Post-genome wide association studies and functional analyses identify association of MPP7 gene variants with site-specific bone mineral density

Su Mei Xiao, Annie Wai Chee Kung, Yi Gao, Kam Shing Lau, Chun Hang Ma, Zhen Lin Zhang, Jian Min Liu, Wiebo Xia, Jin Wei He, Lin Zhao, Min Nie, Wei Zhen Fu, Min Jia Zhang, Jing Sun, Johnny S.H. Kwan, Gloria Hoi Wan Tso, Zhi Jie Dai, Ching Lung Cheung, Cora H. Bow, Anskar Yu Hung LeungKathryn Choon Beng Tan, Pak Chung Sham

Research output: Journal article publicationJournal articleAcademic researchpeer-review

19 Citations (Scopus)

Abstract

Our previous genome-wide association study (GWAS) in a Hong Kong Southern Chinese population with extreme bone mineral density (BMD) scores revealed suggestive association with MPP7, which ranked second after JAG1 as a candidate gene for BMD. To follow-up this suggestive signal, we replicated the top single-nucleotide polymorphism rs4317882 of MPP7 in three additional independent Asian-descent samples (n = 2684). The association of rs4317882 reached the genome-wide significance in the meta-analysis of all available subjects (Pmeta= 4.58 × 10-8, n = 4204). Site heterogeneity was observed, with a larger effect on spine than hip BMD. Further functional studies in a zebrafish model revealed that vertebral bone mass was lower in an mpp7 knock-down model compared with the wide-type (P = 9.64 × 10-4, n = 21). In addition, MPP7 was found to have constitutive expression in human bone-derived cells during osteogenesis. Immunostaining of murine MC3T3-E1 cells revealed that the Mpp7 protein is localized in the plasma membrane and intracytoplasmic compartment of osteoblasts. In an assessment of the function of identified variants, an electrophoretic mobility shift assay demonstrated the binding of transcriptional factor GATA2 to the risk allele 'A' but not the 'G' allele of rs4317882. An mRNA expression study in human peripheral blood mononuclear cells confirmed that the low BMD-related allele 'A' of rs4317882 was associated with lower MPP7 expression (P = 9.07 × 10-3, n = 135). Our data suggest a genetic and functional association of MPP7 with BMD variation.
Original languageEnglish
Article numberddr586
Pages (from-to)1648-1657
Number of pages10
JournalHuman Molecular Genetics
Volume21
Issue number7
DOIs
Publication statusPublished - 1 Apr 2012
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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