Meta-analysis identifies a MECOM gene as a novel predisposing factor of osteoporotic fracture

Background Osteoporotic fracture (OF) as a clinical endpoint is a major complication of osteoporosis. To screen for OF susceptibility genes, we performed a genome-wide association study and carried out de novo replication analysis of an East Asian population. Methods Association was tested using a logistic regression analysis. A meta-analysis was performed on the combined results using effect size and standard errors estimated for each study. Results In a combined meta-analysis of a discovery cohort (288 cases and 1139 controls), three hospital based sets in replication stage I (462 cases and 1745 controls), and an independent ethnic group in replication stage II (369 cases and 560 for controls), we identified a new locus associated with OF (rs784288 in the MECOM gene) that showed genome-wide significance (p=3.59×10−8; OR 1.39). RNA interference revealed that a MECOM knockdown suppresses osteoclastogenesis. Conclusions Our findings provide new insights into the genetic architecture underlying OF in East Asians.

[1]  Eun-Hee Cho,et al.  Low Handgrip Strength is Associated with Low Bone Mineral Density and Fragility Fractures in Postmenopausal Healthy Korean Women , 2012, Journal of Korean medical science.

[2]  H. Kwon,et al.  Relationship between Vitamin D, Parathyroid Hormone, and Bone Mineral Density in Elderly Koreans , 2012, Journal of Korean medical science.

[3]  E. Demerath,et al.  A genome-wide association study of aging , 2011, Neurobiology of Aging.

[4]  F. Camargo,et al.  PR-domain-containing Mds1-Evi1 is critical for long-term hematopoietic stem cell function. , 2011, Blood.

[5]  Cathal Seoighe,et al.  Evidence for intron length conservation in a set of mammalian genes associated with embryonic development , 2011, BMC Bioinformatics.

[6]  Taesung Park,et al.  Large-scale genome-wide association studies in east Asians identify new genetic loci influencing metabolic traits , 2011, Nature Genetics.

[7]  Lorna M. Lopez,et al.  Genome-wide association and large scale follow-up identifies 16 new loci influencing lung function , 2011, Nature Genetics.

[8]  Christian Gieger,et al.  Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure , 2011, Nature Genetics.

[9]  Tom R. Gaunt,et al.  Genetic Variants in Novel Pathways Influence Blood Pressure and Cardiovascular Disease Risk , 2011, Nature.

[10]  B. Han,et al.  Association of SMAD2 polymorphisms with bone mineral density in postmenopausal Korean women , 2011, Osteoporosis International.

[11]  Christian Gieger,et al.  Genome-Wide Association Studies of Serum Magnesium, Potassium, and Sodium Concentrations Identify Six Loci Influencing Serum Magnesium Levels , 2010, PLoS genetics.

[12]  E. Liu,et al.  A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci , 2010, Nature Genetics.

[13]  L. Liang,et al.  An Integration of Genome-Wide Association Study and Gene Expression Profiling to Prioritize the Discovery of Novel Susceptibility Loci for Osteoporosis-Related Traits , 2010, PLoS genetics.

[14]  Bjarni V. Halldórsson,et al.  Association of JAG1 with bone mineral density and osteoporotic fractures: a genome-wide association study and follow-up replication studies. , 2010, American journal of human genetics.

[15]  Meng Li,et al.  Genome-Wide Association Study Identifies ALDH7A1 as a Novel Susceptibility Gene for Osteoporosis , 2010, PLoS genetics.

[16]  R Steven,et al.  Report assessing vertebral fractures , 2009 .

[17]  Jehyuk Lee,et al.  A Robust Approach to Identifying Tissue-Specific Gene Expression Regulatory Variants Using Personalized Human Induced Pluripotent Stem Cells , 2009, PLoS genetics.

[18]  Yurii S. Aulchenko,et al.  Twenty bone mineral density loci identified by large-scale meta-analysis of genome-wide association studies , 2009, Nature Genetics.

[19]  Bjarni V. Halldórsson,et al.  Sequence variants in the CLDN14 gene associate with kidney stones and bone mineral density , 2009, Nature Genetics.

