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Meta-analysis of genome-wide studies identifies MEF2C SNPs associated with bone mineral density at forearm.

ABSTRACT: Forearm fractures affect 1.7 million individuals worldwide each year and most occur earlier in life than hip fractures. While the heritability of forearm bone mineral density (BMD) and fracture is high, their genetic determinants are largely unknown.To identify genetic variants associated with forearm BMD and forearm fractures.BMD at distal radius, measured by dual-energy x-ray absorptiometry, was tested for association with common genetic variants. We conducted a meta-analysis of genome-wide association studies for BMD in 5866 subjects of European descent and then selected the variants for replication in 715 Mexican American samples. Gene-based association was carried out to supplement the single-nucleotide polymorphism (SNP) association test. We then tested the BMD-associated SNPs for association with forearm fracture in 2023 cases and 3740 controls.We found that five SNPs in the introns of MEF2C were associated with forearm BMD at a genome-wide significance level (p<5×10(-8)) in meta-analysis (lead SNP, rs11951031[T] -0.20 SDs per allele, p=9.01×10(-9)). The gene-based association test suggested an association between MEF2C and forearm BMD (p=0.003). The association between MEF2C variants and risk of fracture did not achieve statistical significance (SNP rs12521522[A]: OR=1.14 (95% CI 0.92 to 1.35), p=0.14). Meta-analysis also revealed two genome-wide suggestive loci at CTNNA2 and 6q23.2.These findings demonstrate that variants at MEF2C were associated with forearm BMD, implicating this gene in the determination of BMD at forearm.

SUBMITTER: Zheng HF

PROVIDER: S-EPMC3769185 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Meta-analysis of genome-wide studies identifies MEF2C SNPs associated with bone mineral density at forearm.

Zheng Hou-Feng HF Duncan Emma L EL Yerges-Armstrong Laura M LM Eriksson Joel J Bergström Ulrica U Leo Paul J PJ Leslie William D WD Goltzman David D Blangero John J Hanley David A DA Carless Melanie A MA Streeten Elizabeth A EA Lorentzon Mattias M Brown Matthew A MA Spector Tim D TD Pettersson-Kymmer Ulrika U Ohlsson Claes C Mitchell Braxton D BD Richards J Brent JB

Journal of medical genetics 20130409 7

<h4>Background</h4>Forearm fractures affect 1.7 million individuals worldwide each year and most occur earlier in life than hip fractures. While the heritability of forearm bone mineral density (BMD) and fracture is high, their genetic determinants are largely unknown.<h4>Aim</h4>To identify genetic variants associated with forearm BMD and forearm fractures.<h4>Methods</h4>BMD at distal radius, measured by dual-energy x-ray absorptiometry, was tested for association with common genetic variants. ...[more]

PMID: 23572186

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Project description:Previous genome-wide association studies (GWAS) have identified common variants in genes associated with variation in bone mineral density (BMD), although most have been carried out in combined samples of older women and men. Meta-analyses of these results have identified numerous single-nucleotide polymorphisms (SNPs) of modest effect at genome-wide significance levels in genes involved in both bone formation and resorption, as well as other pathways. We performed a meta-analysis restricted to premenopausal white women from four cohorts (n?=?4061 women, aged 20 to 45 years) to identify genes influencing peak bone mass at the lumbar spine and femoral neck. After imputation, age- and weight-adjusted bone-mineral density (BMD) values were tested for association with each SNP. Association of an SNP in the WNT16 gene (rs3801387; p?=?1.7?×?10(-9) ) and multiple SNPs in the ESR1/C6orf97 region (rs4870044; p?=?1.3?×?10(-8) ) achieved genome-wide significance levels for lumbar spine BMD. These SNPs, along with others demonstrating suggestive evidence of association, were then tested for association in seven replication cohorts that included premenopausal women of European, Hispanic-American, and African-American descent (combined n?=?5597 for femoral neck; n?=?4744 for lumbar spine). When the data from the discovery and replication cohorts were analyzed jointly, the evidence was more significant (WNT16 joint p?=?1.3?×?10(-11) ; ESR1/C6orf97 joint p?=?1.4?×?10(-10) ). Multiple independent association signals were observed with spine BMD at the ESR1 region after conditioning on the primary signal. Analyses of femoral neck BMD also supported association with SNPs in WNT16 and ESR1/C6orf97 (p?<?1?×?10(-5) ). Our results confirm that several of the genes contributing to BMD variation across a broad age range in both sexes have effects of similar magnitude on BMD of the spine in premenopausal women. These data support the hypothesis that variants in these genes of known skeletal function also affect BMD during the premenopausal period.

