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

Zheng, Hou-Feng, Duncan, Emma L., Yerges-Armstrong, Laura M., Eriksson, Joel, Bergström, Ulrice, Leo, Paul J., Leslie, William D., Goltzman, David, Blangero, John, Hanley, David A., Carless, Melanie A., Streeten, Elizabeth A., Lorentzon, Mattias, Brown, Matthew A., Spector, Tim D., Pettersson-Kymmer, Ulrika, Ohlsson, Claes, Mitchell, Braxton D., & Richards, J. Brent (2013) Meta-analysis of genome-wide studies identifies MEF2C SNPs associated with bone mineral density at forearm. Journal of Medical Genetics, 50(7), pp. 473-478.

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Abstract

Background

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.

Aim

To identify genetic variants associated with forearm BMD and forearm fractures.

Methods

BMD at distal radius, measured by dualenergy x-ray absorptiometry, was tested for association with common genetic variants. We conducted a metaanalysis 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.

Results

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.

Conclusions

These findings demonstrate that variants at MEF2C were associated with forearm BMD, implicating this gene in the determination of BMD at forearm.

Impact and interest:

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ID Code: 89273
Item Type: Journal Article
Refereed: Yes
Keywords: mef2c protein, membrane protein, unclassified drug, adult, article, bone density, cohort analysis, controlled study, dual energy X ray absorptiometry, forearm fracture, genetic analysis, genetic association, genetic variability, Hispanic, human, major clinical study, priority journal, risk assessment, single nucleotide polymorphism
DOI: 10.1136/jmedgenet-2012-101287
ISSN: 0022-2593
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2013 The Authors
Deposited On: 19 Oct 2015 22:28
Last Modified: 21 Mar 2016 00:02

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