The genetic and metabolic basis of kidney stone disease

Kidney stone disease (KSD) is a common, heritable, frequently recurrent condition affecting approximately 10–20% of people. Patients may be asymptomatic or experience severe pain, haematuria, urinary tract infections, and, in extreme cases, multi-organ failure. KSD and its treatments reduce health-related quality of life and its rising prevalence will cost the National Health Service over £300 million annually in England by 2030. Despite their relevance, the mechanisms underlying stone formation remain poorly understood, limiting effective preventive strategies. In this thesis, I investigate the genetic architecture of KSD to uncover molecular mechanisms and therapeutic targets for the disease. I conduct the largest genetic association studies of KSD to date, integrating combined-sex, and sex-specific analyses, European- and trans-ancestry data, and common and rare genetic variants. These studies identify novel genetic associations with KSD and highlight genes linked to mineral metabolism and renal structural disorders. Using Mendelian randomisation (MR) and colocalisation analyses, I reveal a shared genetic architecture between adiposity and KSD, implicating a causal GIPR missense variant which I propose alters renal tubular osteopontin secretion, affecting risk of stone formation. Drug-target MR analyses suggest that modulating gastric inhibitory polypeptide receptor pathways may reduce KSD risk. To investigate the mechanisms linking mineral metabolism and renal cysts to KSD, I integrate multiomic and chromatin interaction data with MR and colocalisation analyses. I identify three biological pathways contributing to approximately 12–17% of KSD cases: impaired DGKδ-mediated calcium-sensing receptor signalling; increased NaPi-IIa-mediated renal phosphate excretion; and defective 24-α-hydroxylase-mediated 1,25-dihydroxyvitamin D inactivation. I further establish a causal, bidirectional relationship between non-polycystic renal cysts and KSD, implicating TBX2-mediated effects. These findings support a “lithogenic triad” of urine supersaturation, stasis, and tubular epithelial injury in KSD pathogenesis. By integrating multiple analytical approaches with distinct and orthogonal sources of bias , I provide insights into causal mechanisms and therapeutic targets for KSD, laying the foundation for future translational research.