Genetic architecture and mechanisms shared between kidney and ureteral stones, cardiovascular diseases, and metabolic syndrome: A comprehensive GWAS analysis.

BACKGROUND

Our study aims to investigate the shared genetic architecture between kidney and ureteral stones (KUS) and cardiovascular diseases (CVDs), as well as metabolic syndrome (MetS), and explore the shared risk loci, potentially critical tissues and relevant genetic mechanisms.

METHODS

Dependent on large-scale genome-wide association study (GWAS) summary-level data sets, we observed genetic correlations between KUS and CVDs, as well as MetS, and cross-diseases pleiotropic analysis was conducted to identify shared pleiotropic loci and genes. Furthermore, we performed functional annotation and tissue-specific analysis to detect potential relationships between complex traits. We performed heritability enrichment analysis to determine potentially critical tissues. At last, we investigate the causal effects between KUS and other traits using bidirectional Mendelian randomization (MR).

RESULTS

Our findings underlined shared genetic architecture between three CVDs, two MetS and KUS. We identified 937 pleiotropic loci at the genome-wide significance level (p < 5 × 10), 35 of which were annotated as genomic risk loci. Among them, 4 had strong evidence of colocalization (PP.H4 > 0.7). In addition, a total of 163 unique pleiotropic genes (pFDR <0.05) were recognized at the gene level, including FTO, NEK4, GNL3, GLT8D1, SMIM4, PBRM1 and TFAP2B. Pathway analysis illustrated the essential biological process including metabolic processes, transcriptional regulation processes, transmembrane transport of drugs, and cardiac structure development were involved in these diseases. Analysis of tissue enrichment at single nucleotide polymorphism (SNP) level and gene level indicated pleiotropic mechanisms may engage in prostate, pancreas, adipose subcutaneous, and muscle skeletal. HyPrColoc method and metabolite enrichment analysis revealed tryptophan metabolism might be a crucial shared metabolic pathway in two different diseases. At last, bidirectional MR analysis demonstrated no strong evidence of causal associations between KUS and CVDs, as well as MetS.

CONCLUSIONS

Our study determined shared genetic architecture between KUS and CVDs, as well as MetS, and unraveled underlying genetic mechanisms.