Abstract
Summary
We tested whether two genetic variants were associated with BMD at multiple clinically relevant skeletal sites in Caucasians. We found that variant rs7776725 is consistently associated with hip, spine, wrist and whole-body BMD, which highlights the potential importance of this variant or linked variants for osteoporosis.
Introduction
A recent genome-wide association study identified two single nucleotide polymorphisms (SNPs), rs7776725 and rs1721400, that were associated with bone mineral density (BMD) variation at the radius, tibia and calcaneus in a Korean population. In this study, we aimed to test whether the association of these two genetic variants can be replicated in Caucasians and whether their association with BMD can be extended to other clinically relevant skeletal sites.
Methods
We performed this study in two large cohorts of unrelated US Caucasians. Area BMD at the hip, spine, wrist (ultra-distal radius) and whole body were measured with Hologic dual-energy X-ray absorptiometer. SNPs were genotyped with Affymetrix human genome-wide genotyping arrays. Association analyses were performed using PLINK.
Results
We detected highly significant association (combined p = 1.42 × 10−16) of rs7776725 with wrist BMD but only borderline association signal (combined p = 0.017) for rs1721400 with wrist BMD. In addition, we found that rs7776725 was associated with BMD at the hip, spine and whole body. At the FAM3C gene locus where rs7776725 was located, we identified several other SNPs (rs4727922, rs1803389, rs718766 and rs7793554) that were also associated with BMD.
Conclusions
This is the first follow-up association study of rs7776725 and rs1721400 with BMD. The rs7776725 showed consistent association with BMD at multiple clinically important skeletal sites, which highlighted the potential importance of rs7776725 or linked SNPs for risk of osteoporosis. Further in-depth re-sequencing studies and functional assays are necessary to elucidate the underlying mechanisms.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Wardlaw GM (1993) Putting osteoporosis in perspective. J Am Diet Assoc 93(9):1000–1006
Tse KY, Macias BR, Meyer RS, Hargens AR (2009) Heritability of bone density: regional and gender differences in monozygotic twins. J Orthop Res 27(2):150–154
Guo Y, Tan LJ, Lei SF, Yang TL, Chen XD, Zhang F, Chen Y, Pan F, Yan H, Liu X, Tian Q, Zhang ZX, Zhou Q, Qiu C, Dong SS, Xu XH, Guo YF, Zhu XZ, Liu SL, Wang XL, Li X, Luo Y, Zhang LS, Li M, Wang JT, Wen T, Drees B, Hamilton J, Papasian CJ, Recker RR, Song XP, Cheng J, Deng HW Genome-wide association study identifies ALDH7A1 as a novel susceptibility gene for osteoporosis. PLoS Genet 6 (1):e1000806
Xiong DH, Liu XG, Guo YF, Tan LJ, Wang L, Sha BY, Tang ZH, Pan F, Yang TL, Chen XD, Lei SF, Yerges LM, Zhu XZ, Wheeler VW, Patrick AL, Bunker CH, Guo Y, Yan H, Pei YF, Zhang YP, Levy S, Papasian CJ, Xiao P, Lundberg YW, Recker RR, Liu YZ, Liu YJ, Zmuda JM, Deng HW (2009) Genome-wide association and follow-up replication studies identified ADAMTS18 and TGFBR3 as bone mass candidate genes in different ethnic groups. Am J Hum Genet 84(3):388–398
Kung AW, Xiao SM, Cherny S, Li GH, Gao Y, Tso G, Lau KS, Luk KD, Liu JM, Cui B, Zhang MJ, Zhang ZL, He JW, Yue H, Xia WB, Luo LM, He SL, Kiel DP, Karasik D, Hsu YH, Cupples LA, Demissie S, Styrkarsdottir U, Halldorsson BV, Sigurdsson G, Thorsteinsdottir U, Stefansson K, Richards JB, Zhai G, Soranzo N, Valdes A, Spector TD, Sham PC Association of JAG1 with bone mineral density and osteoporotic fractures: a genome-wide association study and follow-up replication studies. Am J Hum Genet 86 (2):229–239
