Abstract
With population aging, prevalence of low bone mineral density (BMD) and associated fracture risk are increased. To determine whether low circulating thyroid stimulating hormone (TSH) levels within the normal range are causally related to BMD, we conducted a two-sample Mendelian randomization (MR) study. Furthermore, we tested whether common genetic variants in the TSH receptor (TSHR) gene and genetic variants influencing expression of TSHR (expression quantitative trait loci [eQTLs]) are associated with BMD. For both analyses, we used summary-level data of genomewide association studies (GWASs) investigating BMD of the femoral neck (n = 32,735) and the lumbar spine (n = 28,498) in cohorts of European ancestry from the Genetic Factors of Osteoporosis (GEFOS) Consortium. For the MR study, we selected 20 genetic variants that were previously identified for circulating TSH levels in a GWAS meta-analysis (n = 26,420). All independent genetic instruments for TSH were combined in analyses for both femoral neck and lumbar spine BMD. In these studies, we found no evidence that a genetically determined 1-standard deviation (SD) decrease in circulating TSH concentration was associated with femoral neck BMD (0.003 SD decrease in BMD per SD decrease of TSH; 95% CI, -0.053 to 0.048; p = 0.92) or lumbar spine BMD (0.010 SD decrease in BMD per SD decrease of TSH; 95% CI, -0.069 to 0.049; p = 0.73). A total of 706 common genetic variants have been mapped to the TSHR locus and expression loci for TSHR. However, none of these genetic variants were associated with BMD at the femoral neck or lumbar spine. In conclusion, we found no evidence for a causal effect of circulating TSH on BMD, nor did we find any association between genetic variation at the TSHR locus or expression thereof and BMD. © 2018 The Authors. Journal of Bone and Mineral Research Published by WileyPeriodicals, Inc.
Highlights
Bone is a dynamic tissue that undergoes continuous remodeling to maintain its strength and integrity.[1]
Mendelian randomization (MR) studies can be performed on circulating thyroid stimulating hormone (TSH) and fT4 levels within the normal reference range,(17) because these measures of thyroid status have been shown to be partly and independently genetically determined in large-scale genomewide association studies (GWASs).(18,19) Even though TSH and fT4 levels are highly correlated, different genetic variants were associated with circulating levels of TSH than with fT4.(18) The genetic independence of these traits highlights the individuality of the HPT-axis set point, and allows for separate analyses of TSH and fT4
Using the IVW analyses (Table 2), we found no evidence for an association between genetically determined lower circulating levels of TSH and femoral neck bone mineral density (BMD) (0.003 standard deviation (SD) decrease in BMD per SD decrease in TSH; 95% confidence interval (CI), À0.053 to 0.048; p 1⁄4 0.92) (Fig. 1C) or lumbar spine BMD (0.010 SD decrease in BMD per SD decrease in TSH; 95% CI, –0.069 to 0.049; p 1⁄4 0.73) (Fig. 1D)
Summary
Bone is a dynamic tissue that undergoes continuous remodeling to maintain its strength and integrity.[1] When bone remodeling is uncoupled and resorption exceeds formation, bone mineral density (BMD) progressively decreases and leads to osteoporosis.[2] To develop therapies that are more effective and accompanied by fewer side effects than current treatments, further research into the molecular mechanisms underlying the pathogenesis of osteoporosis is required. One of these potential underlying mechanisms is thyroid status. MR studies can be performed on circulating TSH and fT4 levels within the normal reference range,(17) because these measures of thyroid status have been shown to be partly and independently genetically determined in large-scale genomewide association studies (GWASs).(18,19) Even though TSH and fT4 levels are highly correlated, different genetic variants were associated with circulating levels of TSH than with fT4.(18) The genetic independence of these traits highlights the individuality of the HPT-axis set point, and allows for separate analyses of TSH and fT4
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