title: Genome-wide association study for radiographic vertebral fractures: a potential role for the 16q24 BMD locus.
abstract: Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fractures applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged > 55 years; and comprising 329 cases and 2666 controls with radiographic scoring (McCloskey–Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, and Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey–Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han–Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at p < 5 × 10− 8. In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p = 4.6 × 10− 8. However, the association was not significant across 5720 cases and 21,791 controls from 14 studies. Fixed-effects meta-analysis summary estimate was 1.06 (95% CI: 0.98–1.14; p = 0.17), displaying high degree of heterogeneity (I2 = 57%; Qhet p = 0.0006). Under Han–Eskin alternative random effects model the summary effect was significant (p = 0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size > 1.25) may still be consistent with an effect size < 1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions is needed to confirm or reject the involvement of this locus on the risk for vertebral fractures.
authors: Ling
authors: L
authors: Oei
authors: Karol
authors: K
authors: Estrada
authors: Emma L
authors: EL
authors: Duncan
authors: Claus
authors: C
authors: Christiansen
authors: Ching-Ti
authors: CT
authors: Liu
authors: Bente L
authors: BL
authors: Langdahl
authors: Barbara
authors: B
authors: Obermayer-Pietsch
authors: José A
authors: JA
authors: Riancho
authors: Richard L
authors: RL
authors: Prince
authors: Natasja M
authors: NM
authors: van Schoor
authors: Eugene
authors: E
authors: McCloskey
authors: Yi-Hsiang
authors: YH
authors: Hsu
authors: Evangelos
authors: E
authors: Evangelou
authors: Evangelia
authors: E
authors: Ntzani
authors: David M
authors: DM
authors: Evans
authors: Nerea
authors: N
authors: Alonso
authors: Lise B
authors: LB
authors: Husted
authors: Carmen
authors: C
authors: Valero
authors: Jose L
authors: JL
authors: Hernandez
authors: Joshua R
authors: JR
authors: Lewis
authors: Stephen K
authors: SK
authors: Kaptoge
authors: Kun
authors: K
authors: Zhu
authors: L Adrienne
authors: LA
authors: Cupples
authors: Carolina
authors: C
authors: Medina-Gómez
authors: Liesbeth
authors: L
authors: Vandenput
authors: Ghi Su
authors: GS
authors: Kim
authors: Seung
authors: S
authors: Hun Lee
authors: Martha C
authors: MC
authors: Castaño-Betancourt
authors: Edwin H G
authors: EH
authors: Oei
authors: Josefina
authors: J
authors: Martinez
authors: Anna
authors: A
authors: Daroszewska
authors: Marjolein
authors: M
authors: van der Klift
authors: Dan
authors: D
authors: Mellström
authors: Lizbeth
authors: L
authors: Herrera
authors: Magnus K
authors: MK
authors: Karlsson
authors: Albert
authors: A
authors: Hofman
authors: Östen
authors: Ö
authors: Ljunggren
authors: Huibert A P
authors: HA
authors: Pols
authors: Lisette
authors: L
authors: Stolk
authors: Joyce B J
authors: JB
authors: van Meurs
authors: John P A
authors: JP
authors: Ioannidis
authors: M Carola
authors: MC
authors: Zillikens
authors: Paul
authors: P
authors: Lips
authors: David
authors: D
authors: Karasik
authors: André G
authors: AG
authors: Uitterlinden
authors: Unnur
authors: U
authors: Styrkarsdottir
authors: Matthew A
authors: MA
authors: Brown
authors: Jung-Min
authors: JM
authors: Koh
authors: J Brent
authors: JB
authors: Richards
authors: Jonathan
authors: J
authors: Reeve
authors: Claes
authors: C
authors: Ohlsson
authors: Stuart H
authors: SH
authors: Ralston
authors: Douglas P
authors: DP
authors: Kiel
authors: Fernando
authors: F
authors: Rivadeneira
mesh_terms: D000368:Aged; D015519:Bone Density / Q000235:genetics*; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D005260:Female; D056426:Genetic Loci / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D009426:Netherlands; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011859:Radiography; D015203:Reproducibility of Results; D016103:Spinal Fractures / Q000000981:diagnostic imaging* / Q000235:genetics*