Epigenomewide DNA Methylation Study for Osteoporosis Risk

Summary

Principal Investigator: Hong Wen Deng
Abstract: DESCRIPTION (provided by applicant): Osteoporosis is a common disease mainly characterized by low bone mineral density (BMD) and increased risk of fractures. Peripheral blood monocytes (PBMs) may not only act as precursors of osteoclasts, the bone resorption cells, but also produce cytokines important for osteoclast differentiation, activation, and apoptosis, and thus represent major systemic cells for bone metabolism. Alterations in DNA methylation as an important epigenetic regulator of gene expression, is significant in the etiology of human complex diseases. In vitro studies have shown that DNA methylation is involved in osteoclastogenesis;however, the in vivo significance of global DNA methylation profiles (methylome) in humans underlying osteoporosis risk is unknown. Our Hypothesis is that altered DNA methylation profiles in PBMs and the associated changes in gene expression and osteoclastogenesis contribute to peak BMD variation in humans. Our Goal/Expectation is to i) identify differentially methylated regions (DMRs) in PBMs at the whole methylome level between premenopausal women with extremely high peak BMD and those with extremely low peak BMD;ii) study potential epigenetic mechanisms of osteoporosis, namely, how the DMRs identified may influence the peak BMD variation through affecting the expression of the relevant genes and subsequent osteoclastogenesis. Methods: 1) PBMs and their DNAs and total RNAs will be extracted from 160 premenopausal Caucasian females aged 25-40 years, including 80 with extremely high peak BMD and 80 with extremely low peak BMD (but otherwise matched). 2) DMRs will be identified by performing state-of-the-art methylome profiling studies with the cutting-edge technology MeDIP-seq (methylated DNA immunoprecipitation assays followed by next-generation sequencing) in a discovery sample of 80 subjects (including 40 with high and 40 with low BMD). 3) The identified DMRs will be subject to confirmation by bisulfite sequencing in an independent replication sample (including 40 with high and 40 with low BMD), and their target genes will be identified by correlating the DNA methylation data with the mRNA expression levels of the potential candidate target genes in PBMs of the total 160 subjects. 4) The roles of the identified most significant DMR-affiliated target genes on osteoclastogenesis will be further investigated by cell based in vitro assays. This highly novel R01 project holds great promise of award to generate breakthroughs in the osteoporosis research field. The results may lead to a major paradigm shift by expanding current genetic epidemiology studies of osteoporosis, from classical DNA variants to novel epigenetics/epigenomics mechanisms of DNA modification. Therefore, the results will be highly important for understanding the underlying molecular mechanisms, and thus help prevention and treatment, of osteoporosis.
Funding Period: 2012-09-01 - 2017-08-31
more information: NIH RePORT

