title: The ESR1 (6q25) locus is associated with calcaneal ultrasound parameters and radial volumetric bone mineral density in European men.
abstract: OBJECTIVE
  Genome-wide association studies (GWAS) have identified 6q25, which incorporates the oestrogen receptor α gene (ESR1), as a quantitative trait locus for areal bone mineral density (BMD(a)) of the hip and lumbar spine. The aim of this study was to determine the influence of this locus on other bone health outcomes; calcaneal ultrasound (QUS) parameters, radial peripheral quantitative computed tomography (pQCT) parameters and markers of bone turnover in a population sample of European men.
  
  
  METHODS
  Eight single nucleotide polymorphisms (SNP) in the 6q25 locus were genotyped in men aged 40-79 years from 7 European countries, participating in the European Male Ageing Study (EMAS). The associations between SNPs and measured bone parameters were tested under an additive genetic model adjusting for centre using linear regression.
  
  
  RESULTS
  2468 men, mean (SD) aged 59.9 (11.1) years had QUS measurements performed and bone turnover marker levels measured. A subset of 628 men had DXA and pQCT measurements. Multiple independent SNPs showed significant associations with BMD using all three measurement techniques. Most notably, rs1999805 was associated with a 0.10 SD (95%CI 0.05, 0.16; p = 0.0001) lower estimated BMD at the calcaneus, a 0.14 SD (95%CI 0.05, 0.24; p = 0.004) lower total hip BMD(a), a 0.12 SD (95%CI 0.02, 0.23; p = 0.026) lower lumbar spine BMD(a) and a 0.18 SD (95%CI 0.06, 0.29; p = 0.003) lower trabecular BMD at the distal radius for each copy of the minor allele. There was no association with serum levels of bone turnover markers and a single SNP which was associated with cortical density was also associated with cortical BMC and thickness.
  
  
  CONCLUSIONS
  Our data replicate previous associations found between SNPs in the 6q25 locus and BMD(a) at the hip and extend these data to include associations with calcaneal ultrasound parameters and radial volumetric BMD.
authors.affiliation: Arthritis Research UK Epidemiology Unit, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom. kata.holliday@manchester.ac.uk
authors.forename: Kate L
authors.initials: KL
authors.lastname: Holliday
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Pye
authors.forename: Wendy
authors.initials: W
authors.lastname: Thomson
authors.forename: Steven
authors.initials: S
authors.lastname: Boonen
authors.forename: Herman
authors.initials: H
authors.lastname: Borghs
authors.forename: Dirk
authors.initials: D
authors.lastname: Vanderschueren
authors.forename: Evelien
authors.initials: E
authors.lastname: Gielen
authors.forename: Ilpo T
authors.initials: IT
authors.lastname: Huhtaniemi
authors.forename: Judith E
authors.initials: JE
authors.lastname: Adams
authors.forename: Kate A
authors.initials: KA
authors.lastname: Ward
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Bartfai
authors.forename: Felipe
authors.initials: F
authors.lastname: Casanueva
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Finn
authors.forename: Gianni
authors.initials: G
authors.lastname: Forti
authors.forename: Aleksander
authors.initials: A
authors.lastname: Giwercman
authors.forename: Thang S
authors.initials: TS
authors.lastname: Han
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kula
authors.forename: Fernand
authors.initials: F
authors.lastname: Labrie
authors.forename: Michael E J
authors.initials: ME
authors.lastname: Lean
authors.forename: Neil
authors.initials: N
authors.lastname: Pendleton
authors.forename: Margus
authors.initials: M
authors.lastname: Punab
authors.forename: Frederick C W
authors.initials: FC
authors.lastname: Wu
authors.forename: Terence W
authors.initials: TW
authors.lastname: O'Neill
mesh_terms: D015502:Absorptiometry, Photon; D000368:Aged; D000483:Alleles; D015519:Bone Density / Q000235:genetics*; D002111:Calcaneus / Q000000981:diagnostic imaging*; D004958:Estradiol / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics*; D056726:Genetic Association Studies; D056426:Genetic Loci / Q000235:genetics*; D005838:Genotype; D006262:Health; D006615:Hip / Q000502:physiology; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011884:Radius / Q000000981:diagnostic imaging / Q000502:physiology*; D014463:Ultrasonography; D044465:White People / Q000235:genetics*
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004958:Estradiol