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

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.

Bone Mass and Strength are Significantly Improved in Mice Overexpressing Human WNT16 in Osteocytes

“…This could lead to different dose-response curves proposed recently between Wnt16 expression and bone mass in these two compartments (15). These results are in consistent with previous human GWAS studies demonstrating the association between WNT16 and BMD at skeletal sites with predominant trabecular bone such as spine and heel (5, 10, 11). Overall these data suggest that WNT16 exerts distinct effect on compartment-specific bone mass, depending on whether it is perturbed physiologically (knockout of Wnt16) or manipulated pharmacologically (overexpression of WNT16).…”

Integrating GWAS and Co-expression Network Data Identifies Bone Mineral Density Genes SPTBN1 and MARK3 and an Osteoblast Functional Module

“…7q31.31 region, which contained two independent associations in GEFOSII and three OFM genes; WNT16 , FAM3C and CPED1 . This region appears to be quite genetically complex and there is evidence from other GWASs that it contains more than just the two associations identified by GEFOSII (Chesi et al, 2015; Cho et al, 2009; Estrada et al, 2012; Kemp et al, 2014; Medina-Gómez et al, 2012; Moayyeri et al, 2014; Zhang et al, 2013a; Zheng et al, 2012). As a result, it is possible that all three OFM genes located in the 7q31.31 region are responsible for independent genetic associations with BMD.…”

Analysis of the Bone MicroRNome in Osteoporotic Fractures

“…This may be difficult because of cost reasons and also the complexities inherent to obtaining bone tissue samples. Establishing large collaborative consortia on bone epigenetics, following the paths set for the genomic association studies, may help to accomplish this goal [5,33]. Also, from the experience accumulated by comparing the results of genome-wide association studies and candidate gene studies, an unbiased ''miRNome-wide'' approach may be preferable.…”