Genome-Wide Association Study of Bone Mineral Density in Korean Men

Osteoporosis is a medical condition of global concern, with increasing incidence in both sexes. Bone mineral density (BMD), a highly heritable trait, has been proven a useful diagnostic factor in predicting fracture. Because medical information is lacking about male osteoporotic genetics, we conducted a genome-wide association study of BMD in Korean men. With 1,176 participants, we analyzed 4,414,664 single nucleotide polymorphisms (SNPs) after genomic imputation, and identified five SNPs and three loci correlated with bone density and strength. Multivariate linear regression models were applied to adjust for age and body mass index interference. Rs17124500 (p = 6.42 × 10-7), rs34594869 (p = 6.53 × 10-7) and rs17124504 (p = 6.53 × 10-7) in 14q31.3 and rs140155614 (p = 8.64 × 10-7) in 15q25.1 were significantly associated with lumbar spine BMD (LS-BMD), while rs111822233 (p = 6.35 × 10-7) was linked with the femur total BMD (FT-BMD). Additionally, we analyzed the relationship between BMD and five genes previously identified in Korean men. Rs61382873 (p = 0.0009) in LRP5, rs9567003 (p = 0.0033) in TNFSF11 and rs9935828 (p = 0.0248) in FOXL1 were observed for LS-BMD. Furthermore, rs33997547 (p = 0.0057) in ZBTB and rs1664496 (p = 0.0012) in MEF2C were found to influence FT-BMD and rs61769193 (p = 0.0114) in ZBTB to influence femur neck BMD. We identified five SNPs and three genomic regions, associated with BMD. The significance of our results lies in the discovery of new loci, while also affirming a previously significant locus, as potential osteoporotic factors in the Korean male population.

[1]  B. Cho,et al.  Genetic association of APOA5 and APOE with metabolic syndrome and their interaction with health-related behavior in Korean men , 2015, Lipids in Health and Disease.

[2]  Seungbok Lee,et al.  A Common Variant of NGEF Is Associated with Abdominal Visceral Fat in Korean Men , 2015, PloS one.

[3]  S. Inoue,et al.  Recent genetic discoveries in osteoporosis, sarcopenia and obesity. , 2015, Endocrine journal.

[4]  S. Lei,et al.  Gene-Based Association Analysis Identified Novel Genes Associated with Bone Mineral Density , 2015, PloS one.

[5]  Olivier Delaneau,et al.  Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel , 2014, Nature Communications.

[6]  B. Han,et al.  Replication of Caucasian loci associated with bone mineral density in Koreans , 2013, Osteoporosis International.

[7]  D. Kim,et al.  The prevalence of osteoporosis in Korean adults aged 50 years or older and the higher diagnosis rates in women who were beneficiaries of a national screening program: The Korea National Health and Nutrition Examination Survey 2008–2009 , 2012, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[8]  J. Marchini,et al.  Fast and accurate genotype imputation in genome-wide association studies through pre-phasing , 2012, Nature Genetics.

[9]  V. Montori,et al.  Clinical review. Risk factors for low bone mass-related fractures in men: a systematic review and meta-analysis. , 2012, The Journal of clinical endocrinology and metabolism.

[10]  A. Silman,et al.  A validation of the first genome-wide association study of calcaneus ultrasound parameters in the European Male Ageing Study , 2011, BMC Medical Genetics.

[11]  Bjarni V. Halldórsson,et al.  European Bone Mineral Density Loci Are Also Associated with BMD in East-Asian Populations , 2010, PloS one.

[12]  I. Redlund‐Johnell,et al.  Smoking predicts incident fractures in elderly men: Mr OS Sweden , 2009, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

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

[14]  G. Mills,et al.  Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1 , 2008, Nature Genetics.

[15]  J. Hentz,et al.  The MUC1 Cytoplasmic Tail and Tandem Repeat Domains Contribute to Mammary Oncogenesis in FVB Mice , 2008, Breast cancer : basic and clinical research.

[16]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[17]  Jacques P. Brown,et al.  The use of clinical risk factors enhances the performance of BMD in the prediction of hip and osteoporotic fractures in men and women , 2007, Osteoporosis International.

[18]  A. Vandewalle,et al.  The Synthetic Androgen Methyltrienolone (R1881) Acts as a Potent Antagonist of the Mineralocorticoid Receptor , 2007, Molecular Pharmacology.

[19]  J. Cauley,et al.  Association of testosterone and estradiol deficiency with osteoporosis and rapid bone loss in older men. , 2006, The Journal of clinical endocrinology and metabolism.

[20]  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.

[21]  A. Uitterlinden,et al.  Loci for regulation of bone mineral density in men and women identified by genome wide linkage scan: the FAMOS study. , 2005, Human molecular genetics.

[22]  R. Eastell,et al.  Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men. , 2000, The Journal of clinical investigation.

[23]  E. Duthie,et al.  Osteoporosis in older men: discovering when and how to treat it. , 1999, Geriatrics.

[24]  T. Spector,et al.  The heritability of bone mineral density, ultrasound of the calcaneus and hip axis length: A study of postmenopausal twins , 1996, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[25]  S. Khosla,et al.  Osteoporosis in men. , 1995, Endocrine reviews.

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

[27]  J J Anderson,et al.  Effects of weight and body mass index on bone mineral density in men and women: The framingham study , 1993, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[28]  J. Clarke,et al.  Medicine , 1907, Bristol medico-chirurgical journal.

[29]  S. E. Park,et al.  Association of osteoporosis susceptibility genes with bone mineral density and bone metabolism related markers in Koreans: the Chungju Metabolic Disease Cohort (CMC) study. , 2014, Endocrine journal.

[30]  J. Eisman,et al.  Genetics of Bone Biology and Skeletal Disease , 2012 .

[31]  Daniel L. Koller,et al.  Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture , 2012, Nature Genetics.

[32]  Tanya M. Teslovich,et al.  LocusZoom: regional visualization of genome-wide association scan results , 2010, Bioinform..

[33]  E. Seeman,et al.  Osteoporosis in Men , 1999, Osteoporosis International.

[34]  D. Bushinsky.  Acidosis and bone. , 1994, Mineral and electrolyte metabolism.