Genetics of Bone Structure and Metabolism


Principal Investigator: Michael C Mahaney
Abstract: PROJECT SUMMARY Osteoporosis, a disorder characterized by progressive, age-related decreases in bone mass and density, disruption of normal bone architecture, and consequent reduction in bone strength, results in increased susceptibility to fracture. In older persons, osteoporotic fracture is associated with substantial comorbidity and mortality. As the world's population ages, the attendant human suffering and economic costs of osteoporosis are predicted to increase dramatically. Research on osteoporosis in the developed, industrialized countries like the U.S., Canada, and the E.U. nations has elucidated the contributions of dietary, behavioral, and environmental factors to age-related fracture risks and has begun to unravel the genetic underpinnings as well. However, most searches for osteoporosis risk genes are less than optimally powered and osteoporosis-related research in developing countries is nascent or nonexistent. We propose to conduct the first combined whole genome linkage and association study for genes affecting variation in bone-related phenotypes in a population from a developing country: the Jirels of Eastern Nepal. With 2000 members already genotyped at over 400 marker loci, the single, unbroken, non-inbred Jirel pedigree currently is the largest and most powerful dataset available to a genome scanning study. (1) We will characterize all 2000 individuals for a broad range of bone-related traits including bone ultrasound attenuation of the calcaneous, bone mineral densities in 3 regions (proximal femur, lumbar spine, and forearm) assessed using dual-energy X-ray absorptiometry, and 12 biomarkers related to bone formation, turn-over, and metabolism. (2) We will use quantitative genetic analysis techniques to determine the amount of variation in each of the bone-related traits that is attributable to genes and assess the degree to which common genes influence pairs of bone-related phenotypes (pleiotropy). (3) We will conduct genome-wide linkage analysis to localize genes for each of the bone related phenotypes - as well as pleiotropic genes affecting multiple phenotypes - to specific chromosomal regions. (4) We will genotype 1000 of the participants for approximately 550,000 single nucleotide polymorphisms and use novel, pedigree-based genetic association methods to nominate and prioritize positional candidate genes for all QTLs. (5) Finally, using these same analytical methods and SNP marker sets, we will perform analyses to validate our findings in 1000 Euro-American participants of a separately funded study of the genetics of osteoporosis-related traits in the Fels Longitudinal study The goals of this project are the localization, identification, and characterization of QTLs influencing bone-related phenotypes, the nomination of positional candidate genes likely contributing to variation in these traits - and, by extension, osteoporosis population directed by co-investigators on this project. risk - in humans in general, as well as those with effects more specific to peoples from an understudied region of the world.
Funding Period: 2009-09-25 - 2014-07-31
more information: NIH RePORT

Detail Information

Research Grants30

  1. Genetic Architecture of Adiposity in Multiple Large Cohorts
    Kari E North; Fiscal Year: 2013
    ..This work will stimulate the discovery of variants and pathways, and potentially extend our understanding of the genetic basis of obesity risk and suggest potential therapeutic targets. ..
  2. Fluoride &Other Factors in Childhood and Adolescent Bone Development
    Steven M Levy; Fiscal Year: 2013
    ..abstract_text> ..
  3. Mineralization Gene Variants: Biochemical Implications and Associations with BMD
    Carrie M Nielson; Fiscal Year: 2013
    ..The study design and analytic methods developed through this work will also be applicable to the study of rare variants in other musculoskeletal candidate genes in the future. ..
  4. Genome Wide Association Study of Bone Mineral Accretion During Childhood
    Babette S Zemel; Fiscal Year: 2013
    Victor J Hruby; Fiscal Year: 2013
  6. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  7. Adiposity and Bone Loss in Spinal Cord Injury
    Leslie R Morse; Fiscal Year: 2013
    ..We will also determine if people with SCI and greater amounts of visceral fat lose more bone than those with SCI and less fat and assess relationships with bone loss and hormones in the blood that are related to fat. ..
  8. Prevention of age-associated musculoskeletal loss by n-3 fatty acids
    Md Mizanur Rahman; Fiscal Year: 2013
    ..abstract_text> ..
  9. Mitochondrial Dysfunction in Neurodegeneration of Aging
    Gary E Gibson; Fiscal Year: 2013
    ..Successful completion of the goals of these projects can be expected to provide new insights into neurodegenerative processes and contribute to novel approaches to ameliorating age-related neurodegenerations. ..
  10. Bone Microarchitecture: The Framingham Osteoporosis Study
    Douglas P Kiel; Fiscal Year: 2013
    Sundeep Khosla; Fiscal Year: 2013
    ..Collectively, these studies strive to provide a comprehensive assesment of the pathogenesis and clinical impact of one of the most important disorders facing our aging population. ..
  12. Osteoporosis in HIV Infected Postmenopausal Women
    ELIZABETH J SHANE; Fiscal Year: 2013
    ..The increasing prevalence of HIV-infection on older minority women and the aging of the HIV-infected population make it critical to elucidate the effects of HIV and its treatment on bone health. ..
    Hong Wen Deng; Fiscal Year: 2013
    ..abstract_text> ..