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IL21R and PTH may underlie variation of femoral neck bone mineral density as revealed by a genome-wide association study.

ABSTRACT: Bone mineral density (BMD) measured at the femoral neck (FN) is the most important risk phenotype for osteoporosis and has been used as a reference standard for describing osteoporosis. The specific genes influencing FN BMD remain largely unknown. To identify such genes, we first performed a genome-wide association (GWA) analysis for FN BMD in a discovery sample consisting of 983 unrelated white subjects. We then tested the top significant single-nucleotide polymorphisms (SNPs; 175 SNPs with p < 5 x 10(-4)) for replication in a family-based sample of 2557 white subjects. Combing results from these two samples, we found that two genes, parathyroid hormone (PTH) and interleukin 21 receptor (IL21R), achieved consistent association results in both the discovery and replication samples. The PTH gene SNPs, rs9630182, rs2036417, and rs7125774, achieved p values of 1.10 x 10(-4), 3.24 x 10(-4), and 3.06 x 10(-4), respectively, in the discovery sample; p values of 6.50 x 10(-4), 5.08 x 10(-3), and 5.68 x 10(-3), respectively, in the replication sample; and combined p values of 3.98 x 10(-7), 9.52 x 10(-6), and 1.05 x 10(-5), respectively, in the total sample. The IL21R gene SNPs, rs8057551, rs8061992, and rs7199138, achieved p values of 1.51 x 10(-4), 1.53 x 10(-4), and 3.88 x 10(-4), respectively, in the discovery sample; p values of 2.36 x 10(-3), 6.74 x 10(-3), and 6.41 x 10(-3), respectively, in the replication sample; and combined p values of 2.31 x 10(-6), 8.62 x 10(-6), and 1.41 x 10(-5), respectively, in the total sample. The effect size of each SNP was approximately 0.11 SD estimated in the discovery sample. PTH and IL21R both have potential biologic functions important to bone metabolism. Overall, our findings provide some new clues to the understanding of the genetic architecture of osteoporosis.

SUBMITTER: Guo Y

PROVIDER: S-EPMC3153368 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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IL21R and PTH may underlie variation of femoral neck bone mineral density as revealed by a genome-wide association study.

Guo Yan Y Zhang Li-Shu LS Yang Tie-Lin TL Tian Qing Q Xiong Dong-Hai DH Pei Yu-Fang YF Deng Hong-Wen HW

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20100501 5

Bone mineral density (BMD) measured at the femoral neck (FN) is the most important risk phenotype for osteoporosis and has been used as a reference standard for describing osteoporosis. The specific genes influencing FN BMD remain largely unknown. To identify such genes, we first performed a genome-wide association (GWA) analysis for FN BMD in a discovery sample consisting of 983 unrelated white subjects. We then tested the top significant single-nucleotide polymorphisms (SNPs; 175 SNPs with p < ...[more]

PMID: 19874204

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Project description:BackgroundGenome-wide association studies (GWASs) routinely identify loci associated with risk factors for osteoporosis. However, GWASs with relatively small sample sizes still lack sufficient power to ascertain the majority of genetic variants with small to modest effect size, which may together truly influence the phenotype. The loci identified only account for a small percentage of the heritability of osteoporosis. This study aims to identify novel genetic loci associated with DXA-derived femoral neck (FNK) bone mineral density (BMD) and quantitative ultrasound of the heel calcaneus estimated BMD (eBMD), and to detect shared/causal variants for the two traits, to assess whether the SNPs or putative causal SNPs associated with eBMD were also associated with FNK-BMD.MethodsNovel loci associated with eBMD and FNK-BMD were identified by the genetic pleiotropic conditional false discovery rate (cFDR) method. Shared putative causal variants between eBMD and FNK-BMD and putative causal SNPs for each trait were identified by the colocalization method. Mendelian randomization analysis addresses the causal relationship between eBMD/FNK-BMD and fracture.ResultsWe identified 9,500 (cFDR < 9.8E-6), 137 (cFDR < 8.9E-4) and 124 SNPs associated with eBMD, FNK-BMD, and both eBMD and FNK-BMD, respectively, with 37 genomic regions where there was a SNP that influences both eBMD and FNK-BMD. Most genomic regions only contained putative causal SNPs associated with eBMD and 3 regions contained two distinct putative causal SNPs influenced both traits, respectively. We demonstrated a causal effect of FNK-BMD/eBMD on fracture.ConclusionMost of SNPs or putative causal SNPs associated with FNK-BMD were also associated with eBMD. However, most of SNPs or putative causal SNPs associated with eBMD were not associated with FNK-BMD. The novel variants we identified may help to account for the additional proportion of variance of each trait and advance our understanding of the genetic mechanisms underlying osteoporotic fracture.