Cho YS, Go MJ, Kim YJ, Heo JY, Oh JH, Ban HJ, Yoon D, Lee MH, Kim DJ, Park M, Cha SH, Kim JW, Han BG, Min H, Ahn Y, Park MS, Han HR, Jang HY, Cho EY, Lee JE, Cho NH, Shin C, Park T, Park JW, Lee JK, Cardon L, Clarke G, McCarthy MI, Lee JY, Lee JK, Oh B, Kim HL (2009) A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat Genet 41(5):527–534
Liu YJ, Liu XG, Wang L, Dina C, Yan H, Liu JF, Levy S, Papasian CJ, Drees BM, Hamilton JJ, Meyre D, Delplanque J, Pei YF, Zhang L, Recker RR, Froguel P, Deng HW (2008) Genome-wide association scans identified CTNNBL1 as a novel gene for obesity. Hum Mol Genet 17(12):1803–1813
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81(3):559–575
Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21(2):263–265
Willer CJ, Li Y, Abecasis GR METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26 (17):2190–2191
Li Y, Willer CJ, Ding J, Scheet P, Abecasis GR MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet Epidemiol 34 (8):816–834
Li Y, Willer C, Sanna S, Abecasis G (2009) Genotype imputation. Annu Rev Genomics Hum Genet 10:387–406
Edderkaoui B, Baylink DJ, Beamer WG, Shultz KL, Wergedal JE, Mohan S (2007) Genetic regulation of femoral bone mineral density: complexity of sex effect in chromosome 1 revealed by congenic sublines of mice. Bone 41(3):340–345
Karasik D, Ferrari SL (2008) Contribution of gender-specific genetic factors to osteoporosis risk. Ann Hum Genet 72(Pt 5):696–714
Barrett-Connor E, Siris ES, Wehren LE, Miller PD, Abbott TA, Berger ML, Santora AC, Sherwood LM (2005) Osteoporosis and fracture risk in women of different ethnic groups. J Bone Miner Res 20(2):185–194
Lei SF, Chen Y, Xiong DH, Li LM, Deng HW (2006) Ethnic difference in osteoporosis-related phenotypes and its potential underlying genetic determination. J Musculoskelet Neuronal Interact 6(1):36–46
Zhu Y, Xu G, Patel A, McLaughlin MM, Silverman C, Knecht K, Sweitzer S, Li X, McDonnell P, Mirabile R, Zimmerman D, Boyce R, Tierney LA, Hu E, Livi GP, Wolf B, Abdel-Meguid SS, Rose GD, Aurora R, Hensley P, Briggs M, Young PR (2002) Cloning, expression, and initial characterization of a novel cytokine-like gene family. Genomics 80(2):144–150
Waerner T, Alacakaptan M, Tamir I, Oberauer R, Gal A, Brabletz T, Schreiber M, Jechlinger M, Beug H (2006) ILEI: a cytokine essential for EMT, tumor formation, and late events in metastasis in epithelial cells. Cancer Cell 10(3):227–239
Katahira T, Nakagiri S, Terada K, Furukawa T Secreted factor FAM3C (ILEI) is involved in retinal laminar formation. Biochem Biophys Res Commun 392 (3):301–306
Acknowledgement
This work was partially supported by grants from the NIH (R01 AR050496, R21 AG027110, R01 AG026564, P50 AR055081, R01 AR057049 and R21 AA015973). The study was also supported by the National Natural Science Foundation of China (31150006, 81000363, 31000554), the Fundamental Research Funds for the Central Universities (2011JBM134), Shanghai Leading Academic Discipline Project (S30501), and startup fund from University of Shanghai for Science and Technology, Xi'an Jiaotong University, and the Ministry of Education of China.
Conflicts of interest
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Zhang, LS., Hu, HG., Liu, YJ. et al. A follow-up association study of two genetic variants for bone mineral density variation in Caucasians. Osteoporos Int 23, 1867–1875 (2012). https://doi.org/10.1007/s00198-011-1863-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00198-011-1863-z