The Genetic Associations Between Kidney Stones, Obesity, Type 2 Diabetes, and Hypertension

Investigate shared genetic changes that contribute to the association of kidney stones with cardiometabolic comorbidities.

Genome-wide association studies (GWAS) and meta-analyses were performed using the UK Biobank, Mayo Clinic Biobank, and FinnGen, complemented by secondary genetic association analyses.

Genetic correlation analyses confirmed modest but significant positive associations between kidney stones and hypertension, obesity, and type 2 diabetes (r_g=0.14 ∼ 0.19, all P<.001). Single nucleotide variants near FTO (for expansion of gene symbols, use search tool at www.genenames.org) were identified as shared risk loci across all conditions. Mendelian randomization analyses demonstrated that higher body mass index (BMI) and waist-hip ratio (WHR) significantly increased the risk of kidney stones, type 2 diabetes, and hypertension. Subsequent GWAS analyses adjusting for BMI or WHR revealed a slightly reduced yet significant genetic correlation between kidney stones and type 2 diabetes (BMI-adjusted: r_g=0.18; 95% CI, 0.07 to 0.28; P=.001; WHR-adjusted: r_g=0.16; 95% CI, 0.06 to 0.25; P<.001), whereas the association of kidney stones with hypertension was nearly eliminated. A multi-trait analysis of GWAS identified one potential shared risk locus between BMI-adjusted kidney stones and type 2 diabetes on chromosome 6 near LINC02537. Further analyses indicated this locus is associated with thyroid-stimulating hormone and free thyroxine levels.

Our study highlights a critical role for shared obesity-related genetic changes in the comorbid relationship between kidney stones and cardiometabolic conditions. There are additional genetic features related to thyroid function that are shared between kidney stones and type 2 diabetes, which appear to be independent of obesity.