Three pleiotropic loci associated with bone mineral density and lean body mass
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ORIGINAL ARTICLE
Three pleiotropic loci associated with bone mineral density and lean body mass Yu‑Xue Zhang1,2 · Shan‑Shan Zhang3,4 · Shu Ran2 · Yu Liu2 · Hong Zhang1,3 · Xiao‑Lin Yang1,3 · Rong Hai5 · Hui Shen6 · Qing Tian6 · Hong‑Wen Deng6 · Lei Zhang1,3 · Yu‑Fang Pei3,4 Received: 14 May 2020 / Accepted: 9 September 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
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 0.8). Meanwhile, 3DSNP (https://cbportal.org/3dsnp/) was used to identify the potential pathogenicity and function of the SNPs (Lu et al. 2017).
Result The basic characteristics of the studied samples are summarized in Table 1. A total of 12,445 subjects from six samples are included in the FNK-BMD and LBM bivariate analyses. Principle components analysis (PCA) was applied to each sample and no population outliers were observed. The 1000 genomes sequencing project generated over 10 million qualified SNPs. After removing variants either of low frequency or of poor imputation accuracy, 12,061,510 variants are qualified for analysis.
Univariate and bivariate analysis of FNK‑BMD and LBM A logarithmic quantile–quantile plot of meta-analysis test statistics for bivariate analyses showed a marked deviation in the tail of the distribution, implying the possible existence of true associations (Fig. 1). The Manhattan plot of the GWAS meta-analyses is displayed in Fig. 2. Univariate GWAS meta-analysis of FNK-BMD identified ten distinct loci at the genome-wide significance (GWS,
Table 1 The basic characteristics of study participants Sample
Anc
Source
N
Female Age (%) (years)
OOS KCOS COS FHS WHI-AA WHI-HIS
EUR EUR EAS EUR AFR AMR
In-house 866 48.15 50.64 (18.16) In-house 2205 76.64 51.53 (13.71) In-house 1538 50.58 34.71 (13.39) dbGAP 6547 44.60 56.00 (13.76) dbGAP 843 100.00 61.17 (7.30) dbGAP 445 100.00 60.11 (7.51)
Height (cm)
FNK-BMD Arm LBM Arm FBM (g/cm2) (kg) (kg)
Leg LBM (kg)
170.98 (9.74) 166.23 (8.41) 164.31 (8.20) 168.03 (9.88) 162.75 (5.76) 158.16 (5.55)
0.81 (0.14) 0.79 (0.15) 0.81 (0.13) 0.94 (0.16) 0.82 (0.14) 0.73 (0.11)
17.98 (4.54) 8.74 (3.53) 16.81 (3.90) 9.04 (3.83) 14.91 (3.47) 4.82 (1.91) 15.16 (3.62) 8.41 (3.62) 13.00 (2.50) 14.15 (5.07) 10.79 (1.96) 11.47 (3.85)
6.47 (2.19) 5.64 (1.90) 4.92 (1.55) 4.09 (0.77) – –
3.04 (1.34) 3.22 (1.77) 1.76 (0.98) 3.59 (2.02) – –
Leg FBM (kg)
Data are presented as mean (sd) OOS Omaha osteoporosis study, KCOS Kansas city osteoporosis study, COS Chinese osteoporosis study,
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