Project description:Osteoporosis is a serious public health issue, which is mostly characterized by low bone mineral density (BMD). To search for additional genetic susceptibility loci underlying BMD variation, an effective strategy is to focus on testing of specific variants with high potential of functional effects. Single nucleotide polymorphisms (SNPs) that introduce or disrupt CpG dinucleotides (CpG-SNPs) may alter DNA methylation levels and thus represent strong candidate functional variants. Here, we performed a targeted GWAS for 63,627 potential functional CpG-SNPs that may affect DNA methylation in bone-related cells, in five independent cohorts (n = 5905). By meta-analysis, 9 CpG-SNPs achieved a genome-wide significance level (p < 7.86 × 10-7) for association with lumbar spine BMD and additional 15 CpG-SNPs showed suggestive significant (p < 5.00 × 10-5) association, of which 2 novel SNPs rs7231498 (NFATC1) and rs7455028 (ESR1) also reached a genome-wide significance level in the joint analysis. Several identified CpG-SNPs were mapped to genes that have not been reported for association with BMD in previous GWAS, such as NEK3 and NFATC1 genes, highlighting the enhanced power of targeted association analysis for identification of novel associations that were missed by traditional GWAS. Interestingly, several genomic regions, such as NEK3 and LRP5 regions, contained multiple significant/suggestive CpG-SNPs for lumbar spine BMD, suggesting that multiple neighboring CpG-SNPs may synergistically mediate the DNA methylation level and gene expression pattern of target genes. Furthermore, functional annotation analyses suggested a strong regulatory potential of the identified BMD-associated CpG-SNPs and a significant enrichment in biological processes associated with protein localization and protein signal transduction. Our results provided novel insights into the genetic basis of BMD variation and highlighted the close connections between genetic and epigenetic mechanisms of complex disease.

Project description:Few studies have systematically evaluated the technical aspects of forearm bone mineral density (BMD) measurement. We found that BMD remained stable regardless of the reference point; however, the ROI identified was not always consistent. Our study highlights the importance of using the same reference point for serial measurements of forearm BMD.BackgroundForearm fractures are clinically important outcomes from the perspective of morbidity, health care costs, and interruption of work. BMD of the forearm, as derived by dual-energy x-ray absorptiometry (DXA), is a better predictor of fracture at the forearm compared with BMD measured at other sites. However, very few studies have evaluated the technical aspects of selecting the ROI for forearm BMD measurement. This study aimed to compare the BMD values measured at the 1/3 radius site using three different reference points: the ulnar styloid process, the radial endplate, and the bifurcation of the ulna and radius.MethodologyHealthy Chinese patients participating in the control group of an ongoing study at Zhejiang Provincial People's Hospital were recruited for this study. For each patient, a DXA scan (GE Lunar Prodigy) of the forearm was performed and BMD values were separately calculated using each of the three reference points to identify the ROI. Pearson correlation coefficients were calculated to examine the correlation between the BMD measures derived from each reference point. The F test and independent t test were applied for more robust analysis of the differences in the variances and means.ResultsSixty-eight healthy Chinese volunteers agreed to participate in this study. The root mean square standard deviation (RMS-SD) percentages of BMD values measured at the 1/3 radius site were 2.19%, 2.23%, and 2.20% when using the ulnar styloid process, radial endplate, and the bifurcation of the ulna and radius as the reference points, respectively. Pearson's correlation coefficients for all pairwise comparisons among these three groups were greater than 0.99. F tests and independent t tests showed p values ranging from 0.92 to 0.99. However, we observed that among 10% of patients, choosing an ROI at the ulnar styloid process led to an inability to accurately determine the BMD at the ultra-distal radius.ConclusionsGiven equal ability to determine BMD at the 1/3 radius accurately, the radial endplate or the bifurcation of the ulna and radius should be preferentially selected as the reference point for routine forearm BMD measurements in order to avoid situations in which the ultra-distal radius BMD cannot be determined.

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.

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Meta-analysis of genome-wide studies identifies MEF2C SNPs associated with bone mineral density at forearm.

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Meta-analysis of genome-wide studies identifies MEF2C SNPs associated with bone mineral density at forearm.

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