Top Publications

  1. pmc Ethnic differentiation of copy number variation on chromosome 16p12.3 for association with obesity phenotypes in European and Chinese populations
    T L Yang
    Key Laboratory of Biomedical Information Engineering of Ministry of Education and Institute of Molecular Genetics, School of Life Science and Technology, Xi an Jiaotong University, Xi an, China
    Int J Obes (Lond) 37:188-90. 2013
  2. pmc Mutant ZP1 in familial infertility
    Hua Lin Huang
    From the Institute of Reproduction and Stem Cell Engineering, Central South University H L H, C L, W L, G X L, H M X, Reproductive and Genetic Hospital of CITIC Xiangya W L, G X L, H M X, and the First High School of Changsha X T, Changsha, and Xiamen Maternal and Child Health Care Hospital X M H, P L and PLA Hospital No 174 A G S, Xiamen all in China the Department of Biostatistics and Bioinformatics, School of Public Health and Tropical Medicine, Tulane University, New Orleans H L H, Y C Z, H W D and the School of Medicine, University of Missouri Kansas City, Kansas City C J P
    N Engl J Med 370:1220-6. 2014
  3. pmc Genome-wide association study identified copy number variants important for appendicular lean mass
    Shu Ran
    Center of System Biomedical Sciences, University of Shanghai for Science and Technology, Shanghai, People s Republic of China
    PLoS ONE 9:e89776. 2014
  4. pmc FISH: fast and accurate diploid genotype imputation via segmental hidden Markov model
    Lei Zhang
    School of Public Health, Xi an Jiaotong University, Shaanxi, China, Department of Biostatistics and Bioinformatics, Tulane University, New Orleans, USA and Center of System Biomedical Sciences, University of Shanghai for Science and Technology, Shanghai, ChinaSchool of Public Health, Xi an Jiaotong University, Shaanxi, China, Department of Biostatistics and Bioinformatics, Tulane University, New Orleans, USA and Center of System Biomedical Sciences, University of Shanghai for Science and Technology, Shanghai, China
    Bioinformatics 30:1876-83. 2014
  5. pmc CNV-TV: a robust method to discover copy number variation from short sequencing reads
    Junbo Duan
    Department of Biomedical Engineering, Tulane University, New Orleans, LA, USA
    BMC Bioinformatics 14:150. 2013
  6. pmc Comprehensive characterization of human genome variation by high coverage whole-genome sequencing of forty four Caucasians
    Hui Shen
    Center for Bioinformatics and Genomics, Department of Biostatistics and Bioinformatics, School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana, USA
    PLoS ONE 8:e59494. 2013
  7. pmc Comparative studies of copy number variation detection methods for next-generation sequencing technologies
    Junbo Duan
    Department of Biomedical Engineering, Tulane University, New Orleans, Louisiana, United States of America
    PLoS ONE 8:e59128. 2013
  8. pmc On combining reference data to improve imputation accuracy
    Jun Chen
    Center for Bioinformatics and Genomics, Department of Biostatistics and Bioinformatics, School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana, United States of America
    PLoS ONE 8:e55600. 2013
  9. pmc Copy number variation on chromosome 10q26.3 for obesity identified by a genome-wide study
    Tie Lin Yang
    Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi an Jiaotong University, Xi an 710049, People s Republic of China
    J Clin Endocrinol Metab 98:E191-5. 2013
  10. pmc Suggestion of GLYAT gene underlying variation of bone size and body lean mass as revealed by a bivariate genome-wide association study
    Yan Fang Guo
    School of Basic Medical Science, Institute of Bioinformatics, Southern Medical University, Guangzhou, People s Republic of China
    Hum Genet 132:189-99. 2013

