NEW WAYS TO FIND HUMAN BMD GENES USING MOUSE QTL MAPPING

Summary

Principal Investigator: D Karasik
Abstract: [unreadable] DESCRIPTION (provided by applicant): Combination of population and animal studies is a viable approach for genetics of complex traits. We identified several quantitative trait loci (QTL) for osteoporosis-related phenotypes in our studies of both rodents and humans. Some of these QTLs show overlap between mice and humans. The objectives of this proposal thus are: (a) to use information from human genome-wide association study (GWA) to refine a murine model to identify strong candidate genes at the syntenic regions containing QTLs, and (b) to directly incorporate the results of the mouse QTL analysis into a human cohort study. We will focus on QTLs for bone mineral density (BMD) and related traits located on mouse chromosomes 8, 15 and 17, syntenic to human regions on 16q22-q23, 8q24, and 6p21-p12, correspondingly, in which we also found linkage with bone mass related traits in humans. After a QTL gene is identified in the mouse, it will be tested in human association studies. We will examine polymorphisms in humans in a hypothesis- driven association study, which has statistical advantages over association studies that test multiple genes with no a priori hypothesis. The proposed work is innovative since it is based on 2 major developments: (a) novel mouse and human resources that allow in-silico comparative genetic study possible; (b) growing detailed knowledge of inter-species homology between the two species. This study thus has the potential to significantly advance current QTL studies by providing a new set of bioinformatics tools for narrowing QTLs by integrating the analytical strengths of several scientific disciplines. This integrated bioinformatic approach ultimately can be extended to gene identification for other complex diseases. [unreadable] [unreadable] [unreadable]
Funding Period: 2007-09-15 - 2010-08-31
more information: NIH RePORT

Top Publications

  1. pmc Bivariate genome-wide linkage analysis of femoral bone traits and leg lean mass: Framingham study
    David Karasik
    Hebrew SeniorLife Institute for Aging Research and Harvard Medical School, Boston, Massachusetts, USA
    J Bone Miner Res 24:710-8. 2009
  2. pmc A new standard genetic map for the laboratory mouse
    Allison Cox
    The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA
    Genetics 182:1335-44. 2009
  3. pmc Mouse BMD quantitative trait loci show improved concordance with human genome-wide association loci when recalculated on a new, common mouse genetic map
    Cheryl L Ackert-Bicknell
    The Jackson Laboratory, Bar Harbor, ME 04609, USA
    J Bone Miner Res 25:1808-20. 2010
  4. pmc Genome-wide pleiotropy of osteoporosis-related phenotypes: the Framingham Study
    David Karasik
    Hebrew SeniorLife Institute for Aging Research and Harvard Medical School, Boston, MA 02131, USA
    J Bone Miner Res 25:1555-63. 2010
  5. pmc Genetic variation in TRPS1 may regulate hip geometry as well as bone mineral density
    Cheryl L Ackert-Bicknell
    The Jackson Laboratory, Bar Harbor, ME 04609, USA
    Bone 50:1188-95. 2012

Detail Information

Publications5

  1. pmc Bivariate genome-wide linkage analysis of femoral bone traits and leg lean mass: Framingham study
    David Karasik
    Hebrew SeniorLife Institute for Aging Research and Harvard Medical School, Boston, Massachusetts, USA
    J Bone Miner Res 24:710-8. 2009
    ..Identification and subsequent characterization of these shared loci may further elucidate the genetic contributions to both osteoporosis and sarcopenia...
  2. pmc A new standard genetic map for the laboratory mouse
    Allison Cox
    The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA
    Genetics 182:1335-44. 2009
    ..We demonstrate that utilization of the revised genetic map improves QTL mapping, partially due to the resolution of previously undetected errors in marker ordering along the chromosome...
  3. pmc Mouse BMD quantitative trait loci show improved concordance with human genome-wide association loci when recalculated on a new, common mouse genetic map
    Cheryl L Ackert-Bicknell
    The Jackson Laboratory, Bar Harbor, ME 04609, USA
    J Bone Miner Res 25:1808-20. 2010
    ..We believe that this is an opportune time for a renewed effort by the genetics community to identify the causal variants regulating BMD using a synergistic mouse-human approach...
  4. pmc Genome-wide pleiotropy of osteoporosis-related phenotypes: the Framingham Study
    David Karasik
    Hebrew SeniorLife Institute for Aging Research and Harvard Medical School, Boston, MA 02131, USA
    J Bone Miner Res 25:1555-63. 2010
    ..Most of the similarity between the quantitative bone phenotypes may be attributed to pleiotropic effects of genes. This knowledge may prove helpful in defining the best phenotypes to be used in genetic studies of osteoporosis...
  5. pmc Genetic variation in TRPS1 may regulate hip geometry as well as bone mineral density
    Cheryl L Ackert-Bicknell
    The Jackson Laboratory, Bar Harbor, ME 04609, USA
    Bone 50:1188-95. 2012
    ..5×10(-4), adjusted P=01.38×10(-2)). In conclusion, we demonstrated that combining association studies in humans with murine models provides an efficient strategy to identify new candidate genes for bone phenotypes...