Genetic Architecture of Untargeted Lipidomics in Cardiometabolic-Disease Patients Combines Strong Polygenic Control and Pleiotropy

Background: Analysis of the genetic control of small metabolites provides powerful information on the regulation of the endpoints of genome expression. Methods: We carried out untargeted liquid chromatography–high-resolution mass spectrometry in 273 individuals characterized for pathophysiological elements of the cardiometabolic syndrome. Results: We quantified 3013 serum lipidomic features, which we used in both genome-wide association studies (GWAS), using a panel of over 2.5 M imputed single-nucleotide polymorphisms (SNPs), and metabolome-wide association studies (MWAS) with phenotypes. Genetic analyses showed that 926 SNPs at 551 genetic loci significantly (q-value < 10⁻⁸) regulate the abundance of 74 lipidomic features in the group, with evidence of monogenic control for only 22 of these. In addition to this strong polygenic control of serum lipids, our results underscore instances of pleiotropy, when a single genetic locus controls the abundance of several distinct lipid features. Using the LIPID MAPS database, we assigned putative lipids, predominantly fatty acyls and sterol lipids, to 77% of the lipidome signals mapped to the genome. We identified significant correlations between lipids and clinical and biochemical phenotypes. Conclusions: These results demonstrate the power of untargeted lipidomic profiling for high-density quantitative molecular phenotyping in human-genetic studies and illustrate the complex genetic control of lipid metabolism.