Detail Information

Publications11

  1. pmc Ethnic differentiation of copy number variation on chromosome 16p12.3 for association with obesity phenotypes in European and Chinese populations
    T L Yang
    Key Laboratory of Biomedical Information Engineering of Ministry of Education and Institute of Molecular Genetics, School of Life Science and Technology, Xi an Jiaotong University, Xi an, China
    Int J Obes (Lond) 37:188-90. 2013
    ..3, for association with obesity in Europeans. The aim of this study was to directly examine the relationship between the CNV 16p12.3 and obesity phenotypes, including body mass index (BMI) and body fat mass...
  2. pmc Mutant ZP1 in familial infertility
    Hua Lin Huang
    From the Institute of Reproduction and Stem Cell Engineering, Central South University H L H, C L, W L, G X L, H M X, Reproductive and Genetic Hospital of CITIC Xiangya W L, G X L, H M X, and the First High School of Changsha X T, Changsha, and Xiamen Maternal and Child Health Care Hospital X M H, P L and PLA Hospital No 174 A G S, Xiamen all in China the Department of Biostatistics and Bioinformatics, School of Public Health and Tropical Medicine, Tulane University, New Orleans H L H, Y C Z, H W D and the School of Medicine, University of Missouri Kansas City, Kansas City C J P
    N Engl J Med 370:1220-6. 2014
    ....
  3. pmc Genome-wide association study identified copy number variants important for appendicular lean mass
    Shu Ran
    Center of System Biomedical Sciences, University of Shanghai for Science and Technology, Shanghai, People s Republic of China
    PLoS ONE 9:e89776. 2014
    ..In summary, our study suggested two novel CNVs and the related genes that may contribute to variation in ALM...
  4. pmc FISH: fast and accurate diploid genotype imputation via segmental hidden Markov model
    Lei Zhang
    School of Public Health, Xi an Jiaotong University, Shaanxi, China, Department of Biostatistics and Bioinformatics, Tulane University, New Orleans, USA and Center of System Biomedical Sciences, University of Shanghai for Science and Technology, Shanghai, ChinaSchool of Public Health, Xi an Jiaotong University, Shaanxi, China, Department of Biostatistics and Bioinformatics, Tulane University, New Orleans, USA and Center of System Biomedical Sciences, University of Shanghai for Science and Technology, Shanghai, China
    Bioinformatics 30:1876-83. 2014
    ..However, most of the existing imputation approaches suffer from either inaccurate results or heavy computational demand...
  5. pmc CNV-TV: a robust method to discover copy number variation from short sequencing reads
    Junbo Duan
    Department of Biomedical Engineering, Tulane University, New Orleans, LA, USA
    BMC Bioinformatics 14:150. 2013
    ..However, the performances of these methods are not robust under some conditions, e.g., some of them may fail to detect CNVs of short sizes. There has been a strong demand for reliable detection of CNVs from high resolution NGS data...
  6. pmc Comprehensive characterization of human genome variation by high coverage whole-genome sequencing of forty four Caucasians
    Hui Shen
    Center for Bioinformatics and Genomics, Department of Biostatistics and Bioinformatics, School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana, USA
    PLoS ONE 8:e59494. 2013
    ..Our results contribute towards a comprehensive characterization of human genomic variation, especially for less-common and rare variants, and provide an invaluable resource for future genetic studies of human variation and diseases...
  7. pmc Comparative studies of copy number variation detection methods for next-generation sequencing technologies
    Junbo Duan
    Department of Biomedical Engineering, Tulane University, New Orleans, Louisiana, United States of America
    PLoS ONE 8:e59128. 2013
    ..The computational demands are also studied. The results of our work provide a comprehensive evaluation on the performances of the selected CNV detection methods, which will help biological investigators choose the best possible method...
  8. pmc On combining reference data to improve imputation accuracy
    Jun Chen
    Center for Bioinformatics and Genomics, Department of Biostatistics and Bioinformatics, School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana, United States of America
    PLoS ONE 8:e55600. 2013
    ..Our study is helpful in guiding application of imputation methods in next generation association analyses...
  9. pmc Copy number variation on chromosome 10q26.3 for obesity identified by a genome-wide study
    Tie Lin Yang
    Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi an Jiaotong University, Xi an 710049, People s Republic of China
    J Clin Endocrinol Metab 98:E191-5. 2013
    ..However, a large proportion of the heritability of obesity remains unexplained. Copy number variations (CNVs) might contribute to the missing heritability of obesity...
  10. pmc Suggestion of GLYAT gene underlying variation of bone size and body lean mass as revealed by a bivariate genome-wide association study
    Yan Fang Guo
    School of Basic Medical Science, Institute of Bioinformatics, Southern Medical University, Guangzhou, People s Republic of China
    Hum Genet 132:189-99. 2013
    ..Our findings, together with the prior biological evidence, suggest the importance of GLYAT gene in co-regulation of bone phenotypes and body lean mass...
  11. pmc Replication of 6 obesity genes in a meta-analysis of genome-wide association studies from diverse ancestries
    Li Jun Tan
    Laboratory of Molecular and Statistical Genetics and Key Laboratory of Protein Chemistry and Developmental Biology of the Ministry of Education, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China
    PLoS ONE 9:e96149. 2014
    ..Sex and ethnic differences in genetic susceptibility across populations of diverse ancestries may contribute to a more targeted prevention and customized treatment of obesity...

