Common genetic variation in the Estrogen Receptor Beta (ESR2) gene and osteoarthritis: results of a meta-analysis
- Hanneke JM Kerkhof1, 2,
- Ingrid Meulenbelt2, 3,
- Andrew Carr4,
- Antonio Gonzalez5,
- Deborah Hart6,
- Albert Hofman7,
- Margreet Kloppenburg8,
- Nancy E Lane9,
- John Loughlin10,
- Michael C Nevitt9,
- Huibert AP Pols1,
- Fernando Rivadeneira1, 2, 7,
- Eline P Slagboom2, 3,
- Tim D Spector6,
- Lisette Stolk1, 2,
- Aspasia Tsezou11,
- André G Uitterlinden1, 2, 7,
- Ana M Valdes6 and
- Joyce BJ van Meurs1, 2Email author
© Kerkhof et al; licensee BioMed Central Ltd. 2010
Received: 12 May 2010
Accepted: 16 November 2010
Published: 16 November 2010
The objective of this study was to examine the relationship between common genetic variation of the ESR2 gene and osteoarthritis.
In the discovery study, the Rotterdam Study-I, 7 single nucleotide polymorphisms (SNPs) were genotyped and tested for association with hip (284 cases, 2772 controls), knee (665 cases, 2075 controls), and hand OA (874 cases, 2184 controls) using an additive model. In the replication stage one SNP (rs1256031) was tested in an additional 2080 hip, 1318 knee and 557 hand OA cases and 4001, 2631 and 1699 controls respectively. Fixed- and random-effects meta-analyses were performed over the complete dataset including 2364 hip, 1983 knee and 1431 hand OA cases and approximately 6000 controls.
The C allele of rs1256031 was associated with a 36% increased odds of hip OA in women of the Rotterdam Study-I (OR 1.36, 95% CI 1.08-1.70, p = 0.009). Haplotype analysis and analysis of knee- and hand OA did not give additional information. With the replication studies, the meta-analysis did not show a significant effect of this SNP on hip OA in the total population (OR 1.06, 95% CI 0.99-1.15, p = 0.10). Stratification according to gender did not change the results. In this study, we had 80% power to detect an odds ratio of at least 1.14 for hip OA (α = 0.05).
This study showed that common genetic variation in the ESR2 gene is not likely to influence the risk of osteoarthritis with effects smaller than a 13% increase.
Epidemiological observations show sex-specific differences in the prevalence and incidence of osteoarthritis (OA) : the prevalence of OA among women increases rapidly after the menopause. In addition, men have a higher prevalence of OA before the age of 50 compared to women. This has led to the hypothesis that sex hormones may be involved in the etiology of osteoarthritis . Estrogen receptors α and ß are present in chondrocytes  and several in vitro and in vivo animal experiments showed a chondro-protective effect of estrogens [4, 5]. The estrogen receptors α (ESR1 gene) and β (ESR2 gene) are nuclear proteins. Both function as ligand-regulated transcription factors and show tissue specific expression.
Previously, three studies (in total 577 cases and 1837 controls) reported an association between two Single Nucleotide Polymorphisms (SNPs) (rs2234693 and rs9340799) of the ESR1 gene and radiographic knee and generalized OA [6–8]. However, currently, only one small study (158 cases, 193 controls) investigated the role of variation in the ESR2 gene in relation to OA. A 4.5-fold increased risk of knee OA was observed in individuals carrying long alleles of the c.1092+3607(CA)n repeat polymorphism of the ESR2 gene .
In this study, we examined the relationship between common genetic variation of the ESR2 gene and radiographic hip-, knee- and hand osteoarthritis in a large population-based cohort study (the Rotterdam Study-I). For replication purposes, 6 additional studies were genotyped for common genetic variation in the ESR2 gene and a meta-analysis was performed combining all 7 studies with in total 2364 hip-, 1983 knee-, and 1431 hand OA cases and respectively 6773, 4706 and 3883 controls.
Selection of study populations
We searched PubMed to identify articles which could be included on this meta-analysis on common genetic variation in the ESR2 gene and OA. One study  performed an association study on common genetic variation in the ESR2 gene and OA in Caucasians, but this variant was not of interest to our study. Therefore, only novel, and therefore unbiased data, is included in this meta-analysis. Study populations with both DNA and at least hip OA data available were approached to join this meta-analysis.
