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Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk.

ABSTRACT: Osteoporotic fracture is a major cause of morbidity and mortality worldwide. Low bone mineral density (BMD) is a major predisposing factor to fracture and is known to be highly heritable. Site-, gender-, and age-specific genetic effects on BMD are thought to be significant, but have largely not been considered in the design of genome-wide association studies (GWAS) of BMD to date. We report here a GWAS using a novel study design focusing on women of a specific age (postmenopausal women, age 55-85 years), with either extreme high or low hip BMD (age- and gender-adjusted BMD z-scores of +1.5 to +4.0, n = 1055, or -4.0 to -1.5, n = 900), with replication in cohorts of women drawn from the general population (n = 20,898). The study replicates 21 of 26 known BMD-associated genes. Additionally, we report suggestive association of a further six new genetic associations in or around the genes CLCN7, GALNT3, IBSP, LTBP3, RSPO3, and SOX4, with replication in two independent datasets. A novel mouse model with a loss-of-function mutation in GALNT3 is also reported, which has high bone mass, supporting the involvement of this gene in BMD determination. In addition to identifying further genes associated with BMD, this study confirms the efficiency of extreme-truncate selection designs for quantitative trait association studies.

SUBMITTER: Duncan EL

PROVIDER: S-EPMC3080863 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk.

Duncan Emma L EL Danoy Patrick P Kemp John P JP Leo Paul J PJ McCloskey Eugene E Nicholson Geoffrey C GC Eastell Richard R Prince Richard L RL Eisman John A JA Jones Graeme G Sambrook Philip N PN Reid Ian R IR Dennison Elaine M EM Wark John J Richards J Brent JB Uitterlinden Andre G AG Spector Tim D TD Esapa Chris C Cox Roger D RD Brown Steve D M SD Thakker Rajesh V RV Addison Kathryn A KA Bradbury Linda A LA Center Jacqueline R JR Cooper Cyrus C Cremin Catherine C Estrada Karol K Felsenberg Dieter D Glüer Claus-C CC Hadler Johanna J Henry Margaret J MJ Hofman Albert A Kotowicz Mark A MA Makovey Joanna J Nguyen Sing C SC Nguyen Tuan V TV Pasco Julie A JA Pryce Karena K Reid David M DM Rivadeneira Fernando F Roux Christian C Stefansson Kari K Styrkarsdottir Unnur U Thorleifsson Gudmar G Tichawangana Rumbidzai R Evans David M DM Brown Matthew A MA

PLoS genetics 20110421 4

Osteoporotic fracture is a major cause of morbidity and mortality worldwide. Low bone mineral density (BMD) is a major predisposing factor to fracture and is known to be highly heritable. Site-, gender-, and age-specific genetic effects on BMD are thought to be significant, but have largely not been considered in the design of genome-wide association studies (GWAS) of BMD to date. We report here a GWAS using a novel study design focusing on women of a specific age (postmenopausal women, age 55-8 ...[more]

PMID: 21533022

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Project description:In adult hypophosphatasia (HPP) patients, elevated lumbar spine dual X-ray absorptiometry (DXA) values are associated with markers of disease severity and disease-specific fracture risk while femoral bone mineral density (BMD), being largely unaffected by the disease severity, may still be useful to monitor other causes of increased fracture risk due to low BMD.IntroductionHypophosphatasia (HPP) is a rare inherited metabolic disorder due to deficient activity of the tissue-nonspecific alkaline phosphatase (TNAP). Clinical manifestation in adult HPP patients is manifold including an increased risk for fractures, but data regarding clinical significance of DXA measurement and associations with fracture risk and disease severity is scarce.MethodsRetrospective single-center analysis of DXA scans in patients with confirmed HPP (documented mutation, clinical symptoms, low alkaline phosphatase activity). Further data evaluation included disease-related fractures, laboratory results (alkaline phosphatase, pyridoxalphosphate, phosphoethanolamine), and medical history.ResultsAnalysis included 110 patients (84 female, mean age of 46.2 years) of whom 37.3% (n = 41) were harboring two mutations. Average T-Score level at the lumbar spine was - 0.1 (SD 1.9), and mean total hip T-Score was - 1.07 (SD 0.15). Both lower ALP activity and higher substrate levels (pyridoxalphosphate and phosphoethanolamine) were significantly correlated with increased lumbar spine T-Score levels (p < 0.001) while BMD at the hip was not affected by indicators of disease severity. Increased lumbar spine BMD was significantly associated with an increased risk for HPP-related fractures, prevalent in 22 (20%) patients (p < 0.001) with 21 of them having biallelic mutations.ConclusionBMD in adult HPP patients is not systematically reduced. Conversely, increased lumbar spine BMD appears to be associated with severely compromised mineralization and increased risk for HPP-related fractures while BMD at the hip appears unaffected by indicators of disease severity, suggesting suitability of this anatomic location for assessing and discerning disorders with increased fracture risk owing to reduced BMD like osteoporosis.Trial registration numberGerman register for clinical studies (DRKS00014022) DATE OF REGISTRATION: 02/10/2018 - retrospectively registered.

Project description:Background:Both copper deficiency and overexposure have been associated with adverse health effects. Evidence linking copper to bone mineral density (BMD) and total fracture, however, is limited. Methods:This nationally representative cross-sectional study enrolled participants from the National Health and Nutrition Examination Survey (2011-2014) in the United States. Using unadjusted and multivariate adjusted logistic regression analyses and a two-piecewise linear regression model with a smoothing function, we evaluated the associations between serum copper levels, bone mineral density and total fracture in 722 participants. Results:The study sample (n = 722, mean age: 56.47 ± 11.55 y) represented a population of which 47.2% were men; 43.91% were non-Hispanic white, 18.84% non-Hispanic black and 13.71% Mexican American; 25.9% had total fracture. In the multivariate logistic regression analysis, individuals in the lowest category (<98.5 ?g/dL) of serum copper concentration had 0.049 g/cm2 lower total femur BMD and 0.045 g/cm2 lower femoral neck BMD than those in the second concentration category (98.5-114 ?g/dL). Individuals in the highest category (?134 ?g/dL) of serum copper concentration had an approximately 4-fold increase in the risk of total fracture than those in the second concentration category. There were no significant associations between per 10 ?g/dL increases in serum copper levels and total fracture in multivariate logistic regression analysis after multivariate adjustment (all p > 0.05). However, a differential association between serum copper levels and total fractures between men and women was observed (odds ratio = 1.81, 95% confidence interval 1.08-3.03, p = 0.026 for men and odds ratio = 1.07, 95% confidence interval 0.86-1.32, p = 0.552 for women). Conclusion:Moderate serum copper levels are critically important for bone health. Lower serum copper levels are significantly associated with decreased BMD in the total femur and femoral neck. Higher serum copper levels are significantly associated with increased total fracture, especially in men. The Translational Potential of this Article:The impact of serum copper concentrations on bone mineral density and total fracture can provide insights into clinical application of copper-containing supplements and biomaterials.

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Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk.

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Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk.

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