Meta-analysis of urinary metabolite GWAS studies identifies novel genome-wide significant loci

Abstract

Genome-wide association studies (GWAS) have substantially enhanced the understanding of genetic influences on phenotypic outcomes; however, realizing their full potential requires an aggregate analysis of numerous studies. Here we represent the first comprehensive meta-analysis of urinary metabolite GWAS studies, aiming to consolidate existing data on metabolite-SNP associations, evaluate consistency across studies, and unravel novel genetic links. Following an extensive literature review and data collection through the EMBL-EBI GWAS Catalog, PubMed, and metabolomix.com, we employed a sample size-based meta-analytic approach to evaluate the significance of previously reported GWAS associations. Our analysis identified 48 independent lead SNPs correlated with the levels of 14 unique urinary metabolites: alanine, 3-aminoisobutyrate, betaine, creatine, creatinine, formate, glycine, glycolate, histidine, 2-hydroxybutyrate, lysine, threonine, trimethylamine, and tyrosine. Notably, the results revealed a novel locus for tyrosine (rs4594899, SLC12A7,P = 6.6 × 10–9, N = 2623), and three newly associated independent SNPs within known loci: one for glycine (rs1755615, GLDC, P = 2.4 × 10–10, N = 5319), and two for 3-aminoisobutyrate (rs79053399, RAI14, P = 6.9 × 10–10, N = 4656; rs36071744, TTC23L,P = 2.97 × 10–10, N = 4872). These findings underscore the potential of urinary metabolite GWAS meta-analyses in revealing novel genetic factors that may aid in the understanding of disease processes and highlight the necessity for larger and more comprehensive future studies.