A detailed description of all studies is described in the supplementary material (see additional file 1). In short, the discovery study is the Rotterdam Study-I, a prospective population-based cohort which comprises men and women aged 55 years and older . The medical ethics committee of Erasmus University Medical School approved the study and written informed consent was obtained from each participant. The Chingford Study is another population-based longitudinal cohort, which includes 1,003 women derived from the age/sex register of a large general practice (n >11,000) in North London . The Guy's St. Thomas' Trust and the Waltham Forest Trust ethics committees approved the study protocol of the Chingford Study. The Genetics osteoARthritis and Progression (GARP) study, consists of Caucasian sibling pairs and trios of Dutch origin affected by osteoarthritis at multiple sites . Written informed consent was obtained from each subject involved in the GARP study as approved by the ethical committees of the Leiden University Medical Center. The Oxford TJR sample comprises subjects ascertained using the criteria of signs and symptoms of OA sufficiently severe to require joint replacement surgery in the United Kingdom . Ethical approval for the Oxford collection was obtained from the Oxfordshire Clinical Research Ethics Committee, MREC 02/2/108, with each participant providing informed consent for their sample to be used in OA genetics studies. Greek OA cases are TJR patients and all are individuals of Greek origin living in the district of Thessalia in central Greece . This study was approved by the ethics committee of the Larissa University Hospital and all individuals gave their informed consent. The Spanish OA cases are patients undergoing TKR/THR and were followed in the Rheumatology Unit . This study was approved by the Ethical Committee for Clinical Research of Galicia and all cases and controls gave their written informed consent to participate. The Study of Osteoporotic Fractures (SOF) is a multicenter cohort study initiated in 1986 to determine risk factors for osteoporotic fractures in elderly women . The SOF study was approved by the institutional review boards at each of the institutions involved. All subjects provided written informed consent at enrollment and at each clinical examination.
In studies with radiographic OA (ROA), radiographs were scored for the presence of ROA of the hip and knee according to the Kellgren/Lawrence (K/L) score . Hip ROA was defined as at least definite JSN and a definite osteophyte and knee ROA was defined as at least 2 definite osteophytes and possible joint space narrowing. Hand OA was defined as presence of at least one definite osteophyte in 2 out of 3 hand joint groups (DIPs, PIPs, CMC1/TS) of each or both hands. Clinical studies defined hip-, hand- and/or knee- clinical OA (COA) as symptomatic OA (i.e., pain and ROA) or a TJR, which is described in the supplementary material for each study individually. In addition, one study (GARP) selected cases on the basis of both clinical and radiographic OA (CROA) at two or more joint sites among hand, spine (cervical or lumbar), knee or hip.
Genomic DNA was extracted from peripheral blood leukocytes according to standard procedures. In the Rotterdam Study, we genotyped seven tagging SNPs (tSNPs): rs3020450, rs1256031, rs1256044, rs1256061, rs1109056, rs1256064 and rs4986938 (tSNP1 until tSNP7 respectively). These SNPs were selected using the program Tagger, with force include of rs1256031 and rs4986938, incorporated in Haploview. 80% of all common genetic variation in the ESR2 gene is covered by these 7 SNPs. In Additional file 2: Figure S1 the genetic variation in the ESR2 gene is depicted together with the D'and r2 values for the 7 SNPs. We used genotype data of each of the 7 SNPs to infer frequency of the haplotype alleles using the program PHASE version 2.1. Haplotypes with an estimated probability < 95% were excluded from analysis (387 individuals = 5.9%). The rs1256031 SNP was genotyped for the replication studies using a Taqman allelic discrimination assay (Chingford Study, SOF, GARP Study, Oxford Study, Greek cases and Spanish cases) (assay-on-demand service: http://www.appliedbiosystems.com) or by mass spectrometry (homogeneous Mass ARRAY system; Sequenom Inc., San Diego, CA), using standard conditions with genotypes analyzed by Genotyper 3.0 software (Sequenom Inc.)
The allele and genotype frequencies for rs1256064 deviated slightly from HWE proportions in the Rotterdam Study (p = 0.04), all other SNPs were in HWE proportions (data not shown). Genotyping was repeated for a random selection of subjects (5%) to check the accuracy of the genotyping. No discrepancies were detected. In addition, the allele frequency of rs1256064 is not significantly different from that reported in the CEU Hapmap population. No statistically significant deviations from HWE proportions could be detected for the rs1256031 SNP in the replication studies.
