Integration of summary data from GWAS and eQTL studies identified novel causal BMD genes with functional predictions.
paper
Cited
Public
- Authors
- Meng, Xiang-He; Chen, Xiang-Ding; Greenbaum, Jonathan; Zeng, Qin; You, Sheng-Lan; Xiao, Hong-Mei; Tan, Li-Jun; Deng, Hong-Wen
- Year
- 2018
- Journal
- Bone
- PMID
- 29763751
- DOI
- 10.1016/j.bone.2018.05.012
- PMCID
- PMC6346739
PURPOSE: Osteoporosis is a common global health problem characterized by low bone mineral density (BMD) and increased risk of fracture. Genome-wide association studies (GWAS) have identified >100 genetic loci associated with BMD. However, the functional genes responsible for most associations remain largely unknown. We conducted an innovative summary statistic data-based Mendelian randomization (SMR) analysis to identify novel causal genes associated with BMD and explored their potential functional significance. METHODS: After quality control of the largest GWAS meta-analysis data of BMD and the largest expression quantitative trait loci (eQTL) meta-analysis data from peripheral blood samples, 5967 genes were tested using the SMR method. Another eQTL data was used to verify the results. Next we performed a fine-mapping association analysis to investigate the functional SNP in the identified loci. Weighted gene co-expression network analysis (WGCNA) was used to explore functional relationships for the identified novel genes with known putative osteoporosis genes. Further, we assessed functions of the identified genes through in vitro cellular study or previous functional studies. RESULTS: We identified two potentially causal genes (ASB16-AS1 and SYN2) associated with BMD. SYN2 was a novel osteoporosis candidate gene and ASB16-AS1 locus was known to be associated with BMD but was not the nearest gene to the top GWAS SNP. Fine-mapping association analysis showed that rs184478 and rs795000 was predicted to be possible causal SNPs in ASB16-AS1 and SYN2, respectively. ASB16-AS1 co-expressed with several known putative osteoporosis risk genes. In vitro cellular study showed that over-expressed ASB16-AS1 increased the expression of osteoblastogenesis related genes (BMP2 and ALPL), indicating its functional significance. CONCLUSION: Our findings support that ASB16-AS1 and SYN2 may represent two novel functional genes underlying BMD variation. The findings provide a basis for further functional mechanistic studies.
The SMR results at gene loci for BMD. (A) The SMR result at ASB16-AS1 locus for FN-BMD. (B) The SMR result at SYN2 locus for LS-BMD. In the top plot, black dots represent the p values for the SNPs from the latest GWAS meta-analysis for BMD (Y-axis), diamonds represent the p values for probes from the SMR test. In the bottom plot, the eQTL p values of the SNPs were from the eQTL study (Y-axis) for the ILMN_1676731 probe (or ILMN_1781060 probe) tagging ASB16-AS1 (or SYN2).
Estimated genetic associations and 95% confidence intervals with effect sizes in eQTL and GWAS studies for 16 genetic variants in the ASB16-AS1 gene region (A) and 15 genetic variants in the SYN2 gene region (B).
Regional association plot for ASB16-AS1 on chromosome 17. SNPs which were in this region were selected with their p values from the GWAS data of FN-BMD. r2 of pairwise LD is calculated between rs227580 and other SNPs. C17ORF65 is also known as ASB16-AS1.
The gene co-expression relationships for ASB16-AS1. ASB16-AS1 centered network provides a view of all edges and their corresponding nodes connected to ASB16-AS1 with a TOM > 0.15. We only selected those nodes proved to be associated with BMD before. Genes are color coded based on their correlation with ASB16-AS1, white (cor > 0) and grey (cor < 0).
ASB16-AS1 can promote the expression of osteoblastic genes. (A) The relative expressions of two variants of ASB16-AS1 were detected in hFOB1.19 cells. The relative expressions of ASB16-AS1 (B), ALPL (C), BMP2 (D) and RUNX2 (E) were detected after transfection with the pCEP4-ASB16-AS1 using the pCEP4 as control. Bars represented S.D. *p < 0.05, **p < 0.01.
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