[20]  A. Uitterlinden,et al.  Tissue Effect on Genetic Control of Transcript Isoform Variation , 2009, PLoS genetics.

[21]  Jehyuk Lee,et al.  Digital RNA Allelotyping Reveals Tissue-specific and Allele-specific Gene Expression in Human , 2009, Nature Methods.

[22]  Taesung Park,et al.  A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits , 2009, Nature Genetics.

[23]  Yan Guo,et al.  Genome-wide association and follow-up replication studies identified ADAMTS18 and TGFBR3 as bone mass candidate genes in different ethnic groups. , 2009, American journal of human genetics.

[24]  Kari Stefansson,et al.  Multiple genetic loci for bone mineral density and fractures. , 2008, The New England journal of medicine.

[25]  A Hofman,et al.  Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study , 2008, The Lancet.

[26]  Lester L. Peters,et al.  Genome-wide association study identifies novel breast cancer susceptibility loci , 2007, Nature.

[27]  B. Jönsson,et al.  The societal burden of osteoporosis in Sweden. , 2007, Bone.

[28]  A. Tosteson,et al.  Incidence and Economic Burden of Osteoporosis‐Related Fractures in the United States, 2005–2025 , 2007, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[29]  R. Redon,et al.  Relative Impact of Nucleotide and Copy Number Variation on Gene Expression Phenotypes , 2007, Science.

[30]  T. Yamagata,et al.  Dysplastic definitive hematopoiesis in AML1/EVI1 knock-in embryos. , 2005, Blood.

[31]  A. Silman,et al.  Predictive Value of BMD for Hip and Other Fractures , 2005, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[32]  R. Derynck,et al.  Repression of Bone Morphogenetic Protein and Activin-inducible Transcription by Evi-1* , 2005, Journal of Biological Chemistry.

[33]  R. Eastell,et al.  Accuracy of height loss during prospective monitoring for detection of incident vertebral fractures , 2005, Osteoporosis International.

[34]  T. Spector,et al.  Risk of Wrist Fracture in Women Is Heritable and Is Influenced by Genes That Are Largely Independent of Those Influencing BMD , 2004, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[35]  David L. Lacey,et al.  Osteoclast differentiation and activation , 2003, Nature.

[36]  T. Foroud,et al.  Genetics of osteoporosis. , 2002, Endocrine reviews.

[37]  S. Cummings,et al.  Epidemiology and outcomes of osteoporotic fractures , 2002, The Lancet.

[38]  E. Barrett-Connor,et al.  Identification and fracture outcomes of undiagnosed low bone mineral density in postmenopausal women: results from the National Osteoporosis Risk Assessment. , 2001, JAMA.

[39]  L. Wasserman,et al.  Genomic control, a new approach to genetic-based association studies. , 2001, Theoretical population biology.

[40]  Yusuke Nakamura,et al.  A high-throughput SNP typing system for genome-wide association studies , 2001, Journal of Human Genetics.

[41]  K. Roeder,et al.  Genomic Control for Association Studies , 1999, Biometrics.

[42]  M. Fukunaga,et al.  Diagnostic criteria of primary osteoporosis , 1998, Journal of Bone and Mineral Metabolism.

[43]  K. Tanaka,et al.  Structurally altered Evi-1 protein generated in the 3q21q26 syndrome. , 1996, Oncogene.

[44]  S. Ortolani,et al.  Genetics of osteoporosis , 1994, Calcified Tissue International.

[45]  M. Nevitt,et al.  Vertebral fracture assessment using a semiquantitative technique , 1993, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[46]  Browser’s Notes , 2012, Skeletal Radiology.

[47]  Bjarni V. Halldórsson,et al.  New sequence variants associated with bone mineral density , 2009, Nature Genetics.

[48]  L. Melton,et al.  Epidemiology worldwide. , 2003, Endocrinology and metabolism clinics of North America.

[49]  D. Torgerson,et al.  The Cost of Treating Osteoporotic Fractures in the United Kingdom Female Population , 1998, Osteoporosis International.

[50]  D. Kiel.  Assessing vertebral fractures. National Osteoporosis Foundation Working Group on Vertebral Fractures. , 1995, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.