Human Molecular Genetics, 2014, 01, 3054─3068

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

Moayyeri A, Hsu YH, Karasik D, Estrada K, Xiao SM,

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 = 514260), velocity of sound (VOS; n = 515514) and BMD (n = 54566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 511452) and new genotyping in 15 cohorts (de novo n = 524902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5E - 08) 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 < 8.23E -014). In meta-analyses involving 25 cohorts with up to 14985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5E - 026 also had the expected direction of association with any fracture (P < 0.05), including threeSNPswithP < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708).
In conclusion, thisGWAstudy reveals the effect of several genescommon to central DXA-derivedBMDand heel ultrasound/DXAmeasures and points to anewgenetic locus with potential implications for better understanding of osteoporosis pathophysiology

• ISBN or ISSN: 0964-6906

• 본 연구는 질병관리본부 연구개발과제(과제번호 2012-N73005-00) 연구비를 지원받아 수행되었습니다.
• This research was supported by a fund(code 2012-N73005-00) by Research of Korea Centers for Disease Control and Prevention.