Evaluation of WISP1 as a candidate gene for bone mineral density in the Old Order Amish

Xing Wang,Kathleen A Ryan,Mao Fu,Shabnam Salimi,James Perry,Elizabeth Streeten,Alan R Shuldiner,Zhongliang Deng,Zhizhen Li,Dongfang Liu

doi:10.1038/s41598-018-25272-4

Abstract

Wnt1-inducible signaling pathway protein-1 (WISP1) is a novel target of the Wnt pathway for modulating osteogenesis and improving bone strength. However, it is not clear if genetic variants in the WISP1 region are associated with bone mineral density (BMD) in human. The aim of this study is to investigate the role of genetic variation in WISP1 gene as a determinant of BMD in 1,510 Old Order Amish (OOA). We performed regional association analysis of 58 tag variants within 5 kb upstream and downstream to WISP1 with BMD and found 5 variants that were associated with BMD at multiple skeletal sites (P values from 2.89 × 10−6 to 1.62 × 10−2), with some significant associations even after adjustment for multiple comparisons. To replicate these results in an independent dataset, we performed a look-up of BMD associations with these variants in European ancestry subjects from the large GEFOS Consortium and observed the nominal associations of two of these variants with BMD (P values: 0.031 to 0.048). In conclusion, we have demonstrated that genetic variants surrounding WISP1 are associated with BMD at multiple skeletal sites in the OOA, thus influencing osteoporosis risk. These results support a role for the WISP1 gene on influencing variation in BMD.

Highlights

Osteoporosis is a common disorder affecting hundreds of millions of people and is one of the leading causes of fractures in the world
1,510 Old Order Amish (OOA) who were measured for bone mineral density (BMD) using Dual-energy X-ray Absorptiometry (DXA)
Several independent studies, with the goal to detect candidate genes underlying osteoporosis, revealed that many genes in the Wnt signal pathway are associated with lumbar spine, hip femoral neck and whole body BMD, bone strength, cortical bone thickness, and fracture risk[10,24]

Summary

Introduction

Osteoporosis is a common disorder affecting hundreds of millions of people and is one of the leading causes of fractures in the world. Genetic variants of WISP1 have been associated with increasing the risk of these diseases, such as spinal osteoarthritis, scirrhous gastric carcinoma, lung cancer, and myocardial infarction[16,17,18,19]. These findings indicate that WISP1 is necessary for bone formation and regulation of skeletogenesis. The aim of this study was to evaluate the role of polymorphisms around WISP1 locus on BMD at total hip, hip femoral neck, hip intertrochanter, hip trochanter and lumbar spine in 1,510 OOA individuals

Objectives

Methods

Results

Conclusion