Trps1 Differentially Modulates the Bone Mineral Density between Male and Female Mice and Its Polymorphism Associates with BMD Differently between Women and Men

Lishi Wang,Charles R Farber,Linda Myers,Weikuan Gu,Yongjun Wang,Wenli Lu,Lei Zhang,Lu Lu,Gaifen Liu,Abraham A Palmer,Yue Huang,Xiaoyun Liu,Cong-Yi Wang,Yan Jiao,Robert W Williams,Hongwen Deng,Rachel Scheib

doi:10.1371/journal.pone.0084485

Abstract

The objective of our study was to identify genetic factors that regulate bone mineral density (BMD) in mice using well defined recombinant inbred strains. For this purpose we chose the BXD recombinant inbred (RI) strains derived from progeny of the C57BL/6J (B6) and DBA/2J (D2) progenitor strains. We sampled both male and female mice (∼4 each) of 46 strains at 3 months-of-age, measured their BMD, and conducted QTL mapping. The data were analyzed to identify candidates genes contained within the most significant quantitative trait locus (QTL). Evaluation of candidate genes included functional assessment, single nucleotide polymorphism (SNP) genotyping and direct sequencing. We established that there was a QTL for BMD in males on chromosome 15 that has the impact larger than QTLs on all other chromosomes. The QTL on chromosome 15 was narrowed to a genomic region between 38 Mbp and 52 Mbp. By examining transcripts within this region, we found an important candidate gene: trichorhinophalangeal syndrome, type I (Trps1). SNP analysis identified a nonsynonymous SNP (rs32398060) in Trps1 that co-segregated with bone mineral density. Analysis of association between this SNP within TRPS1 and BMD in a human population confirmed its significance.

Highlights

Osteoporosis is a disease characterized by low bone mass primarily due to microarchitectural changes in trabecular bone
For quantitative trait locus (QTL) of tibiae Bone mineral density (BMD) of male mice, permutation tests estimated the scores of suggestive likelihood ratio statistic (LRS) = 10.68, significant LRS = 17.64, and highly significant LRS = 21.95
For QTL of tibiae BMD of female mice, we did not detect any genomic regions with an LRS greater than the suggestive level (LRS 10.55, based on 2,000 permutation tests) from tibiae of female mice

Summary

Introduction

Osteoporosis is a disease characterized by low bone mass primarily due to microarchitectural changes in trabecular bone. Bone mineral density (BMD) is the major genetic determinant for osteoporosis [2,3,4,5]. Low BMD is characterized by enhanced bone fragility and a consequent increase in fracture risk. In spite of the contribution of environmental factors, such as diet, drugs, exercise and coexisting diseases, peak BMD is predominantly determined by genetic influences. Genetic background has been estimated to account for more than 70% of variation in BMD. The identification of the gene/genes that regulate BMD may represent a major advance in understanding the pathogenesis of osteoporosis

Objectives

Methods

Results

Conclusion