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Three pleiotropic loci associated with bone mineral density and lean body mass.

ABSTRACT: Both bone mineral density (BMD) and lean body mass (LBM) are important physiological measures with strong genetic determination. Besides, BMD and LBM might have common genetic factors. Aiming to identify pleiotropic genomic loci underlying BMD and LBM, we performed bivariate genome-wide association study meta-analyses of femoral neck bone mineral density and LBM at arms and legs, and replicated in the large-scale UK Biobank cohort sample. Combining the results from discovery meta-analysis and replication sample, we identified three genomic loci at the genome-wide significance level (p?-8): 2p23.2 (lead SNP rs4477866, discovery p?=?3.47?×?10^-8, replication p?=?1.03?×?10^-4), 16q12.2 (rs1421085, discovery p?=?2.04?×?10^-9, replication p?=?6.47?×?10^-14) and 18q21.32 (rs11152213, discovery p?=?3.47?×?10^-8, replication p?=?6.69?×?10^-6). Our findings not only provide useful insights into lean mass and bone mass development, but also enhance our understanding of the potential genetic correlation between BMD and LBM.

SUBMITTER: Zhang YX

PROVIDER: S-EPMC7903521 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Three pleiotropic loci associated with bone mineral density and lean body mass.

Zhang Yu-Xue YX Zhang Shan-Shan SS Ran Shu S Liu Yu Y Zhang Hong H Yang Xiao-Lin XL Hai Rong R Shen Hui H Tian Qing Q Deng Hong-Wen HW Zhang Lei L Pei Yu-Fang YF

Molecular genetics and genomics : MGG 20200924 1

Both bone mineral density (BMD) and lean body mass (LBM) are important physiological measures with strong genetic determination. Besides, BMD and LBM might have common genetic factors. Aiming to identify pleiotropic genomic loci underlying BMD and LBM, we performed bivariate genome-wide association study meta-analyses of femoral neck bone mineral density and LBM at arms and legs, and replicated in the large-scale UK Biobank cohort sample. Combining the results from discovery meta-analysis and re ...[more]

PMID: 32970232

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Project description:Aiming to identify more genomic loci associated with bone mineral density (BMD), we conducted a joint association analysis of 2 genome-wide association study (GWAS) by the integrative association method multi-trait analysis of GWAS (MTAG). The first one is the single GWAS of estimated heel BMD (eBMD) in the UK biobank (UKB) cohort (N = 426,824), and the second one is the GWAS meta-analysis of total body BMD (TB-BMD) in 66,628 participants from 30 studies. Approximate conditional association analysis was performed in the identified novel loci to identify secondary association signal. Statistical fine-mapping was conducted to prioritize plausible credible risk variants (CRVs). Candidate genes were prioritized based on the analyses of cis- expression quantitative trait locus (cis-eQTL) and cis-protein QTL (cis-pQTL) information as well as the functional category of the SNP. By integrating the information carried in over 490,000 participants, this largest joint analysis of BMD GWAS identified 12 novel genomic loci at the genome-wide significance level (GWS, p = 5.0 × 10-8), nine of which were for eBMD and four were for TB-BMD, explaining an additional 0.11 and 0.23% heritability for the two traits, respectively. These loci include 1p33 (lead SNP rs10493130, peBMD = 3.19 × 10-8), 5q13.2 (rs4703589, peBMD = 4.78 × 10-8), 5q31.3 (rs9324887, pTB-BMD = 1.36 × 10-9), 6p21.32 (rs6905837, peBMD = 3.32 × 10-8), 6q14.1 (rs10806234, peBMD = 2.63 × 10-8), 7q21.11 (rs10806234, pTB-BMD = 3.37 × 10-8), 8q24.12 (rs11995866, peBMD = 6.72 × 10-9), 12p13.31 (rs1639122, peBMD = 4.43 × 10-8), 12p12.1 (rs58489179, peBMD = 4.74 × 10-8), 12q24.23 (rs75499226, peBMD = 1.44 × 10-8), 19q13.31 (rs7255083, pTB-BMD = 2.18 × 10-8) and 22q11.23 (rs13056137, pTB-BMD = 2.54 × 10-8). All lead SNPs in these 12 loci are nominally significant in both original studies as well as consistent in effect direction between them, providing solid evidence of replication. Approximate conditional analysis identified one secondary signal in 5q13.2 (rs11738874, pconditional = 5.06 × 10-9). Statistical fine-mapping analysis prioritized 269 CRVs. A total of 65 candidate genes were prioritized, including those with known biological function to bone development (such as FGF1, COL11A2 and DEPTOR). Our findings provide novel insights into a better understanding of the genetic mechanism underlying bone development as well as candidate genes for future functional investigation.

