Genome Wide Association Study of the Kynurenine Pathway
Abstract
The kynurenine pathway (KP) of tryptophan metabolism plays a key role in physiological processes such as neuronal modulation, aging and immunity. Although genome-wide association studies (GWAS) have identified genetic determinants of selected kynurenine metabolites, the genetic architecture of the pathway as a whole remains incompletely characterized. We performed GWAS on nine KP metabolites and seven biologically informed metabolite-ratios measured by targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) in 4,871 unrelated individuals of Norwegian ancestry from the Hordaland Health Study. We identified 23 independent metabolite-associated loci (mQTLs), including associations for all measured metabolites covering all enzymes in the initial part of the pathway. Many signals replicated known loci at key pathway genes, including IDO1/2, AFMID, KMO, KYNU, HAAO, AADAT while revealing how their effects propagate across multiple pathway intermediates and ratios. Genetic associations were highly consistent with established pathway biology, with enzyme-specific loci predominantly affecting metabolites immediately upstream or downstream of the corresponding reaction. Ratio-based analyses identified additional hits not found by single-metabolite GWAS, reflecting pathway balance and vitamin B6-dependent enzymatic activity. Integration with expression quantitative trait locus data supported a dose-dependent role of KMO expression in regulating the kynurenic acid/quinolinic acid balance. We also identified novel loci that may represent important amino acid metabolism-immune crosstalk in the regulation of KP and previously unrecognized links with fatty acid oxidation, phase II transformation and metabolite efflux processes. Together, the study provides a comprehensive pathway-level view of the genetic determinants for circulating kynurenines and their ratios within a Northern European population.
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