Collaborative Meta-analysis: Associations of 150 Candidate Genes With Osteoporosis and Osteoporotic Fracture

Richards, J. Brent; Kavvoura, Fotini K.; Rivadeneira, Fernando; Styrkársdóttir, Unnur; Estrada, Karol; Halldórsson, Bjarni V.; Hsu, Yi‐Hsiang; Zillikens, M. Carola; Wilson, Scott G.; Mullin, Benjamin H.; Amin, Najaf; Aulchenko, Yurii S.; Cupples, L. Adrienne; Deloukas, Panagiotis; Demissie, Serkalem; Hofman, Albert; Kong, Augustine; Karasik, David; Meurs, Joyce B. J. van; Oostra, Ben A.; Pols, Huibert A. P.; Sigurðsson, Gunnar; Þorsteinsdóttir, Unnur; Soranzo, Nicole; Williams, Frances; Zhou, Yanhua; Ralston, Stuart H.; Þorleifsson, Guðmar; Duijn, Cornelia M. van; Kiel, Douglas P.; Stefánsson, Kári; Uitterlinden, André G.; Ioannidis, John P. A.; Spector, Tim D.

doi:10.7326/0003-4819-151-8-200910200-00006

Cited by 257 publications

(196 citation statements)

References 63 publications

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“…Although none of these SNPs remained significantly associated with LS BMD a after correcting for multiple testing, some of them have been associated previously with LS BMD a in GWAS at genome-wide significant levels, including rs9594738 located approximately 200 kb upstream of RANKL (36) and rs3134057, rs3134058, and rs2073618 within OPG. (43) In addition, rs3134057 and rs3134058 were associated with LS BMD a in the whole-genome study of Styrkarsdottir and colleagues, but not at a genome-wide significance level. (36) Previous candidate gene association studies also have reported an association between rs2073618 and LS BMD a .…”

Section: Discussionmentioning

confidence: 95%

Genetic variation in the RANKL/RANK/OPG signaling pathway is associated with bone turnover and bone mineral density in men

Roshandel

Holliday

Pye

et al. 2010

Journal of Bone and Mineral Research

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The aim of this study was to determine if single-nucleotide polymorphisms (SNPs) in RANKL, RANK, and OPG influence bone turnover and bone mineral density (BMD) in men. Pairwise tag SNPs (r 2 ! 0.8) were selected for RANKL, RANK, and OPG and their 10-kb flanking regions. Selected tag SNPs plus five SNPs near RANKL and OPG, associated with BMD in published genome-wide association studies (GWAS), were genotyped in 2653 men aged 40 to 79 years of age recruited for participation in a population-based study of male aging, the European Male Ageing Study (EMAS). N-terminal propeptide of type I procollagen (PINP) and C-terminal cross-linked telopeptide of type I collagen (CTX-I) serum levels were measured in all men. BMD at the calcaneus was estimated by quantitative ultrasound (QUS) in all men. Lumbar spine and total-hip areal BMD (BMD a ) was measured by dual-energy X-ray absorptiometry (DXA) in a subsample of 620 men. Multiple OPG, RANK, and RANKL SNPs were associated with bone turnover markers. We also identified a number of SNPs associated with BMD, including rs2073618 in OPG and rs9594759 near RANKL. The minor allele of rs2073618 (C) was associated with higher levels of both PINP rs9594759 (C) was associated with lower PINP (b ¼ À1.84, p ¼ .003) and CTX-I (b ¼ À27.02, p ¼ 6.06 Â 10 À8 ) and higher ultrasound BMD at the calcaneus (b ¼ 0.01, p ¼ .037). Our findings suggest that genetic variation in the RANKL/RANK/OPG signaling pathway influences bone turnover and BMD in European men. ß

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Section: Discussionmentioning

confidence: 95%

Genetic variation in the RANKL/RANK/OPG signaling pathway is associated with bone turnover and bone mineral density in men

Roshandel

Holliday

Pye

et al. 2010

Journal of Bone and Mineral Research

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“…Thus, a genome-wide search offers advantages over candidate gene association studies because it provides a more extensive coverage of the genome and the opportunity for truly novel gene discoveries-which is entirely "agnostic" and unconstrained by existing knowledge. In fact, many candidate genes, even if validated by the replication of several studies, were not confirmed by GWAS results (Richards et al 2009). Recent reports from GWAS demonstrate the potential of this approach to identify novel gene associations for common complex conditions.…”

