Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium.
Moayyeri A., Hsu Y-H., Karasik D., Estrada K., Xiao S-M., Nielson C., Srikanth P., Giroux S., Wilson SG., Zheng H-F., Smith AV., Pye SR., Leo PJ., Teumer A., Hwang J-Y., Ohlsson C., McGuigan F., Minster RL., Hayward C., Olmos JM., Lyytikäinen L-P., Lewis JR., Swart KMA., Masi L., Oldmeadow C., Holliday EG., Cheng S., van Schoor NM., Harvey NC., Kruk M., del Greco M F., Igl W., Trummer O., Grigoriou E., Luben R., Liu C-T., Zhou Y., Oei L., Medina-Gomez C., Zmuda J., Tranah G., Brown SJ., Williams FM., Soranzo N., Jakobsdottir J., Siggeirsdottir K., Holliday KL., Hannemann A., Go MJ., Garcia M., Polasek O., Laaksonen M., Zhu K., Enneman AW., McEvoy M., Peel R., Sham PC., Jaworski M., Johansson Å., Hicks AA., Pludowski P., Scott R., Dhonukshe-Rutten RAM., van der Velde N., Kähönen M., Viikari JS., Sievänen H., Raitakari OT., González-Macías J., Hernández JL., Mellström D., Ljunggren O., Cho YS., Völker U., Nauck M., Homuth G., Völzke H., Haring R., Brown MA., McCloskey E., Nicholson GC., Eastell R., Eisman JA., Jones G., Reid IR., Dennison EM., Wark J., Boonen S., Vanderschueren D., Wu FCW., Aspelund T., Richards JB., Bauer D., Hofman A., Khaw K-T., Dedoussis G., Obermayer-Pietsch B., Gyllensten U., Pramstaller PP., Lorenc RS., Cooper C., Kung AWC., Lips P., Alen M., Attia J., Brandi ML., de Groot LCPGM., Lehtimäki T., Riancho JA., Campbell H., Liu Y., Harris TB., Akesson K., Karlsson M., Lee J-Y., Wallaschofski H., Duncan EL., O'Neill TW., Gudnason V., Spector TD., Rousseau F., Orwoll E., Cummings SR., Wareham NJ., Rivadeneira F., Uitterlinden AG., Prince RL., Kiel DP., Reeve J., Kaptoge SK.
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.