GENETIC ANALYSIS OF HIP FRAGILITY

Summary

Principal Investigator: Tatiana M Foroud
Abstract: In 2001, our group began studies to determine the genetics causes of bone fragility. We chose to study rats, rather than mice, because the laboratory rat has proven to be an excellent model for human bone disorders, like osteoporosis. Because rats are larger than mice, it is easier to measure bone structure and strength at the femoral neck, which is a skeletal site of primary focus. Our first study involved a cross between Fischer 344 (F344) and Lewis (LEW) rats. Our second study focusing on Copenhagen 2331 (COP) and Dark Agouti (DA) rats began in 2003 and is the subject of this competitive renewal application. We have successfully mapped quantitative trait loci (QTLs) for femoral neck and femoral midshaft phenotypes, the primary and secondary goals of the project. Our work in the past five years has provided a clear direction for our proposed research in the next five years: we will identify genes within QTLs that affect bone biology. This project has three Aims. First, we will identify causative genes within our two QTLs with largest effect size: Chromosome (Chr) 4 for F344 and LEW rats (13% effect) and Chr 1 for COP and DA rats (14% effect). We plan to generate congenic rat models and conduct gene expression profiling followed by functional studies in vivo and using cultured osteoblasts and osteoclasts to identify genes that directly affect bone biology. Second, we will work with a large, world-wide research consortium to conduct a genome wide association study (GWAS) in heterogeneous stock (HS) rats. The GWAS led by Jonathan Flint will provide phenotypes and genotypes for over 2000 rats. Phenotypes will include: behavioral, metabolic, hematological, hemodynamic, immunological and skeletal (our contribution). Each rat will be genotyped for about 20,000 single nucleotide polymorphisms (SNPs). The results will allow us to identify new QTLs that affect bone traits and to reduce the number of candidate genes at each QTL from several dozen to a mere handful. Finally, we will identify gene expression QTLs (eQTLs) using a genome screen to map transcript abundance in 2nd filial (F2) rats derived from COP and DA progenitors. Variations in expression of individual genes will be mapped to locations on the genome to produce eQTLs. eQTL mapping allows one to identify cis-eQTLs for which expression levels can be correlated with a chosen bone phenotype to identify and prioritize genes most likely to alter bone biology. Also, we will identify trans- genes controlled by a given QTL and with this information we will construct networks of genes that underlie complex bone traits. Another unique feature of eQTL mapping is its ability to identify allele-specific regulation of gene expression on a genome-wide scale. Completion of these Aims will accelerate our progress toward identifying genes that affect bone fragility. PUBLIC HEALTH RELEVANCE: Our study will identify genes that cause bone fragility. We will use several inbred strains of rats in our experiments and apply modern genetics techniques like gene expression microarrays and single nucleotide polymorphism genotyping. Our goal is to find genetic causes for bone weakening conditions like osteoporosis so better treatments can be developed.
Funding Period: ----------------2001 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi Identification of a quantitative trait locus on rat chromosome 4 that is strongly linked to femoral neck structure and strength
    I Alam
    Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Bone 39:93-9. 2006
  2. pmc Combined sequence-based and genetic mapping analysis of complex traits in outbred rats
    Amelie Baud
    Wellcome Trust Centre for Human Genetics, Oxford, UK
    Nat Genet 45:767-75. 2013
  3. pmc High-resolution genome screen for bone mineral density in heterogeneous stock rat
    Imranul Alam
    Department of Medicine, Indiana University School of Medicine, IN, USA
    J Bone Miner Res 29:1619-26. 2014
  4. pmc Genomic expression analysis of rat chromosome 4 for skeletal traits at femoral neck
    Imranul Alam
    Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, Indiana 46202, USA
    Physiol Genomics 35:191-6. 2008
  5. pmc Linkage screen for BMD phenotypes in male and female COP and DA rat strains
    Daniel L Koller
    Department of Medical and Molecular Genetics, Indiana University, Indianapolis, Indiana 46202, USA
    J Bone Miner Res 23:1382-8. 2008
  6. pmc Sex-specific genetic loci for femoral neck bone mass and strength identified in inbred COP and DA rats
    Imranul Alam
    Department of Biomedical Engineering, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
    J Bone Miner Res 23:850-9. 2008
  7. pmc Genetic loci affecting bone structure and strength in inbred COP and DA rats
    Qiwei Sun
    Department of Biomedical Engineering, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Bone 42:547-53. 2008
  8. pmc Epistatic effects contribute to variation in BMD in Fischer 344 x Lewis F2 rats
    Daniel L Koller
    Department of Medical and Molecular Genetics, Indiana University, Purdue University Indianapolis, Indianapolis, Indiana, USA
    J Bone Miner Res 23:41-7. 2008
  9. pmc Epistasis between QTLs for bone density variation in Copenhagen x dark agouti F2 rats
    Daniel L Koller
    Department of Medical and Molecular Genetics, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA
    Mamm Genome 20:180-6. 2009
  10. pmc Genes influencing spinal bone mineral density in inbred F344, LEW, COP, and DA rats
    Imranul Alam
    Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, 46202 5251, USA
    Funct Integr Genomics 10:63-72. 2010