Project description:BACKGROUND:Nutritional factors including vitamin D, magnesium, and fat are known to affect bone mineral accrual. This study aimed to evaluate associations between dietary nutrient intakes (both macronutrients and micronutrients) and bone mineral density (BMD) in children and adolescents. METHODS:Data for this cross-sectional, population-based study were derived from the National Health and Nutrition Examination Survey (NHANES). Participants aged from 8 to 19?years were included. The primary outcome was femoral neck BMD. RESULTS:Multivariate analyses revealed that for participants aged 8 to 11, daily sodium intake was significantly and positively associated with femoral neck BMD (B?=?0.9?×? 10-?5, p?=?0.031); in particular, subgroup analyses by sex found that in male participants aged 8-11, daily total cholesterol intake (B?=?5.3?×?10-?5, p?=?0.030) and calcium intake (B?=?-?2.0?×?10-?5, p?<?0.05) were significantly associated with femoral neck BMD in a positive and negative manner, respectively, but neither were observed in female participants of this age group. In contrast, daily intakes of vitamin D and magnesium were significantly and positively associated with femoral neck BMD in female participants aged 8-11 (B?=?246.8?×?10-?5 and 16.3?×?10-?5, p?=?0.017 and 0.033, respectively). For participants aged 16 to 19, daily total fat intake was significantly and negatively associated with femoral neck BMD (B?=?-?58?×?10-?5, p?=?0.048); further stratification by sex found that magnesium and sodium intakes were significantly and positively associated with femoral neck BMD only in females of this age group (B?=?26.9?×?10-?5 and 2.1?×?10-?5, respectively; both p?<?0.05). However, no significant associations between daily nutrient intakes and femoral neck BMD were identified in participants aged 12-15 before or after subgroup stratification. CONCLUSION:The study found that associations of specific nutrition-related variables with BMD of the femoral neck is dependent upon age and gender.

Project description:BackgroundCow milk contains more calcium, magnesium, potassium, zinc, and phosphorus minerals. For a long time, people have believed that increasing milk intake is beneficial to increasing bone density. Many confounding factors can affect milk consumption, and thus the association described to date may not be causal. We explored the causal relationship between genetically predicted milk consumption and Bone Mineral Density (BMD) of the femoral neck and lumbar spine based on 53,236 individuals from 27 studies of European ancestry using the Mendelian randomization (MR) study. 32,961 individuals of European and East Asian ancestry were used for sensitivity analysis.MethodsA genetic instrument used for evaluating milk consumption is rs4988235, a locus located at 13,910 base pairs upstream of the LCT gene. A Mendelian randomization (MR) analysis was conducted to study the effect of selected single nucleotide polymorphisms (SNPs) and BMD. The summary-level data for BMD of the femoral neck and lumbar spine were obtained from two GWAS meta-analyses ['Data Release 2012' and 'Data Release 2015' in the GEnetic Factors for OSteoporosis Consortium (GEFOS)].Resultswe found that genetically predicted milk consumption was not associated with FN-BMD(OR 1.007; 95% CI 0.991-1.023; P = 0.385), LS-BMD(OR 1.003; 95% CI 0.983-1.024; P = 0.743) by performing a meta-analysis of several different cohort studies. High levels of genetically predicted milk intake were positively associated with increased FN-BMD in Women. The OR for each additional milk intake increasing allele was 1.032 (95%CI 1.005-1.059; P = 0.014). However, no causal relationship was found between milk consumption and FN-BMD in men (OR 0.996; 95% CI 0.964-1.029; P = 0.839). Genetically predicted milk consumption was not significantly associated with LS-BMD in women (OR 1.017; 95% CI 0.991-1.043; P = 0.198) and men (OR 1.011; 95% CI 0.978-1.045; P = 0.523).ConclusionOur study found that women who consume more milk have a higher FN-BMD. When studying the effect of milk consumption on bone density in further studies, we need to pay more attention to women.

Dataset Information

IL21R and PTH may underlie variation of femoral neck bone mineral density as revealed by a genome-wide association study.

Publications

IL21R and PTH may underlie variation of femoral neck bone mineral density as revealed by a genome-wide association study.

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