Meta-analysis of genome-wide association studies identifies two loci associated with circulating osteoprotegerin levels

Abstract

Osteoprotegerin (OPG) is involved in bone homeostasis and tumor cell survival. Circulating OPG levels are also important biomarkers of various clinical traits, such as cancers and atherosclerosis. OPG levels were measured in serum or in plasma. In a meta-analysis of genome-wide association studies in up to 10 336 individuals from European and Asian origin, we discovered that variants >100 kb upstream of the TNFRSF11B gene encoding OPG and another new locus on chromosome 17q11.2 were significantly associated with OPG variation. We also identified a suggestive locus on chromosome 14q21.2 associated with the trait. Moreover, we estimated that over half of the heritability of OPG levels could be explained by all variants examined in our study. Our findings provide further insight into the genetic regulation of circulating OPG levels.

Figure 1.

Manhattan plot of SNPs for the sex-combined meta-analysis. The X-axis indicates the chromosomal position of each SNP, whereas the Y-axis denotes the evidence of association shown as −log(P-value). The red line indicates genome-wide significance of association (P = 5 × 10⁻⁸).

Figure 2.

QQ plots of SNPs for sex-combined (in black), female-specific (in red) and male-specific (in blue) meta-analyses, respectively.

Figure 3.

Regional association plots and ENCODE annotation of the loci that reached or marginally reached genome-wide significance (P < 5 × 10⁻⁸) in the sex-combined meta-analysis. The X-axis indicates the physical position of each SNP on the chromosome specified, whereas the Y-axis denotes the evidence of association shown as −log(P-value). ENCODE annotation are also provided, including transcription factor-binding sites (TFBS) from 95 cell lines, DNase I hypersensitivity sites (DNase HS) from 125 cell lines, and chromatin states in nine ENCODE cell lines (GM12878, H1-hSEC, K562, HepG2, HUVEC, HMEC, HSMM, NHEK and NHLF). The chromatin states are annotated as follows: strong enhancer (orange), weak enhancer (yellow), active promoter (red), poised promoter (pink), insulator (blue), transcribed (pale green), transcription transition (dark green), repressed (dark gray) and heterochromatin (pale gray).

Figure 3.

Regional association plots and ENCODE annotation of the loci that reached or marginally reached genome-wide significance (P < 5 × 10⁻⁸) in the sex-combined meta-analysis. The X-axis indicates the physical position of each SNP on the chromosome specified, whereas the Y-axis denotes the evidence of association shown as −log(P-value). ENCODE annotation are also provided, including transcription factor-binding sites (TFBS) from 95 cell lines, DNase I hypersensitivity sites (DNase HS) from 125 cell lines, and chromatin states in nine ENCODE cell lines (GM12878, H1-hSEC, K562, HepG2, HUVEC, HMEC, HSMM, NHEK and NHLF). The chromatin states are annotated as follows: strong enhancer (orange), weak enhancer (yellow), active promoter (red), poised promoter (pink), insulator (blue), transcribed (pale green), transcription transition (dark green), repressed (dark gray) and heterochromatin (pale gray).

Figure 3.

Regional association plots and ENCODE annotation of the loci that reached or marginally reached genome-wide significance (P < 5 × 10⁻⁸) in the sex-combined meta-analysis. The X-axis indicates the physical position of each SNP on the chromosome specified, whereas the Y-axis denotes the evidence of association shown as −log(P-value). ENCODE annotation are also provided, including transcription factor-binding sites (TFBS) from 95 cell lines, DNase I hypersensitivity sites (DNase HS) from 125 cell lines, and chromatin states in nine ENCODE cell lines (GM12878, H1-hSEC, K562, HepG2, HUVEC, HMEC, HSMM, NHEK and NHLF). The chromatin states are annotated as follows: strong enhancer (orange), weak enhancer (yellow), active promoter (red), poised promoter (pink), insulator (blue), transcribed (pale green), transcription transition (dark green), repressed (dark gray) and heterochromatin (pale gray).