European Bone Mineral Density Loci Are Also Associated with BMD in East-Asian Populations

Abstract

Most genome-wide association (GWA) studies have focused on populations of European ancestry with limited assessment of the influence of the sequence variants on populations of other ethnicities. To determine whether markers that we have recently shown to associate with Bone Mineral Density (BMD) in Europeans also associate with BMD in East-Asians we analysed 50 markers from 23 genomic loci in samples from Korea (n = 1,397) and two Chinese Hong Kong sample sets (n = 3,869 and n = 785). Through this effort we identified fourteen loci that associated with BMD in East-Asian samples using a false discovery rate (FDR) of 0.05; 1p36 (ZBTB40, P = 4.3×10−9), 1p31 (GPR177, P = 0.00012), 3p22 (CTNNB1, P = 0.00013), 4q22 (MEPE, P = 0.0026), 5q14 (MEF2C, P = 1.3×10−5), 6q25 (ESR1, P = 0.0011), 7p14 (STARD3NL, P = 0.00025), 7q21 (FLJ42280, P = 0.00017), 8q24 (TNFRSF11B, P = 3.4×10−5), 11p15 (SOX6, P = 0.00033), 11q13 (LRP5, P = 0.0033), 13q14 (TNFSF11, P = 7.5×10−5), 16q24 (FOXL1, P = 0.0010) and 17q21 (SOST, P = 0.015). Our study marks an early effort towards the challenge of cataloguing bone density variants shared by many ethnicities by testing BMD variants that have been established in Europeans, in East-Asians.

Susceptibility genes for osteoporotic fracture in postmenopausal chinese women

“…The Wnt signaling pathway is the key regulator of bone mass. The Wnt co-receptor lipoprotein receptor-related proteins, LRP5 (6)(7)(8)10,11) and LRP6, (19,20) were associated with BMD at the GWAS level, whereas WNT4, a member of the Wnt ligands, was associated with vertebral CSA in older Caucasian men. (22) TNFRSF11A was significantly associated with osteoporotic fracture in the collaborative meta-analysis.…”

“…The criteria for exclusion was a history of: (1) serious residual effects of cerebral vascular disease; (2) diabetes mellitus, except for adult asymptomatic hyperglycemia controlled by diet; (3) chronic renal disease manifested by a serum creatinine level of 11.9 mg/dL; (4) chronic liver disease or alcoholism; (5) chronic lung disease; (6) 12 weeks of corticosteroid therapy at pharmacologic levels; (7) 6 months of treatment with anticonvulsant therapy; (8) evidence of other metabolic or inherited bone diseases (eg, hyperparathyroidism or hypoparathyroidism, Paget's disease of bone, osteomalacia, or osteogenesis imperfecta); (9) rheumatoid arthritis or collagen disease; (10) major gastrointestinal disease (eg, peptic ulcer, malabsorption, chronic ulcerative colitis, regional enteritis, or any significant chronic diarrhea); (11) significant disease of any endocrine organ that would affect bone mass (eg, Cushing's syndrome or hyperthyroidism); (12) any neurologic or musculoskeletal condition that would be a nongenetic cause of low bone mass; (13) any disease, treatment, or condition that would be a nongenetic cause of low bone mass; or (14) any previous bisphosphonate treatment or current use of hormone replacement therapy.…”

“…Among them, the associations between variants in ZBTB40, (10) ESR1, (10) TNFRSF11B, (10) LRP5, (10) ADAMTS18, (16) and SPTBN1 (12,18) and osteoporosis have been replicated in both European and East-Asian populations. Another important member of the Wnt signaling pathway, low density lipoprotein receptorrelated protein 6 (LRP6) at 12p13.2, has been identified as being associated with osteoporosis in different ethnic background populations.…”

“…Estrogen receptor 1 (ESR1) at 6q25.1, (5)(6)(7)(8) low density lipoprotein receptor-related protein 4 (LRP4) at 11p11.2, (7)(8)(9) low density lipoprotein receptor-related protein 5 (LRP5) at 11q13.4, (6)(7)(8)10,11) integrin, alpha 1 (ITGA1) at 5q11.2, (8) secreted phosphoprotein 1ADAM metallopeptidase with thrombospondin type 1 motif 18 (ADAMTS18) at 16q23, (16,17) and spectrin, beta, non-erythrocytic 1 (SPTBN1) at 2p21 (5,7,9,12,18) are associated with BMD at the GWAS level. Among them, the associations between variants in ZBTB40, (10) ESR1, (10) TNFRSF11B, (10) LRP5, (10) ADAMTS18, (16) and SPTBN1 (12,18) and osteoporosis have been replicated in both European and East-Asian populations.…”

Wnts produced by Osterix-expressing osteolineage cells regulate their proliferation and differentiation

“…Over the past few years, two of the components essential for Wnt secretion, Wntless (GPR177/Evi/Ski) and Porcupine (4-9), have been associated with bone mineral density variation and skeletal development, respectively. SNPs in Wntless are linked to reduced bone mineral density (10,11), and mutations in Porcupine are associated with focal dermal hypoplasia (12,13), a disorder characterized by multiorgan abnormalities, including those of the skeleton. These findings further underscore the importance of studying the identity and role of Wnt-producing cells in bone development.…”