Abstract: Genome-wide association studies have identified thousands of variants associated with disease risk but the mechanism by which such variants contribute to disease remains largely unknown. Indeed, a major challenge is that variants do not act in isolation but rather in the framework of highly complex biological networks, such as the human metabolic network, which can amplify or buffer the effect of specific risk alleles on disease susceptibility. Here we use genetically predicted reaction fluxes to perform a systematic search for metabolic fluxes acting as buffers or amplifiers of coronary artery disease (CAD) risk alleles. Our analysis identifies 30 risk locus–reaction flux pairs with significant interaction on CAD susceptibility involving 18 individual reaction fluxes and 8 independent risk loci. Notably, many of these reactions are linked to processes with putative roles in the disease such as the metabolism of inflammatory mediators. In summary, this work establishes proof of concept that biochemical reaction fluxes can have non-additive effects with risk alleles and provides novel insights into the interplay between metabolism and genetic variation on disease susceptibility.
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