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Aim: Genetic investigation of human plasma lipidome to get insights into lipid-related disorders beyond traditional lipid measures. Methods and Results: We performed a genome-wide association study (GWAS) of 141 lipid species (n=2,181 individuals), followed by phenome-wide scans (PheWAS) with 44 clinical end-points related to cardiometabolic, psychiatric and gastrointestinal disorders (n=456,941 individuals). SNP-based heritability for lipid species ranged from 0.10-0.54. Lipids with long-chain polyunsaturated fatty acids showed higher heritability and genetic sharing, suggesting considerable genetic regulation at acyl chains levels. We identified 35 genomic regions associated with at least one lipid species (P<5x10-8), revealing 37 new SNP-lipid species pair associations e.g. new association between ABCG5/8 and CE(20:2;0). PheWAS of lipid-species-associated loci suggested new associations of BLK with obesity, FADS2 with thrombophlebitis, and BLK and SPTLC3 with gallbladder disease (false discovery rate <0.05). The association patterns of lipid-species-associated loci supplied clues to their probable roles in lipid metabolism e.g. suggestive role of SYNGR1, MIR100HG, and PTPRN2 in desaturation and/or elongation of fatty acids. At known lipid loci (FADS2, APOA5 and LPL), genetic associations provided detailed insights to their roles in lipid biology and diseases. We also show that traditional lipid measures may fail to capture lipids such as lysophospatidylcholines (LPCs) and phosphatidylcholines (PCs) that are potential disease risk factors, but are not included in routine screens. The full genome-wide association statistics are available on the web-based database (http://35.205.141.92). Conclusion: Our study reveals genetic regulation of plasma lipidome and highlights the potential of lipidomic profiling in disease gene mapping.

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