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Background Elevated plasma levels of alpha-aminoadipic acid (2-AAA) have been associated with the development of type 2 diabetes and atherosclerosis. However, the nature of the association remains unknown. Methods and Results We identified genetic determinants of plasma 2-AAA through meta-analysis of genome-wide association study data in 5456 individuals of European, African, and Asian ancestry from the Framingham Heart Study, Diabetes Prevention Program, Jackson Heart Study, and Shanghai Women's and Men's Health Studies. No single nucleotide polymorphisms reached genome-wide significance across all samples. However, the top associations from the meta-analysis included single-nucleotide polymorphisms in the known 2-AAA pathway gene DHTKD1 , and single-nucleotide polymorphisms in genes involved in mitochondrial respiration ( NDUFS4 ) and macrophage function ( MSR1 ). We used a Mendelian randomization instrumental variable approach to evaluate relationships between 2-AAA and cardiometabolic phenotypes in large disease genome-wide association studies. Mendelian randomization identified a suggestive inverse association between increased 2-AAA and lower high-density lipoprotein cholesterol ( P =0.005). We further characterized the genetically predicted relationship through measurement of plasma 2-AAA and high-density lipoprotein cholesterol in 2 separate samples of individuals with and without cardiometabolic disease (N=98), and confirmed a significant negative correlation between 2-AAA and high-density lipoprotein ( r s =-0.53, P <0.0001). Conclusions 2-AAA levels in plasma may be regulated, in part, by common variants in genes involved in mitochondrial and macrophage function. Elevated plasma 2-AAA associates with reduced levels of high-density lipoprotein cholesterol. Further mechanistic studies are required to probe this as a possible mechanism linking 2-AAA to future cardiometabolic risk.