Meta-Analysis of Genome-Wide Association Studies Identifies Novel Functional CpG-SNPs Associated with Bone Mineral Density at Lumbar Spine

International Journal of Genomics
Chuan QiuHong-Wen Deng

Abstract

Osteoporosis is a serious public health issue, which is mostly characterized by low bone mineral density (BMD). To search for additional genetic susceptibility loci underlying BMD variation, an effective strategy is to focus on testing of specific variants with high potential of functional effects. Single nucleotide polymorphisms (SNPs) that introduce or disrupt CpG dinucleotides (CpG-SNPs) may alter DNA methylation levels and thus represent strong candidate functional variants. Here, we performed a targeted GWAS for 63,627 potential functional CpG-SNPs that may affect DNA methylation in bone-related cells, in five independent cohorts (n = 5905). By meta-analysis, 9 CpG-SNPs achieved a genome-wide significance level (p < 7.86 × 10-7) for association with lumbar spine BMD and additional 15 CpG-SNPs showed suggestive significant (p < 5.00 × 10-5) association, of which 2 novel SNPs rs7231498 (NFATC1) and rs7455028 (ESR1) also reached a genome-wide significance level in the joint analysis. Several identified CpG-SNPs were mapped to genes that have not been reported for association with BMD in previous GWAS, such as NEK3 and NFATC1 genes, highlighting the enhanced power of targeted association analysis for identification of novel as...Continue Reading

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Methods Mentioned

BETA
X-ray
genotyping
acetylation

Software Mentioned

GOEAST
SNiPA
METAL
Minimac
SNPnexus
HaploReg
PLINK

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