title: High-density association study of 383 candidate genes for volumetric BMD at the femoral neck and lumbar spine among older men.
abstract: Genetics is a well-established but poorly understood determinant of BMD. Whereas some genetic variants may influence BMD throughout the body, others may be skeletal site specific. We initially screened for associations between 4608 tagging and potentially functional single nucleotide polymorphisms (SNPs) in 383 candidate genes and femoral neck and lumbar spine volumetric BMD (vBMD) measured from QCT scans among 862 community-dwelling white men >or=65 yr of age in the Osteoporotic Fractures in Men Study (MrOS). The most promising SNP associations (p < 0.01) were validated by genotyping an additional 1156 white men from MrOS. This analysis identified 8 SNPs in 6 genes (APC, DMP1, FGFR2, FLT1, HOXA, and PTN) that were associated with femoral neck vBMD and 13 SNPs in 7 genes (APC, BMPR1B, FOXC2, HOXA, IGFBP2, NFATC1, and SOST) that were associated with lumbar spine vBMD in both genotyping samples (p < 0.05). Although most associations were specific to one skeletal site, SNPs in the APC and HOXA gene regions were associated with both femoral neck and lumbar spine BMD. This analysis identifies several novel and robust genetic associations for volumetric BMD, and these findings in combination with other data suggest the presence of genetic loci for volumetric BMD that are at least to some extent skeletal-site specific.
authors.affiliation: Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Yerges
authors.forename: Lambertus
authors.initials: L
authors.lastname: Klei
authors.forename: Jane A
authors.initials: JA
authors.lastname: Cauley
authors.forename: Kathryn
authors.initials: K
authors.lastname: Roeder
authors.forename: Candace M
authors.initials: CM
authors.lastname: Kammerer
authors.forename: Susan P
authors.initials: SP
authors.lastname: Moffett
authors.forename: Kristine E
authors.initials: KE
authors.lastname: Ensrud
authors.forename: Cara S
authors.initials: CS
authors.lastname: Nestlerode
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Marshall
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Hoffman
authors.forename: Cora
authors.initials: C
authors.lastname: Lewis
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lang
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Barrett-Connor
authors.forename: Robert E
authors.initials: RE
authors.lastname: Ferrell
authors.forename: Eric S
authors.initials: ES
authors.lastname: Orwoll
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Zmuda
mesh_terms: D015519:Bone Density / Q000235:genetics*; D005269:Femur; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D006801:Humans; D008159:Lumbar Vertebrae; D008297:Male; D020641:Polymorphism, Single Nucleotide