Scientific Experts

  • Daniel L Koller
  • Andrew Saykin
  • Imranul Alam
  • Tatiana Foroud
  • Amelie Baud
  • Shanker Swaminathan
  • Qiwei Sun
  • Tomas Olsson
  • Carola Rintisch
  • Ngan Huynh
  • Victor Guryev
  • Paul Flicek
  • Diana Ekman
  • Pim Toonen
  • Elisabeth Beattie
  • Margarita Diez
  • Ewart de Bruijn
  • Tomas Malinauskas
  • Oliver Hummel
  • Esther Martínez-Membrives
  • Alan Gillett
  • Martin W McBride
  • Jonathan Flint
  • Nada Abdelmagid
  • Toni Cañete
  • Young Ae Lee
  • Carme Mont-Cardona
  • Jonatan Tuncel
  • William H Miller
  • Norbert Hubner
  • Sophie Calderari
  • Herbert Schulz
  • Kim C Worley
  • Diana Zelenika
  • Edwin Cuppen
  • Richard A Gibbs
  • Marie Therese Bihoreau
  • Rikard Holmdahl
  • Anna F Dominiczak
  • Gloria Blázquez
  • Pernilla Stridh
  • Mark Lathrop
  • E Yvonne Jones
  • Santosh S Atanur
  • Kathrin Saar
  • Johan Ockinger
  • Delyth Graham
  • Tim J Aitman
  • David J Adams
  • Donna M Muzny
  • Adolf Tobeña
  • Andre Ortlieb Guerreiro-Cacais
  • Frans Paul Ruzius
  • Ulrika Norin
  • Giannino Patone
  • Thomas Keane
  • Martina Johannesson
  • Anja Bauerfeind
  • Richard Mott
  • David A Wheeler
  • Nico Lansu
  • Roel Hermsen
  • Heidi Hauser
  • Maja Jagodic
  • Regina Lopez-Aumatell
  • Amennai D Beyeen
  • Matthias Heinig
  • Elia Vicens-Costa
  • Samreen Falak
  • Dominique Gauguier
  • Mary Osborne-Pellegrin
  • Alberto Fernandez-Teruel
  • Sira Díaz-Morán
  • Karmen K Yoder
  • Steven G Potkin
  • Matthew J Huentelman
  • Michael W Weiner
  • Sungeun Kim
  • John D West
  • Kwangsik Nho
  • Li Shen
  • Chester A Mathis
  • David W Craig
  • Shannon L Risacher
  • Robert A Koeppe
  • Mark Inlow
  • Clifford R Jack
  • William J Jagust
  • Charles H Turner
  • Lucinda G Carr

