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

Area of Science:

• Endocrinology
• Genetics
• Population Health

Background:

• Primary hyperparathyroidism (PHPT) lacks hypothesis-free genetic association studies.
• Understanding the genetic underpinnings of PHPT is crucial for targeted interventions.

Purpose of the Study:

• To investigate genetic associations with PHPT using genome-wide association study (GWAS) and candidate gene approaches.
• To identify specific genetic variants and their combined effects on PHPT risk.

Main Methods:

• Cross-sectional study of European White individuals in Scotland.
• Utilized electronic medical records and genetic biobank data for case and control identification.
• Employed logistic regression, odds ratios (ORs), and genetic risk score (GRS) analysis.

Main Results:

• GWAS identified 34 top single-nucleotide variations, with LPAR3-rs147672681 reaching genome-wide significance (P = 1.2e-08).
• SOX9, SLITRK5, and BCDIN3D-AS1 variants showed statistically significant increased PHPT risk (P < 1.5e-03).
• GRS analysis revealed a dose-dependent increase in PHPT risk with accumulating risk alleles (P < 1.0e-04).

Conclusions:

• Genetic variants at SOX9, SLITRK5, LPAR3, and BCDIN3D-AS1 are implicated in PHPT.
• Accumulation of PHPT-risk alleles significantly increases risk in both males and females.
• This study provides novel genetic insights into PHPT etiology.