Detailed information on the statistical methods is provided in the supplementary material (see additional file 1). In summary, odds ratios (ORs) with 95% confidence intervals (CI) were estimated with logistic regression (additive model) for all the associations between SNPs and OA phenotypes and were subsequently adjusted for gender, age and BMI (if available). The meta-analysis was performed using the program Comprehensive Meta-analysis by Biostat http://www.meta-analysis.com using fixed-effects and random-effects models. Odds ratios and 95% confidence intervals of each study were used to estimate the overall effect size for the association between SNP rs1256031 and hip OA. If the heterogeneity metric I2 exceeded 25% a random-effects model (DerSimonian and Laird) was also used for the analysis, otherwise only a fixed effects model (inverse variance method) was applied. The analyses were performed on the total population of all studies and were subsequently stratified for gender to reveal, if any, gender-specific associations. A p-value ≤ 0.05 was considered statistically significant. Unless otherwise stated, SPSS version 15.0 software (SPSS INC., Chicago, USA) was used for all analyses.
Baseline characteristics of all studies
N (hip OA cases/controls)
N (knee OA cases/controls)
N (hand OA cases/controls)
Mean age (range)
Mean BMI (range)
Risk of OA according to rs1256031 (tSNP2) genotypes in the Rotterdam Study-I
Women Rotterdam Study-I
Men Rotterdam Study-I
Nr cases/total 1 (%)
OR (95% CI) 2
Nr cases/total 1 (%)
OR (95% CI) 2
Allele and genotype frequencies of rs1256031 (tSNP2) for hip OA cases and controls
In this study, we showed by meta-analysis of 7 studies summarizing 2364 hip OA cases and 6773 controls, 1983 knee OA cases and 4706 controls and 1431 hand OA cases and 3883 controls, that common genetic variation in the ESR2 gene is not likely to be associated with an increased risk of osteoarthritis.
However, we have to note that we had 80% power to detect odds ratio's of 1.14 and therefore we cannot exclude that smaller effects may exist. As only novel data was included in this meta-analysis, the risk of publication bias is eliminated by this study.
The significant association of SNP rs1256031 and hip OA in the Rotterdam Study-I was only present in women, not in men. We have previously reported that this SNP was associated with an increased risk of vertebral and fragility fractures specifically in women . It was hypothesized that significant effects are not observed in men since elderly men have higher estradiol levels compared to postmenopausal women. These higher serum levels of estrogens in men may mask an impaired ESR2 signaling caused by the genetic variation and may also explain why we observed an association between SNP rs1256031 of the ESR2 gene and hip OA only in women. However, the relationship between rs1256031 and hip OA was not supported by replication studies. Previously, Patsopoulos et al. showed that claims of sex-related differences in genetic association studies are most often spurious or insufficiently documented . Also in this study, where we initially did see a sex-specific association, replication studies could not corroborate this result. As the effect sizes in men and women are similar it is unlikely that interaction is present between the SNP and gender. This observation does not rule out a very subtle difference in the association between males and females and rs1256031 genotypes, but the current study is underpowered to robustly assess this.
The small case-control study by Fytili et al. (158 cases, 193 controls) reported that individuals carrying long alleles of the c.1092+3607 (CA)n repeat polymorphism of the ESR2 gene have a 4.5-fold increased risk of knee OA. Since this repeat polymorphism was not studied in this meta-analysis and it is not known whether this repeat is in LD with rs1256031 we cannot conclude that we did or did not replicate the finding of the case-control study of Fytili and co-workers .
At this moment, genome-wide association studies (GWAS) are state-of-art studies to indentify novel genetic loci involved in complex diseases like OA. In the genome-wide association studies published to date, common genetic variation in the ESR2 gene has not been found associated with OA [20–23]. In addition, GWAS on bone-related traits like bone mineral density (BMD) did also not observe any genome-wide significant associations between common genetic variation in the ESR2 gene and BMD [24–26].
It is not likely that there is an association between common genetic variation in the ESR2 gene and hand-, hip- or knee OA although associations with very small effect sizes can not be excluded.
We would like to thank all participants of the Rotterdam study and the many field workers at the research center in Rotterdam, The Netherlands. We are grateful to Dr. E. Odding, Dr. A. P. Bergink, Dr. M. Reijman and Dr. S. Dahaghin for scoring the radiographs, we thank P. Arp for laboratory work for the Rotterdam Study. We would like to thank Dr Doyle, Dr Thompson, Dr Hakim and Maxine Daniels for support of the Chingford Study. We further thank for the GARP study the support of the cooperating hospitals and all the field workers, including among others Dr. N. Riyazi and Dr. H.M. Kroon for scoring radiographs.