Section: Gwas Approach For Aging Genes Discoverymentioning

confidence: 99%

“…Studies of rarer variants require much more powerful designs. Both new discovery by GWAS and replication of association findings, especially for complex quantitative phenotypes, require large sample sizes; therefore, multiple consortia, such as GIANT ), GEFOS (Richards et al 2009;), CHARGE (Psaty et al 2009), SunLight (Wang et al 2010), and others, were formed.…”

Section: Gwas Approach For Aging Genes Discoverymentioning

confidence: 99%

How pleiotropic genetics of the musculoskeletal system can inform genomics and phenomics of aging

Karasik

2010

AGE

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Genetic study can provide insight into the biologic mechanisms underlying inter-individual differences in susceptibility to (or resistance to) organisms' aging. Recent advances in molecular genetics and genetic epidemiology provide the necessary tools to perform a study of the genetic sources of biological aging. However, to be successful, the genetic study of a complex condition requires a heritable phenotype to be developed and validated. Genome-wide association studies offer an unbiased approach to identify new candidate genes for human diseases. It is hypothesized that convergent results from multiple aging-related traits will point out the genes responsible for the general aging of the organism. This perspective focuses on the musculoskeletal aging as an example of an approach to identify a downstream common pathway that summarizes aging processes. Since the musculoskeletal traits are linked to the state of many vital functions, disability, and ultimately survival rates, we postulate that there is significance in studying musculoskeletal aging. Construction of an integrated phenotype of aging can be achieved based on shared genetics among multiple musculoskeletal biomarkers. Valid biomarkers from other systems of the organism should be similarly explored. The new composite aging score needs to be validated by determining whether it predicts all-cause mortality, incidences of major chronic diseases, and disability late in life. Comprehensive databases on biomarkers of musculoskeletal aging in multiple large cohort studies, along with information on various health outcomes, are needed to validate the proposed measure of biological aging.

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“…These SNPs have not yet been reported to be associated with bone density in previous GWAS. [29][30][31] Two of them, on 15q14-15 and 22q11, are located in genes that are known to be expressed in skeletal muscle: 32,33 GLUT 11 encoded by SLC2A11 on 22q11 and RYR3 on 15q14-15. Because muscle contraction has a major impact on bone density, this might represent an indirect role of these genes on bone density.…”

Section: Simulation Studymentioning

confidence: 99%

Bivariate association analysis in selected samples: application to a GWAS of two bone mineral density phenotypes in males with high or low BMD

et al. 2011

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Our specific aims were to evaluate the power of bivariate analysis and to compare its performance with traditional univariate analysis in samples of unrelated subjects under varying sampling selection designs. Bivariate association analysis was based on the seemingly unrelated regression (SUR) model that allows different genetic models for different traits. We conducted extensive simulations for the case of two correlated quantitative phenotypes, with the quantitative trait locus making equal or unequal contributions to each phenotype. Our simulation results confirmed that the power of bivariate analysis is affected by the size, direction and source of the phenotypic correlations between traits. They also showed that the optimal sampling scheme depends on the size and direction of the induced genetic correlation. In addition, we demonstrated the efficacy of SUR-based bivariate test by applying it to a real Genome-Wide Association Study (GWAS) of Bone Mineral Density (BMD) values measured at the lumbar spine (LS) and at the femoral neck (FN) in a sample of unrelated males with low BMD (LS Z-scores rÀ2) and with high BMD (LS and FN Z-scores 40.5). A substantial amount of top hits in bivariate analysis did not reach nominal significance in any of the two single-trait analyses. Altogether, our studies suggest that bivariate analysis is of practical significance for GWAS of correlated phenotypes.

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Collaborative Meta-analysis: Associations of 150 Candidate Genes With Osteoporosis and Osteoporotic Fracture

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Cited by 257 publications

References 63 publications

Genetic variation in the RANKL/RANK/OPG signaling pathway is associated with bone turnover and bone mineral density in men

Genetic variation in the RANKL/RANK/OPG signaling pathway is associated with bone turnover and bone mineral density in men

How pleiotropic genetics of the musculoskeletal system can inform genomics and phenomics of aging

Bivariate association analysis in selected samples: application to a GWAS of two bone mineral density phenotypes in males with high or low BMD

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