Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium.

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  • Additional Information
    • Source:
      Publisher: IRL Press at Oxford University Press Country of Publication: England NLM ID: 9208958 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1460-2083 (Electronic) Linking ISSN: 09646906 NLM ISO Abbreviation: Hum Mol Genet Subsets: MEDLINE
    • Publication Information:
      Original Publication: Oxford, England ; New York : IRL Press at Oxford University Press, c1992-
    • Subject Terms:
      Genome-Wide Association Study*; Calcaneus/*diagnostic imaging ; Fractures, Bone/*genetics ; Osteoporosis/*genetics; Adult ; Aged ; Aged, 80 and over ; Bone Density ; Calcaneus/physiology ; Cohort Studies ; Female ; Fractures, Bone/diagnostic imaging ; Fractures, Bone/metabolism ; Fractures, Bone/physiopathology ; Genetic Predisposition to Disease ; Humans ; Male ; Middle Aged ; Osteoporosis/diagnostic imaging ; Osteoporosis/metabolism ; Osteoporosis/physiopathology ; Polymorphism, Single Nucleotide ; Ultrasonography ; Young Adult
    • Abstract:
      Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.
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    • Grant Information:
      MR/L003120/1 United Kingdom MRC_ Medical Research Council; MC_UU_12015/1 United Kingdom MRC_ Medical Research Council; G0400491 United Kingdom MRC_ Medical Research Council; MC_UU_12011/1 United Kingdom MRC_ Medical Research Council; MC_UP_A620_1014 United Kingdom MRC_ Medical Research Council; R01 AG005407 United States AG NIA NIH HHS; G0401527 United Kingdom MRC_ Medical Research Council; RG/08/014/24067 United Kingdom BHF_ British Heart Foundation; G0701863 United Kingdom MRC_ Medical Research Council; MR/K006312/1 United Kingdom MRC_ Medical Research Council; K01 AR062655 United States AR NIAMS NIH HHS; MC_U106179471 United Kingdom MRC_ Medical Research Council; U01 AR066160 United States AR NIAMS NIH HHS; MC_PC_U127561128 United Kingdom MRC_ Medical Research Council; G1000143 United Kingdom MRC_ Medical Research Council
    • Publication Date:
      Date Created: 20140117 Date Completed: 20150112 Latest Revision: 20220129
    • Publication Date:
      20231215
    • Accession Number:
      PMC4038791
    • Accession Number:
      10.1093/hmg/ddt675
    • Accession Number:
      24430505