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Pathway analysis of genome-wide association study for bone mineral density

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Abstract

The aim of this study was to identify the candidate causal single nucleotide polymorphisms (SNPs) and candidate causal mechanisms that contribute to bone mineral density (BMD) and to generate a SNP to gene to pathway hypothesis using an analytical pathway-based approach. We used hip BMD GWAS data of the genotypes of 301,019 SNPs in 5,715 Europeans. ICSNPathway (identify candidate causal SNPs and pathways) analysis was applied to the BMD GWAS dataset. The first stage involved the pre-selection of candidate causal SNPs by linkage disequilibrium analysis and the functional SNP annotation of the most significant SNPs found. The second stage involved the annotation of biological mechanisms for the pre-selected candidate causal SNPs using improved-gene set enrichment analysis. ICSNPathway analysis identified seven candidate SNPs, eight candidate pathways, and seven hypothetical biological mechanisms. Eight pathways are as follows; gamma-hexachlorocyclohexane degradation (nominal p-value < 0.001, false discovery rate (FDR) <0.001), regulation of the smoothened signaling pathway (nominal p-value < 0.001, FDR = 0.016), TACI and BCMA stimulation of B cell immune response (nominal p-value < 0.001, FDR = 0.021), endonuclease activity (nominal p-value = 0.001, FDR = 0,026), regulation of defense response to virus (nominal p-value = 0.001, FDR = 0.028), serine_type_endopeptidase_inhibitor_activity (nominal p-value = 0.001, FDR = 0.044), endoribonuclease activity (nominal p-value = 0.002, FDR = 0.045), and myeloid leukocyte differentiation (nominal p-value = 0.001, FDR = 0.050). The most significant causal pathway was gamma-hexachlorocyclohexane degradation. CYP3A5, PON2, PON3, CMBL, PON1, ALPL, CYP3A43, CYP3A7, ACP6, ACPP, and ALPI (p < 0.05) are involved in the pathway of gamma-hexachlorocyclohexane degradation. Further examination of the gene contents revealed that DBR1, DICER1, EXO1, FEN1, POP1, POP4, RPP30, and RPP38 were involved in 2 of the 8 pathways (p < 0.05). By applying ICSNPathway analysis to BMD GWAS data, we identified seven candidate SNPs and eight pathways involving gamma-hexachlorocyclohexane degradation, which may contribute to low BMD.

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Acknowledgments

The authors gratefully acknowledge the efforts of those involved in the generation of BMD GWAS data.

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Authors and Affiliations

  1. Division of Rheumatology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, 126-1, Anam-dong 5-ga, Seongbuk-gu, Seoul, 136-705, Korea

    Young Ho Lee, Sung Jae Choi, Jong Dae Ji & Gwan Gyu Song

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  1. Young Ho Lee
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  2. Sung Jae Choi
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Correspondence to Young Ho Lee.

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Lee, Y.H., Choi, S.J., Ji, J.D. et al. Pathway analysis of genome-wide association study for bone mineral density. Mol Biol Rep 39, 8099–8106 (2012). https://doi.org/10.1007/s11033-012-1657-1

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  • DOI: https://doi.org/10.1007/s11033-012-1657-1

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