This work was supported by European Commission Grant QLK6-CT-2002-02629 (GENOMOS), NWO (911-03-012;014-93-015), European Commission framework 7 programme TREAT-OA (grant 200800) and the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) (grant 050-060-810). The Oxford Study is funded by the UK NIHR Biomedical Research Centre for ageing and Age-related disease award to the Newcastle upon Tyne Hospitals NHS Foundation Trust. The genotype work for the GARP Study was supported by the Netherlands Organization of Scientific Research (MW 904-61-095, 911-03-016, 917 66344 and 911-03-012), Leiden University Medical Centre and the Centre of Medical System Biology and Dutch Arthritis Association. The Leiden University Medical Centre, the Dutch Arthritis Association and Pfizer Inc., Groton, CT, USA support the GARP study. The Chingford Study is supported by the Arthritis Research UK.
- Felson DT, Nevitt MC: The effects of estrogen on osteoarthritis. Curr Opin Rheumatol. 1998, 10: 269-72. 10.1097/00002281-199805000-00019.View ArticlePubMedGoogle Scholar
- Spector TD, Campion GD: Generalised osteoarthritis: a hormonally mediated disease. Ann Rheum Dis. 1989, 48: 523-7. 10.1136/ard.48.6.523.View ArticlePubMedPubMed CentralGoogle Scholar
- Ushiyama T, Ueyama H, Inoue K, Ohkubo I, Hukuda S: Expression of genes for estrogen receptors alpha and beta in human articular chondrocytes. Osteoarthritis Cartilage. 1999, 7: 560-6. 10.1053/joca.1999.0260.View ArticlePubMedGoogle Scholar
- Corvol MT, Carrascosa A, Tsagris L, Blanchard O, Rappaport R: Evidence for a direct in vitro action of sex steroids on rabbit cartilage cells during skeletal growth: influence of age and sex. Endocrinology. 1987, 120: 1422-9. 10.1210/endo-120-4-1422.View ArticlePubMedGoogle Scholar
- Lee YJ, Lee EB, Kwon YE, Lee JJ, Cho WS, Kim HA, Song YW: Effect of estrogen on the expression of matrix metalloproteinase (MMP)-1, MMP-3, and MMP-13 and tissue inhibitor of metalloproternase-1 in osteoarthritis chondrocytes. Rheumatol Int. 2003, 23: 282-8. 10.1007/s00296-003-0312-5.View ArticlePubMedGoogle Scholar
- Bergink AP, van Meurs JB, Loughlin J, Arp PP, Fang Y, Hofman A, van Leeuwen JP, van Duijn CM, Uitterlinden AG, Pols HA: Estrogen receptor alpha gene haplotype is associated with radiographic osteoarthritis of the knee in elderly men and women. Arthritis Rheum. 2003, 48: 1913-22. 10.1002/art.11046.View ArticlePubMedGoogle Scholar
- Jin SY, Hong SJ, Yang HI, Park SD, Yoo MC, Lee HJ, Hong MS, Park HJ, Yoon SH, Kim BS, Yim SV, Park HK, Chung JH: Estrogen receptor-alpha gene haplotype is associated with primary knee osteoarthritis in Korean population. Arthritis Res Ther. 2004, 6: R415-21. 10.1186/ar1207.View ArticlePubMedPubMed CentralGoogle Scholar
- Ushiyama T, Ueyama H, Inoue K, Nishioka J, Ohkubo I, Hukuda S: Estrogen receptor gene polymorphism and generalized osteoarthritis. J Rheumatol. 1998, 25: 134-7.PubMedGoogle Scholar
- Fytili P, Giannatou E, Papanikolaou V, Stripeli F, Karachalios T, Malizos K, Tsezou A: Association of repeat polymorphisms in the estrogen receptors alpha, beta, and androgen receptor genes with knee osteoarthritis. Clin Genet. 2005, 68: 268-77. 10.1111/j.1399-0004.2005.00495.x.View ArticlePubMedGoogle Scholar
