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Bone and Mineral Metabolism

ORF43-04 - Cross-Trait Genetic Architecture of Mineral Homeostasis

Monday, June 15, 2026
9:45 AM - 10:00 AM CT
Location: Room W184ABC
Disclosure(s):
Michael Mannstadt, MD: Alexion Pharmaceutical: Advisory Board (), Clinical Trial Investigator (); BridgeBio: Advisory Board (), Clinical Trial Investigator (); MBX: Advisory Board (); septerna: Consultant (); Shire Pharmaceuticals/Takeda: Advisory Board (), Clinical Trial Investigator (), Consultant ()

Genome-wide association studies (GWAS) have identified loci associated with mineral traits, however their relevance to mineral metabolism regulation is unclear as most traits are typically analysed independently, overlooking their coordinated regulation. We aimed to characterize the cross-trait genetic architecture of mineral metabolism and to map variant effects to regulatory pathways to establish their physiological relevance. We conducted GWAS of serum albumin-adjusted calcium, phosphate, 25-hydroxyvitamin D, and alkaline phosphatase in 274,547 to 403,674 individuals of European ancestry in the UK Biobank (UKB) and validated associations in 133,403 individuals from the US Geisinger Health System cohort. A total of 964 association signals (p < 5x10-9) were identified and 29% annotated to reported mineral metabolism genes. Using these loci as anchors, we leveraged cross-trait genetic effects to define physiological axes corresponding to parathyroid hormone (PTH) synthesis, fibroblast growth factor-23 (FGF23) secretion and bone mineralisation, and vitamin D metabolism. Projecting uncharacterized association signals and loci onto these axes enabled novel assignment of 128 genes to calcitropic processes. To validate this cross-trait genetic architecture, we generated polygenic risk scores (PRS) for each axis and conducted phenome-wide association studies across 1,578 diseases and traits in the UKB. The PTH synthesis PRS was associated with hyperparathyroid disorders (odds ratio (OR)=1.9, p< 5x10-15), the FGF23 and bone mineralisation PRS with osteoporosis and fractures (OR=1.2, p< 0.05), and the vitamin D PRS with renal calculi (OR=1.9, p< 0.01). Further assessment of variants linked to the PTH synthesis axis was conducted using chromatin accessibility (ATAC-seq) profiles from n=3 healthy human parathyroid glands. This analysis revealed a 12-fold enrichment of variants within parathyroid open chromatin regions (p < 0.0001). One novel PTH synthesis-associated variant, p.Pro9Leu in the PITPNM2 gene which mediates phosphatidylinositol transfer, was functionally assessed in HEK293 cells by measurement of intracellular calcium responses and shown to significantly increase calcium-sensing receptor signaling (p < 0.01), consistent with a role in PTH synthesis. In summary, this cross-trait study advances understanding of the genetic architecture of mineral metabolism and provides a framework for mechanistic discovery and therapeutic development for mineral disorders.