Abstract: TH-OR87
Mapping the Genetic Architecture of Kidney Stones in the Million Veteran Program
Session Information
- Non-Cystic Genetic Kidney Diseases: Disease Genes, Modifiers, and Therapies
October 24, 2024 | Location: Room 23, Convention Center
Abstract Time: 05:20 PM - 05:30 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Hsi, Ryan, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Wilson, Otis D., Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Chen, Hua-Chang, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Triozzi, Jefferson Lorenzo, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Robinson-Cohen, Cassianne, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Yu, Zhihong, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Wang, Guanchao, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Ikizler, Talat Alp, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Siew, Edward D., Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Tao, Ran, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Hung, Adriana, Vanderbilt University Medical Center, Nashville, Tennessee, United States
Group or Team Name
- Million Veteran Program.
Background
Kidney stones are common, with a 10-20% lifetime prevalence. The prevalence is higher in men and are commonly recurrent. Treatment for recurrent stones has been linked to a decline in renal function. The heritability of kidney stones is 45-50%.
Methods
We identified 29,815 veterans of European ancestry with a diagnosis of kidney stones. Patients with bladder stones, with endocrine causes, or diagnoses of gastrointestinal malabsorption, were excluded. There were 408,294 controls. GWAS was performed using logistic regression, additive model (MAF>1%), imputed to TOPMed, adjusted for age, sex, and first 10 principal components of ancestry.
Results
Mean age 62 (SD12), 4% were women and 36% had diabetes. We identified 80 SNPs in 35 loci at the significance threshold of p=5E-08. Known loci included: The strongest signal was for UMOD/PDILT (p-value 1.86E-37), uric acid transporter ABCG2 (p-value 9.31E-15), alkaline phosphatase gene ALPL (p-value 9.55E-13), calcium-sensing receptor gene CASR (p value 1.23E-11), PLCL1 associated with Alkaline phosphatase levels, STAP2 associated with Vit D levels, LINC02003 associated with levels of PTH. Others: DGKD, DGKH, HIBADH, MRPL33, ZFPM1, BCAS3. Novel loci included: NSD1(p-value 1.72E-40) associated with urate levels and BMI, polycystin 2 PKD2 (p-value 3.22E-17), Corticotropin Releasing Hormone Receptor 1 CRHR1 (p-value 1.58E-22) and Growth Hormone Releasing Hormone Receptor GHRHR (p-value 2.44E-09), Calcineurin Like EF-Hand Protein 1, CHP1(p-value 1.61E-09) all involved in calcium metabolism. Other novel loci, many of which are associated with kidney function or bone density included: MAPT, MED1, PLEKHM1, PDE3A, TTC33, CHAF1B, PPHLN1, RAB36, WDFY1, MICA, HLA-C, EXD1, FBXL20, FGFR4, GCAT, CKD12, ARHGAP27.
Conclusion
Our study identified several loci (13 known and 22 novel) involved in renal tubular handling of lithogenic substrates and of inhibitors of crystallization. Some of these loci may represent therapeutic targets. Future work should include functional analyses.
Funding
- Veterans Affairs Support