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

Enrique Soto-Pedre; Paul J Newey; Sundararajan Srinivasan; Moneeza K Siddiqui; Colin N A Palmer; Graham P Leese

doi:10.1210/clinem/dgac527

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

J Clin Endocrinol Metab. 2022 Nov 25;107(12):3302-3308. doi: 10.1210/clinem/dgac527.

Authors

Enrique Soto-Pedre¹, Paul J Newey^{1

2}, Sundararajan Srinivasan¹, Moneeza K Siddiqui¹, Colin N A Palmer^{1

3}, Graham P Leese^{1

2}

Affiliations

¹ Division of Population Health & Genomics, School of Medicine, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, UK.
² Department of Endocrinology and Diabetes, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, UK.
³ Centre for Pharmacogenetics and Pharmacogenomics, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, UK.

Abstract

Context: A hypothesis-free genetic association analysis has not been reported for patients with primary hyperparathyroidism (PHPT).

Objective: 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 conducted among patients of European White 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 variations (formerly single-nucleotide polymorphisms), and LPAR3-rs147672681 reached genome-wide statistical significance (P = 1.2e-08). Using a more restricted PHPT definition, 8722 individuals with data on the GWAS-identified loci were found. Age- and sex-adjusted ORs for the effect alleles of SOX9-rs11656269, SLITRK5-rs185436526, and BCDIN3D-AS1-rs2045094 showed statistically 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 statistically significant linear trend across quartiles (P < 1.0e-04). Results were similar when stratifying by sex.

Conclusion: 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 male and female carriers of greater numbers of PHPT-risk alleles both have a statistically significant increased risk of PHPT.

Keywords: genetics; genome-wide association study; polygenic risk score; primary hyperparathyroidism.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cross-Sectional Studies
Female
Genome-Wide Association Study*
Humans
Hyperparathyroidism, Primary* / epidemiology
Hyperparathyroidism, Primary* / genetics
Male
Risk Factors

Abstract

Publication types

MeSH terms

Grants and funding