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Delineating the Hemostaseome as an aid to individualize the analysis of the hereditary basis of thrombotic and bleeding disorders

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Abstract

Next-generation sequencing and genome-wide association studies represent powerful tools to identify genetic variants that confer disease risk within populations. On their own, however, they cannot provide insight into how these variants contribute to individual risk for diseases that exhibit complex inheritance, or alternatively confer health in a given individual. Even in the case of well-characterized variants that confer a significant disease risk, more healthy individuals carry the variant, with no apparent ill effect, than those who manifest disease. Access to low-cost genome sequence data promises to provide an unprecedentedly detailed view of the nature of the hereditary component of complex diseases, but requires the large-scale comparison of sequence data from individuals with and without disease to deliver a clinical calibration. The provision of informatics support remains problematic as there are currently no means to interpret the data generated. Here, we initiate this process, a prerequisite for such a study, by narrowing the focus from an entire genome to that of a single biological system. To this end, we examine the ‘Hemostaseome,’ and more specifically focus on DNA sequence changes pertaining to those human genes known to impact upon hemostasis and thrombosis that can be analyzed coordinately, and on an individual basis, to interrogate how specific combinations of variants act to confer disease predisposition. As a first step, we delineate known members of the Hemostaseome and explore the nature of the genetic variants that may cause disease in individuals whose hemostatic balance has become shifted toward either a prothrombotic or anticoagulant phenotype.

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Acknowledgments

This work was supported by NIH grant numbers 1R43HG004678-01 and 5R43HG004678-02 awarded to K.F. and 3rd Millennium, Inc. We gratefully acknowledge the use of the Database of Genomic Variants (http://projects.tcag.ca/variation/?source=hg18) for the initial identification of published CNV reports spanning the genes of the Hemostaseome. Additional citations present in Online Resources 1 and 3 but not present in the text have their full citations annotated in Online Resource 4. To access links in HGMD®, register at the Web site (http://www.hgmd.org) and then log in to successfully engage embedded links within the article.

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Authors and Affiliations

  1. 3rd Millennium Inc., 395 Totten Pond Road, Suite 201, Waltham, MA, 02451, USA

    Kim Fechtel & Marika L. Osterbur

  2. Institute of Human Genetics, University of Ulm, Albert-Einstein-Allee 11, Ulm, Germany

    Hildegard Kehrer-Sawatzki

  3. Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK

    Peter D. Stenson & David N. Cooper

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  1. Kim Fechtel
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  2. Marika L. Osterbur
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Correspondence to Kim Fechtel.

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Fechtel, K., Osterbur, M.L., Kehrer-Sawatzki, H. et al. Delineating the Hemostaseome as an aid to individualize the analysis of the hereditary basis of thrombotic and bleeding disorders. Hum Genet 130, 149–166 (2011). https://doi.org/10.1007/s00439-011-0984-y

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