Thyroid Stimulating Hormone and Bone Mineral Density: Evidence From a Two-Sample Mendelian Randomization Study and a Candidate Gene Association Study

TY - JOUR

T1 - Thyroid Stimulating Hormone and Bone Mineral Density

T2 - Evidence From a Two-Sample Mendelian Randomization Study and a Candidate Gene Association Study

AU - van Vliet, Nicolien A

AU - Noordam, Raymond

AU - van Klinken, Jan B

AU - Westendorp, Rudi Gj

AU - Bassett, Jh Duncan

AU - Williams, Graham R

AU - van Heemst, Diana

N1 - © 2018 The Authors. Journal of Bone and Mineral Research Published by WileyPeriodicals, Inc.

PY - 2018/7

Y1 - 2018/7

N2 - 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.

AB - 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.

U2 - 10.1002/jbmr.3426

DO - 10.1002/jbmr.3426

M3 - Journal article

C2 - 29544020

SN - 0884-0431

VL - 33

SP - 1318

EP - 1325

JO - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

JF - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

IS - 7

ER -