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ContextPrimary hyperparathyroidism (PHPT) is associated with increased risk of morbidity and death, and vitamin D levels are a potentially confounding variable.ObjectiveThe aim of this study was to assess morbidity and mortality associated with primary hyperparathyroidism (PHPT).MethodsIn this population-based retrospective matched cohort study, data linkage of biochemistry, hospital admissions, prescribing, imaging, pathology, and deaths was used to identify patients across the region of Tayside, Scotland, who had PHPT from 1997 to 2019. Cox proportional hazards models and hazards ratios (HR) were used to explore the relationship between exposure to PHPT and several clinical outcomes. Comparisons were made with an age- and gender-matched cohort.ResultsIn 11 616 people with PHPT (66.8% female), with a mean follow-up period of 8.8 years, there was an adjusted HR of death of 2.05 (95% CI, 1.97-2.13) for those exposed to PHPT. There was also an increased risk of cardiovascular disease (HR = 1.34; 95% CI, 1.24-1.45), cerebrovascular disease (HR = 1.29; 95% CI, 1.15-1.45), diabetes (HR = 1.39; 95% CI, 1.26-1.54), renal stones (HR = 3.02; 95% CI, 2.19-4.17) and osteoporosis (HR = 1.31; 95% CI, 1.16-1.49). Following adjustment for serum vitamin D concentrations (n = 2748), increased risks for death, diabetes, renal stones, and osteoporosis persisted, but not for cardiovascular or cerebrovascular disease.ConclusionIn a large population-based study, PHPT was associated with death, diabetes, renal stones, and osteoporosis, independent of serum vitamin D concentration.

Objective: 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. Methods: 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. Results: Replication in 9,452 euthyroid individuals confirmed known loci previously reported. The 58 polymorphisms accounted for 11.08% of the TSH variation (p < 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 (p = 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, p = 2.4e−03), while no difference in a similar comparison was observed in women (OR = 0.93, p = 0.61). Sensitivity analysis yielded similar results. Conclusions: 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.