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