Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture

Abstract

Bone mineral density (BMD) is the most important predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and East Asian ancestry. We tested the top-associated BMD markers for replication in 50,933 independent subjects and for risk of low-trauma fracture in 31,016 cases and 102,444 controls. We identified 56 loci (32 novel)associated with BMD atgenome-wide significant level (P<5×10−8). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal-stem-cell differentiation, endochondral ossification and the Wnt signalling pathways. However, we also discovered loci containing genes not known to play a role in bone biology. Fourteen BMD loci were also associated with fracture risk (P<5×10−4, Bonferroni corrected), of which six reached P<5×10−8 including: 18p11.21 (C18orf19), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

Genomewide meta‐analysis identifies loci associated with IGF ‐I and IGFBP ‐3 levels with impact on age‐related traits

“…We also examined the associations of the IGF‐I‐ and IGFBP‐3‐associated SNPs with anthropometric traits (height, BMI, waist‐to‐hip ratio, and fat percentage) (Heid et al ., 2010; Lango Allen et al ., 2010; Speliotes et al ., 2010), bone mineral density (Estrada et al ., 2012), risk of type 2 diabetes (Voight et al ., 2010; Morris et al ., 2012) and related traits (fasting glucose, 2‐h glucose, HbA1c, fasting insulin, proinsulin, HOMA‐IR, and HOMA‐B) (Dupuis et al ., 2010; Saxena et al ., 2010; Soranzo et al ., 2010), and coronary artery disease (Coronary Artery Disease Genetics C, 2011; Schunkert et al ., 2011; Consortium CAD and Deloukas, 2013) (Table S9, Supporting information). Many nominal associations were expected because of the known influence of the IGF system on these traits.…”

“…Top SNPs associated with levels of IGF‐I and IGFBP‐3 were examined in relationship to other phenotypes using published data on serum metabolites (Suhre et al ., 2011; Shin et al ., 2014), anthropometric traits (Heid et al ., 2010; Lango Allen et al ., 2010; Speliotes et al ., 2010), bone mineral density (Estrada et al ., 2012), diabetes (Voight et al ., 2010; Morris et al ., 2012) and glycemic traits (Dupuis et al ., 2010; Saxena et al ., 2010; Soranzo et al ., 2010), coronary artery disease (Coronary Artery Disease Genetics C, 2011; Schunkert et al ., 2011; Consortium CAD and Deloukas, 2013), and survival beyond 90 years (Broer et al ., 2015). Detailed information of the published datasets used including its references is given in Table S9 (Supporting information).…”

Metabolomic Pathways to Osteoporosis in Middle-Aged Women: A Genome-Metabolome-Wide Mendelian Randomization Study

“…Our previous study showed that one of these metabolites, epiandrosterone sulfate, was significantly associated with chronic widespread musculoskeletal pain 24. The SNP rs4646450 has shown significant association with femoral neck BMD in the GEFOS consortium meta‐analysis 17. Importantly, all the causally associated metabolites in the TwinsUK study showed direct association with BMD in the HKOS population, and collectively explained 2.7% variance of BMD variation at the total hip.…”

Affinity proteomics discovers decreased levels of AMFR in plasma from Osteoporosis patients

“…This resulted in a discovery derived list of 142 antibodies targeting 72 unique proteins. This collection was further supplemented with 25 candidate proteins (34 antibodies) proposed by genome wide association study analysis 24, 25, and as shown in Fig. 1B, eight protein targets were found to overlap with the discovery derived list.…”