strategies. This review aims to highlight the need for and problems with complex data integration, and proposes a framework for data integration. While there are many obstacles to overcome, biological models based upon multiple datasets will probably become the basis that drives future biomedical research.

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          Most cited references23

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          An integrative genomics approach to infer causal associations between gene expression and disease.

          A key goal of biomedical research is to elucidate the complex network of gene interactions underlying complex traits such as common human diseases. Here we detail a multistep procedure for identifying potential key drivers of complex traits that integrates DNA-variation and gene-expression data with other complex trait data in segregating mouse populations. Ordering gene expression traits relative to one another and relative to other complex traits is achieved by systematically testing whether variations in DNA that lead to variations in relative transcript abundances statistically support an independent, causative or reactive function relative to the complex traits under consideration. We show that this approach can predict transcriptional responses to single gene-perturbation experiments using gene-expression data in the context of a segregating mouse population. We also demonstrate the utility of this approach by identifying and experimentally validating the involvement of three new genes in susceptibility to obesity.
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            Osteoarthritis.

            Osteoarthritis (OA) is characterized by degeneration of articular cartilage, limited intraarticular inflammation with synovitis, and changes in peri-articular and subchondral bone. Multiple factors are involved in the pathogenesis of OA, including mechanical influences, the effects of aging on cartilage matrix composition and structure, and genetic factors. Since the initial stages of OA involve increased cell proliferation and synthesis of matrix proteins, proteinases, growth factors, cytokines, and other inflammatory mediators by chondrocytes, research has focused on the chondrocyte as the cellular mediator of OA pathogenesis. The other cells and tissues of the joint, including the synovium and subchondral bone, also contribute to pathogenesis. The adult articular chondrocyte, which normally maintains the cartilage with a low turnover of matrix constituents, has limited capacity to regenerate the original cartilage matrix architecture. It may attempt to recapitulate phenotypes of early stages of cartilage development, but the precise zonal variations of the original cartilage cannot be replicated. Current pharmacological interventions that address chronic pain are insufficient, and no proven structure-modifying therapy is available. Cartilage tissue engineering with or without gene therapy is the subject of intense investigation. There are multiple animal models of OA, but there is no single model that faithfully replicates the human disease. This review will focus on questions currently under study that may lead to better understanding of mechanisms of OA pathogenesis and elucidation of effective strategies for therapy, with emphasis on mechanisms that affect the function of chondrocytes and interactions with surrounding tissues. 2007 Wiley-Liss, Inc.
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              Mendelian randomization as an instrumental variable approach to causal inference.

              In epidemiological research, the causal effect of a modifiable phenotype or exposure on a disease is often of public health interest. Randomized controlled trials to investigate this effect are not always possible and inferences based on observational data can be confounded. However, if we know of a gene closely linked to the phenotype without direct effect on the disease, it can often be reasonably assumed that the gene is not itself associated with any confounding factors - a phenomenon called Mendelian randomization. These properties define an instrumental variable and allow estimation of the causal effect, despite the confounding, under certain model restrictions. In this paper, we present a formal framework for causal inference based on Mendelian randomization and suggest using directed acyclic graphs to check model assumptions by visual inspection. This framework allows us to address limitations of the Mendelian randomization technique that have often been overlooked in the medical literature.
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                Author and article information

                Journal
                Genome Med
                Genome Medicine
                BioMed Central
                1756-994X
                2009
                30 March 2009
                : 1
                : 3
                : 35
                Affiliations
                [1 ]VTT Technical Research Centre of Finland, Tietotie 2, PO Box 1000, FIN-02044, Espoo, Finland
                [2 ]Metabolic Research Laboratories, Level 4, Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK
                Article
                gm35
                10.1186/gm35
                2664946
                19341506
                7a40a226-c6e9-4e18-bb0e-6aa847dc2ee4
                Copyright ©2009 BioMed Central Ltd
                History
                Categories
                Review

                Molecular medicine
                Molecular medicine

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