Project description:BackgroundGenome-wide association studies (GWASs) routinely identify loci associated with risk factors for osteoporosis. However, GWASs with relatively small sample sizes still lack sufficient power to ascertain the majority of genetic variants with small to modest effect size, which may together truly influence the phenotype. The loci identified only account for a small percentage of the heritability of osteoporosis. This study aims to identify novel genetic loci associated with DXA-derived femoral neck (FNK) bone mineral density (BMD) and quantitative ultrasound of the heel calcaneus estimated BMD (eBMD), and to detect shared/causal variants for the two traits, to assess whether the SNPs or putative causal SNPs associated with eBMD were also associated with FNK-BMD.MethodsNovel loci associated with eBMD and FNK-BMD were identified by the genetic pleiotropic conditional false discovery rate (cFDR) method. Shared putative causal variants between eBMD and FNK-BMD and putative causal SNPs for each trait were identified by the colocalization method. Mendelian randomization analysis addresses the causal relationship between eBMD/FNK-BMD and fracture.ResultsWe identified 9,500 (cFDR < 9.8E-6), 137 (cFDR < 8.9E-4) and 124 SNPs associated with eBMD, FNK-BMD, and both eBMD and FNK-BMD, respectively, with 37 genomic regions where there was a SNP that influences both eBMD and FNK-BMD. Most genomic regions only contained putative causal SNPs associated with eBMD and 3 regions contained two distinct putative causal SNPs influenced both traits, respectively. We demonstrated a causal effect of FNK-BMD/eBMD on fracture.ConclusionMost of SNPs or putative causal SNPs associated with FNK-BMD were also associated with eBMD. However, most of SNPs or putative causal SNPs associated with eBMD were not associated with FNK-BMD. The novel variants we identified may help to account for the additional proportion of variance of each trait and advance our understanding of the genetic mechanisms underlying osteoporotic fracture.

Project description:Circulating osteo progenitor (COP) cells are a heterogeneous population of cells that circulate within the peripheral blood with characteristics of the bone marrow mesenchymal stem and progenitor pool. Little is known about the behavior of this cell population in humans. The aim of this study was to identify whether a relationship exists between COP cells (as a percentage of the peripheral blood monocytic cells) and musculoskeletal morphometry and to identify if COP have potential clinical utility as a biomarker for osteoporosis. We recruited 57 older adults (median age: 69 years; IQR: 65, 75 years) living independently in the community and performed cross-sectional analysis to identify associations between the percentage of COP cells and body composition parameters, and through receiver operating characteristic analysis, we evaluated their ability to act as a biomarker of osteoporosis. COP cells were moderately associated with whole-body bone mineral density (BMD) (r = 0.323, p = 0.014) and bone mineral content (BMC) (r = 0.387, p = 0.003), neck of femur BMD (r = 0.473, p < 0.001), and BMC (r = 0.461, p < 0.001) as well as appendicular lean mass (ALM) (p = 0.038) and male sex (p = 0.044) in univariable analysis. In multivariable analysis controlling for age, gender, height, and weight, COP cells remained strongly associated with neck of femur BMD (p = 0.001) and content (p = 0.003). COP cells were also a good predictor of osteoporosis (dual-energy X-ray absorptiometry [DXA] T-score < -2.5) at the neck of femur (cutoff: 0.4%; sensitivity: 100%; specificity 79%) and total body (cutoff: 0.35%; sensitivity: 80%; specificity: 81%). This study shows strong relationships between bone parameters and COP cell number and male sex. They also have potential as a biomarker of osteoporosis, which may provide a new tool for advanced detection and screening in clinical settings. Future larger evaluation studies should verify the cutoffs for biomarker use, and further explore the relationship between COP cells and muscle. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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Three pleiotropic loci associated with bone mineral density and lean body mass.

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Three pleiotropic loci associated with bone mineral density and lean body mass.

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