Identification of 4 New Loci Associated With Primary Hyperparathyroidism (PHPT) and a Polygenic Risk Score for PHPT

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Objective: A hypothesis-free genetic association analysis has not been reported for patients with primary hyperparathyroidism (PHPT). We aimed to investigate genetic associations with PHPT using both genome-wide association study (GWAS) and candidate gene approaches.

Methods: A cross-sectional study was done among patients of European Caucasian ethnicity recruited in Tayside (Scotland, UK). Electronic medical records were used to identify PHPT cases and controls, and linked to genetic biobank data. Genetic associations were performed by logistic regression models and Odds Ratios (ORs). The combined effect of the genotypes was researched by genetic risk score (GRS) analysis.

Results: We identified 15,622 individuals for the GWAS that yielded 34 top single-nucleotide polymorphisms, and LPAR3-rs147672681 reached genome-wide statistical significance (P=1.2e-08). Using a more restricted PHPT definition 8,722 individuals with data on the GWAS-identified loci were found. Age-sex adjusted ORs for the effect alleles of SOX9-rs11656269, SLITRK5-rs185436526, and BCDIN3D-AS1-rs2045094 showed significant increased risks (P<1.5e-03). GRS analysis of 5482 individuals showed an OR of 2.51 (P=1.6e-04), 3.78 (P=4.0e-08) and 7.71 (P=5.3e-17) for the second, third and fourth quartiles respectively compared to the first, and there was a significant linear trend across quartiles (P<1.0e-04). Results were similar when stratifying by gender.

Conclusions: Using genetic loci discovered in a GWAS of PHPT carried out in a Scottish population, this study suggests new evidence for the involvement of genetic variants at SOX9, SLITRK5, LPAR3 and BCDIN3D-AS1. It also suggests that both male and female carriers of greater numbers of PHPT-risk alleles have a significant increased risk of PHPT.

Original languageEnglish
Pages (from-to)3302-3308
Number of pages7
JournalJournal of Clinical Endocrinology and Metabolism
Issue number12
Early online date14 Sept 2022
Publication statusPublished - Dec 2022


  • primary hyperparathyroidism
  • genetics
  • genome-wide association study
  • polygenic risk score


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