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

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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 includingESR1(6q25.1: rs4869739, rs3020331, rs2982552),SPTBN1(2p16.2: rs11898505),RSPO3(6q22.33: rs7741021),WNT16(7q31.31: rs2908007),DKK1(10q21.1: rs7902708) andGPATCH1(19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close toTMEM135, 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 atP< 5 × 10−6 also had the expected direction of association with any fracture (P< 0.05), including three SNPs withP< 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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