Evidence of a Causal Relationship between Serum Thyroid-Stimulating Hormone and Osteoporotic Bone Fractures

Abstract

<b><i>Objective:</i></b> We aimed to validate the association of genome-wide association study (GWAS)-identified loci and polygenic risk score with serum thyroid-stimulating hormone (TSH) concentrations and the diagnosis of hypothyroidism. Then, the causal relationship between serum TSH and osteoporotic bone fracture risk was tested. <b><i>Methods:</i></b> A cross-sectional study was done among patients of European Caucasian ethnicity recruited in Tayside (Scotland, UK). Electronic medical records (EMRs) were used to identify patients and average serum TSH concentration and linked to genetic biobank data. Genetic associations were performed by linear and logistic regression models. One-sample Mendelian randomization (MR) was used to test causality of serum TSH on bone fracture risk. <b><i>Results:</i></b> Replication in 9,452 euthyroid individuals confirmed known loci previously reported. The 58 polymorphisms accounted for 11.08% of the TSH variation (<i>p</i> < 1e−04). TSH-GRS was directly associated with the risk of hypothyroidism with an odds ratio (OR) of 1.98 for the highest quartile compared to the first quartile (<i>p</i> = 2.2e−12). MR analysis of 5,599 individuals showed that compared with those in the lowest tertile of the TSH-GRS, men in the highest tertile had a decreased risk of osteoporotic bone fracture (OR = 0.59, <i>p</i> = 2.4e−03), while no difference in a similar comparison was observed in women (OR = 0.93, <i>p</i> = 0.61). Sensitivity analysis yielded similar results. <b><i>Conclusions:</i></b> EMRs linked to genomic data in large populations allow replication of GWAS discoveries without additional genotyping costs. This study suggests that genetically raised serum TSH concentrations are causally associated with decreased bone fracture risk in men.

Investigating the causal relationship between thyroid dysfunction diseases and osteoporosis: a two-sample Mendelian randomization analysis

“…In recent years, numerous researchers have conducted studies focusing on targets for longevity and age-related diseases [40][41][42] . Previous studies have explored associations between thyroid hormone-related characteristics such as hyperthyroidism, TSH, and TSH receptors and bone density in relation to TDFDs and osteoporosis, but the results seem to be inconsistent [43][44][45][46] . The present study included five distinct clinical phenotypes of thyroid disorders (including hyperthyroidism, hypothyroidism, and nonfunctional thyroid disease) as well as three clinical phenotypes of osteoporosis (including osteoporosis and fracture), providing a more comprehensive investigation into the causal association between TDFDs and osteoporosis.…”

Higher serum free thyroxine levels are associated with increased risk of hip fractures in older men

“… 16 In a one-sample Mendelian randomization study ( n = 5599), genetically raised serum TSH was causally associated with decreased risk of an osteoporotic fracture in men but not in women. 17 In subjects with normal TSH in a Danish register-based study, the risks of hip fractures and MOF were increased with each SD unit of TSH decrease. 18 In a pooled analysis of 13 prospective cohort studies, in adults with baseline TSH of 0.45–4.49 mIU/L, lower TSH levels as well as higher FT4 levels were associated with increased risk of hip fractures.…”

The effects of common genetic variation in 96 genes involved in thyroid hormone regulation on TSH and FT4 concentrations

“…Also, multiple studies have demonstrated that even subtle variation in thyroid function within the reference range associates with an increased risk of cardiovascular diseases, fractures, dementia, depression, and even mortality (4,(6)(7)(8)(9)(10)(11)(12). Some of these associations were found to be causal based on Mendelian randomization studies (13)(14)(15)(16). Therefore, there is…”