title: Meta-analysis of genome-wide studies identifies MEF2C SNPs associated with bone mineral density at forearm.
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.
  
  
  OBJECTIVE
  To identify genetic variants associated with forearm BMD and forearm fractures.
  
  
  METHODS
  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.
  
  
  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.
authors.affiliation: Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, Lady Davis Institute, Jewish General Hospital, McGill University, 3755, Côte Ste-Catherine Road, Montreal, Québec H3T 1E2, Canada. hou.zheng@mail.mcgill.ca
authors.forename: Hou-Feng
authors.initials: HF
authors.lastname: Zheng
authors.forename: Emma L
authors.initials: EL
authors.lastname: Duncan
authors.forename: Laura M
authors.initials: LM
authors.lastname: Yerges-Armstrong
authors.forename: Joel
authors.initials: J
authors.lastname: Eriksson
authors.forename: Ulrica
authors.initials: U
authors.lastname: Bergström
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Leo
authors.forename: William D
authors.initials: WD
authors.lastname: Leslie
authors.forename: David
authors.initials: D
authors.lastname: Goltzman
authors.forename: John
authors.initials: J
authors.lastname: Blangero
authors.forename: David A
authors.initials: DA
authors.lastname: Hanley
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Carless
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Streeten
authors.forename: Mattias
authors.initials: M
authors.lastname: Lorentzon
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brown
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.forename: Ulrika
authors.initials: U
authors.lastname: Pettersson-Kymmer
authors.forename: Claes
authors.initials: C
authors.lastname: Ohlsson
authors.forename: Braxton D
authors.initials: BD
authors.lastname: Mitchell
authors.forename: J Brent
authors.initials: JB
authors.lastname: Richards
mesh_terms: D015502:Absorptiometry, Photon; D015519:Bone Density / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005542:Forearm / Q000503:physiopathology*; D055106:Genome-Wide Association Study; D006801:Humans; D064326:MEF2 Transcription Factors / Q000235:genetics; D008297:Male; D020641:Polymorphism, Single Nucleotide; D044465:White People
chemical_list: D064326:MEF2 Transcription Factors; C578040:MEF2C protein, human
keywords: Complex traits; Genetic epidemiology; Genome-wide