Detail Information

Publications14

  1. ncbi Identification of a quantitative trait locus on rat chromosome 4 that is strongly linked to femoral neck structure and strength
    I Alam
    Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Bone 39:93-9. 2006
    ..These findings represent an important first step in localizing and identifying genes that influence hip fragility...
  2. pmc Combined sequence-based and genetic mapping analysis of complex traits in outbred rats
    Amelie Baud
    Wellcome Trust Centre for Human Genetics, Oxford, UK
    Nat Genet 45:767-75. 2013
    ....
  3. pmc High-resolution genome screen for bone mineral density in heterogeneous stock rat
    Imranul Alam
    Department of Medicine, Indiana University School of Medicine, IN, USA
    J Bone Miner Res 29:1619-26. 2014
    ....
  4. pmc Genomic expression analysis of rat chromosome 4 for skeletal traits at femoral neck
    Imranul Alam
    Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, Indiana 46202, USA
    Physiol Genomics 35:191-6. 2008
    ..This study provides a shortened list of genetic determinants of skeletal traits at the hip and may lead to novel approaches for prevention and treatment of hip fracture...
  5. pmc Linkage screen for BMD phenotypes in male and female COP and DA rat strains
    Daniel L Koller
    Department of Medical and Molecular Genetics, Indiana University, Indianapolis, Indiana 46202, USA
    J Bone Miner Res 23:1382-8. 2008
    ..These results confirm that the genetic influence on BMD in the rat model is quite complex and would seem to be influenced by a number of different genes, some of which have sex-specific effects...
  6. pmc Sex-specific genetic loci for femoral neck bone mass and strength identified in inbred COP and DA rats
    Imranul Alam
    Department of Biomedical Engineering, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
    J Bone Miner Res 23:850-9. 2008
    ..The purpose of this study is to identify sex-independent and sex-specific quantitative trait loci (QTLs) for femoral neck density, structure, and strength in inbred Copenhagen 2331 (COP) and Dark Agouti (DA) rats...
  7. pmc Genetic loci affecting bone structure and strength in inbred COP and DA rats
    Qiwei Sun
    Department of Biomedical Engineering, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Bone 42:547-53. 2008
    ..Our study demonstrates strong evidence of linkage for bone structure and strength to multiple rat chromosomes...
  8. pmc Epistatic effects contribute to variation in BMD in Fischer 344 x Lewis F2 rats
    Daniel L Koller
    Department of Medical and Molecular Genetics, Indiana University, Purdue University Indianapolis, Indianapolis, Indiana, USA
    J Bone Miner Res 23:41-7. 2008
    ..Several significant interactions were identified, involving both previously identified and novel QTLs...
  9. pmc Epistasis between QTLs for bone density variation in Copenhagen x dark agouti F2 rats
    Daniel L Koller
    Department of Medical and Molecular Genetics, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA
    Mamm Genome 20:180-6. 2009
    ..These results provide new information regarding the mode of action of previously identified QTL in the rat, as well as identifying novel loci that act in combination with known QTL or with other novel loci to contribute to BMD variation...
  10. pmc Genes influencing spinal bone mineral density in inbred F344, LEW, COP, and DA rats
    Imranul Alam
    Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, 46202 5251, USA
    Funct Integr Genomics 10:63-72. 2010
    ..Of these, 14 genes (Akap1, Asgr2, Esd, Fam101b, Irf1, Lcp1, Ltc4s, Mdp-1, Pdhb, Plxdc1, Rabep1, Rhot1, Slc2a4, Xpo4) were confirmed by qPCR. We identified several novel candidate genes influencing spinal vBMD in rats...
  11. pmc Identification of genes influencing skeletal phenotypes in congenic P/NP rats
    Imranul Alam
    Department of Biomedical Engineering, Indiana University Purdue University Indianapolis IUPUI, Indianapolis, IN 46202, USA
    J Bone Miner Res 25:1314-25. 2010
    ..We identified several candidate genes, including some novel genes on chromosome 4 segregating for skeletal phenotypes in reciprocal congenic P and NP rats...
  12. pmc Heterogeneous stock rat: a unique animal model for mapping genes influencing bone fragility
    Imranul Alam
    Indiana University School of Medicine, Indiana University Indianapolis, IN, USA
    Bone 48:1169-77. 2011
    ....
  13. pmc Amyloid pathway-based candidate gene analysis of [(11)C]PiB-PET in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort
    Shanker Swaminathan
    Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine, Indianapolis, IN, USA
    Brain Imaging Behav 6:1-15. 2012
    ..Pathway-based genetic analysis of targeted molecular imaging phenotypes appears promising to help elucidate disease pathophysiology and identify potential therapeutic targets...
  14. pmc Differentially expressed genes strongly correlated with femur strength in rats
    Imranul Alam
    Department of Biomedical Engineering, Indiana University Purdue University Indianapolis IUPUI, Indianapolis, IN 46202 5251, USA
    Genomics 94:257-62. 2009
    ....