Research Grants30

  1. HORMONAL CONTROL OF CALCIUM METABOLISM
    John T Potts; Fiscal Year: 2013
    ....
  2. ERK Signaling in Inflammatory Bone Loss
    Francis Young In Lee; Fiscal Year: 2013
    ..Overall impact is high in that we expect to unravel novel anti-osteoclastogenic mechanisms and therapeutic promise of rhCRG in the context of inflammatory osteolysis. ..
  3. Epigenome-Wide Association Study of DNA Methylation and Atherosclerosis
    Yongmei Liu; Fiscal Year: 2013
    ..The knowledge obtained should yield new biomarkers for ASCVD diagnosis and uncover unique therapeutic targets for future targeted interventions. ..
  4. The Role of Podocalyxin in Osteoclast Activity and Bone Metabolism
    Megan M Weivoda; Fiscal Year: 2013
    ..Additionally, studying the role of sex steroids in the Vav/PODXLdel bone phenotype may elucidate mechanisms that contribute to postmenopausal and age-related bone loss. ..
  5. The Role Of Osteoclast PODXL, A Mediator Of Cell Adhesion, In Bone Metabolism
    Merry Jo Oursler; Fiscal Year: 2013
    ....
  6. Signal Transduction Mechanism of Osteoclast Differentiation
    Nandini Ghosh-Choudhury; Fiscal Year: 2013
    ..Our results will demonstrate how BMP-2 can orchestrate a complex transcriptional network in osteoblasts to tightly regulate osteoclast activation. ..
  7. DAP12 and ITAM-signals in Osteoclastogenesis
    Mary C Nakamura; Fiscal Year: 2013
    ..3. Determine the requirement for ROS during rapid osteoclastogenesis in the absence of ITAM- adapter signals. ..
  8. The role of the atypical PKCs in osteoclast function
    JULIA THERESE WARREN; Fiscal Year: 2013
    ..We propose to study the mechanisms by which the osteoclast, the sole bone resorbing cell, functions. This will help provide the foundations for novel therapeutic development to treat osteoporosis. ..
  9. Connection of Mineral and Energy Metabolism by the Nuclear Receptor PPAR-gamma
    Yihong Wan; Fiscal Year: 2013
    ..Therefore, this investigation will significantly impact the broader scientific, clinical, and patient community. ..
  10. Center for GI Infection and Injury
    MARY KOLB ESTES; Fiscal Year: 2013
    ..A large, multi-ethnic population of infants and adults with Digestive Diseases emphasizes a need and opportunities for this Center. ..
  11. 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. ..
  12. Cellular Senescence and Aging
    James L Kirkland; Fiscal Year: 2013
    ..Our approach will provide timely, innovative, and clinically relevant interventional results based on addressing the fundamental question of the role of cellular senescence that has remained unanswered for many years. ..
  13. Egg to Embryo: Gene Regulatory Circuitry in Development
    Eric H Davidson; Fiscal Year: 2013
    ..In the DAVIDSON COMPONENT the GRN will be expanded to include all regulatory genes predicted by genomic analysis, and observed to be expressed specifically in the endomesodermal territories, (cont.) ..
  14. Biosynthesis and Function of Lactosaminyl Glycans in Hematopoiesis
    Robert Sackstein; Fiscal Year: 2013
    ..This research effort should yield new treatments to improve marrow function in such conditions. (End of Abstract) ..
  15. PHYSIOLOGY OF BONE METABOLISM IN AN AGING POPULATION
    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. ..
  16. ROBUST AND POWERFUL TEST OF CANDIDATE GENES TO BONE MASS
    Hong Wen Deng; Fiscal Year: 2013
    ..abstract_text> ..