- Hofman A, Breteler MM, van Duijn CM, Janssen HL, Krestin GP, Kuipers EJ, Stricker BH, Tiemeier H, Uitterlinden AG, Vingerling JR, Witteman JC: The Rotterdam Study: 2010 objectives and design update. Eur J Epidemiol. 2009, 24: 553-72. 10.1007/s10654-009-9386-z.View ArticlePubMedPubMed CentralGoogle Scholar
- Hart DJ, Spector TD: The relationship of obesity, fat distribution and osteoarthritis in women in the general population: the Chingford Study. J Rheumatol. 1993, 20: 331-5.PubMedGoogle Scholar
- Riyazi N, Meulenbelt I, Kroon HM, Ronday KH, Hellio le Graverand MP, Rosendaal FR, Breedveld FC, Slagboom PE, Kloppenburg M: Evidence for familial aggregation of hand, hip, and spine but not knee osteoarthritis in siblings with multiple joint involvement: the GARP study. Ann Rheum Dis. 2005, 64: 438-43. 10.1136/ard.2004.024661.View ArticlePubMedGoogle Scholar
- Chapman K, Takahashi A, Meulenbelt I, Watson C, Rodriguez-Lopez J, Egli R, Tsezou A, Malizos KN, Kloppenburg M, Shi D, Southam L, van der Breggen R, Donn R, Qin J, Doherty M, Slagboom PE, Wallis G, Kamatani N, Jiang Q, Gonzalez A, Loughlin J, Ikegawa S: A meta-analysis of European and Asian cohorts reveals a global role of a functional SNP in the 5' UTR of GDF5 with osteoarthritis susceptibility. Hum Mol Genet. 2008, 17: 1497-504. 10.1093/hmg/ddn038.View ArticlePubMedGoogle Scholar
- Rodriguez-Lopez J, Pombo-Suarez M, Liz M, Gomez-Reino JJ, Gonzalez A: Lack of association of a variable number of aspartic acid residues in the asporin gene with osteoarthritis susceptibility: case-control studies in Spanish Caucasians. Arthritis Res Ther. 2006, 8: R55-10.1186/ar1920.View ArticlePubMedPubMed CentralGoogle Scholar
- Cummings SR, Nevitt MC, Browner WS, Stone K, Fox KM, Ensrud KE, Cauley J, Black D, Vogt TM: Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N Engl J Med. 1995, 332: 767-73. 10.1056/NEJM199503233321202.View ArticlePubMedGoogle Scholar
- Kellgren JH, Lawrence JS: Radiological assessment of osteo-arthrosis. Ann Rheum Dis. 1957, 16: 494-502. 10.1136/ard.16.4.494.View ArticlePubMedPubMed CentralGoogle Scholar
- Stephens M, Smith NJ, Donnelly P: A new statistical method for haplotype reconstruction from population data. American journal of human genetics. 2001, 68: 978-89. 10.1086/319501.View ArticlePubMedPubMed CentralGoogle Scholar
- Rivadeneira F, van Meurs JB, Kant J, Zillikens MC, Stolk L, Beck TJ, Arp P, Schuit SC, Hofman A, Houwing-Duistermaat JJ, van Duijn CM, van Leeuwen JP, Pols HA, Uitterlinden AG: Estrogen receptor beta (ESR2) polymorphisms in interaction with estrogen receptor alpha (ESR1) and insulin-like growth factor I (IGF1) variants influence the risk of fracture in postmenopausal women. J Bone Miner Res. 2006, 21: 1443-56. 10.1359/jbmr.060605.View ArticlePubMedGoogle Scholar
- Patsopoulos NA, Tatsioni A, Ioannidis JP: Claims of sex differences: an empirical assessment in genetic associations. Jama. 2007, 298: 880-93. 10.1001/jama.298.8.880.View ArticlePubMedGoogle Scholar
- Kerkhof HJ, Lories RJ, Meulenbelt I, Jonsdottir I, Valdes AM, Arp P, Ingvarsson T, Jhamai M, Jonsson H, Stolk L, Thorleifsson G, Zhai G, Zhang F, Zhu Y, van der Breggen R, Carr A, Doherty M, Doherty S, Felson DT, Gonzalez A, Halldorsson BV, Hart DJ, Hauksson VB, Hofman A, Ioannidis JP, Kloppenburg M, Lane NE, Loughlin J, Luyten FP, Nevitt MC, Parimi N, Pols HA, Rivadeneira F, Slagboom EP, Styrkársdóttir U, Tsezou A, van de Putte T, Zmuda J, Spector TD, Stefansson K, Uitterlinden AG, van Meurs JB: A genome-wide association study identifies an osteoarthritis susceptibility locus on chromosome 7q22. Arthritis Rheum. 2010, 62: 499-510.PubMedPubMed CentralGoogle Scholar
