Identification of IDUA and WNT16 Phosphorylation‐Related Non‐Synonymous Polymorphisms for Bone Mineral Density in Meta‐Analyses of Genome‐Wide Association Studies

Tianhua Niu, Ning Liu, Xun Yu, Ming Zhao, Hyung Jin Choi, Paul J Leo, Matthew A Brown, Lei Zhang, Yu‐Fang Pei, Hui Shen, Hao He, Xiaoying Fu, Shan Lu, Xiang‐Ding Chen, Li‐Jun Tan, Tie‐Lin Yang, Yan Guo, Nam H Cho, Jie Shen, Yan‐Fang Guo, Geoffrey C Nicholson, Richard L Prince, John A Eisman, Graeme Jones, Philip N Sambrook, Qing Tian, Xue‐Zhen Zhu, Christopher J Papasian, Emma L Duncan, André G Uitterlinden, Chan Soo Shin, Shuanglin Xiang, Hong‐Wen Deng

Protein phosphorylation regulates a wide variety of cellular processes. Thus, we hypothesize that single nucleotide polymorphisms (SNPs) that may modulate protein phosphorylation could affect osteoporosis risk. Based on a previous conventional genome-wide association (GWA) study, we conducted a three-stage meta-analysis targeting phosphorylation-related SNPs (phosSNPs) for femoral neck (FN)-, total hip (HIP)-, and Lumbar Spine (LS)-BMD phenotypes. In stage 1, 9,593 phosSNPs were meta-analyzed in 11,140 individuals of various ancestries. Genome-wide significance (GWS) and suggestive significance were defined by α = 5.21 × 10(-6) (0.05/9,593) and 1.00 × 10(-4) , respectively. In stage 2, 9 stage 1-discovered phosSNPs (based on α = 1.00 × 10(-4) ) were in silico meta-analyzed in Dutch, Korean, and Australian cohorts. In stage 3, four phosSNPs that replicated in stage 2 (based on α = 5.56 × 10(-3) , 0.05/9) were de novo genotyped in two independent cohorts. IDUA rs3755955 and rs6831280, and WNT16 rs2707466 were associated with BMD phenotypes in each respective stage, and in 3 stages combined, achieving GWS for both FN-BMD (P-value = 8.36 × 10(-10) , 5.26 × 10(-10) , and 3.01 × 10(-10) , respectively) and HIP-BMD (P-value = 3.26 × 10(-6) , 1.97 × 10(-6) , and 1.63 × 10(-12) , respectively). Although in vitro studies demonstrated no differences in expressions of wild-type and mutant forms of IDUA and WNT16B proteins, in silico analysis predicts that WNT16 rs2707466 directly abolishes a phosphorylation site, which could cause a deleterious effect on WNT16 protein, and that IDUA phosSNPs rs3755955 and rs6831280 could exert indirect effects on nearby phosphorylation sites. Further studies will be required to determine the detailed and specific molecular effects of these BMD-associated non-synonymous variants. This article is protected by copyright. All rights reserved.