- Valdes AM, Loughlin J, Timms KM, van Meurs JJ, Southam L, Wilson SG, Doherty S, Lories RJ, Luyten FP, Gutin A, Abkevich V, Ge D, Hofman A, Uitterlinden AG, Hart DJ, Zhang F, Zhai G, Egli RJ, Doherty M, Lanchbury J, Spector TD: Genome-wide association scan identifies a prostaglandin-endoperoxide synthase 2 variant involved in risk of knee osteoarthritis. Am J Hum Genet. 2008, 82: 1231-40. 10.1016/j.ajhg.2008.04.006.View ArticlePubMedPubMed CentralGoogle Scholar
- Zhai G, van Meurs JB, Livshits G, Meulenbelt I, Valdes AM, Soranzo N, Hart D, Zhang F, Kato BS, Richards JB, Williams FM, Inouye M, Kloppenburg M, Deloukas P, Slagboom E, Uitterlinden A, Spector TD: A genome-wide association study suggests that a locus within the ataxin 2 binding protein 1 gene is associated with hand osteoarthritis: the TREAT-OA consortium. J Med Genet. 2009, 46: 614-6. 10.1136/jmg.2009.067314.View ArticlePubMedPubMed CentralGoogle Scholar
- Evangelou E, Valdes AM, Kerkhof HJ, Styrkarsdottir U, Zhu Y, Meulenbelt I, Lories RJ, Karassa FB, Tylzanowski P, Bos SD, arcOGEN consortium, Akune T, Arden NK, Carr A, Chapman K, Cupples LA, Dai J, Deloukas P, Doherty M, Doherty S, Engstrom G, Gonzalez A, Halldorsson BV, Hammond CL, Hart DJ, Helgadottir H, Hofman A, Ikegawa S, Ingvarsson T, Jiang Q, Jonsson H, Kaprio J, Kawaguchi H, Kisand K, Kloppenburg M, Kujala UM, Lohmander LS, Loughlin J, Luyten FP, Mabuchi A, McCaskie A, Nakajima M, Nilsson PM, Nishida N, Ollier WER, Panoutsopoulou K, van de Putte T, Ralston SH, Rivadeneira F, Saarela J, Schulte-Merker S, Slagboom PE, Sudo A, Tamm A, Tamm A, Thorleifsson G, Thorsteinsdottir U, Tsezou A, Wallis GA, Wilkinson JM, Yoshimura N, Zeggini E, Zhai G, Zhang F, Jonsdottir I, Uitterlinden AG, Felson DT, van Meurs JB, Stefansson K, Ioannidis JPA, Spector TD: Meta-analysis of genome-wide association studies confirms a susceptibility locus for knee osteoarthritis on chromosome 7q22. Ann Rheum Dis. 2010,Google Scholar
- Rivadeneira F, Styrkarsdottir U, Estrada K, Halldórsson BV, Hsu YH, Richards JB, Zillikens MC, Kavvoura FK, Amin N, Aulchenko YS, Cupples LA, Deloukas P, Demissie S, Grundberg E, Hofman A, Kong A, Karasik D, van Meurs JB, Oostra B, Pastinen T, Pols HA, Sigurdsson G, Soranzo N, Thorleifsson G, Thorsteinsdottir U, Williams FM, Wilson SG, Zhou Y, Ralston SH, van Duijn CM, Spector T, Kiel DP, Stefansson K, Ioannidis JP, Uitterlinden AG, Genetic Factors for Osteoporosis (GEFOS) Consortium: Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet. 2009, 41: 1199-206. 10.1038/ng.446.View ArticlePubMedPubMed CentralGoogle Scholar
- Koller DL, Ichikawa S, Lai D, Padgett LR, Doheny KF, Pugh E, Paschall J, Hui SL, Edenberg HJ, Xuei X, Peacock M, Econs MJ, Foroud T: Genome-wide association study of bone mineral density in premenopausal European-American women and replication in African-American women. J Clin Endocrinol Metab. 2010, 95: 1802-9. 10.1210/jc.2009-1903.View ArticlePubMedPubMed CentralGoogle Scholar
- 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. 2010, 86: 229-39. 10.1016/j.ajhg.2009.12.014.View ArticlePubMedPubMed CentralGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/11/164/prepub