Genetic Studies of Metabolomics Change After a Liquid Meal Illuminate Novel Pathways for Glucose and Lipid Metabolism

Humans spend the greater part of the day in a postprandial state. However, the genetic basis of postprandial blood measures is relatively uncharted territory. We set out to examine the genetics of variation in concentrations of postprandial metabolites (t=150 min) in response to a liquid mixed meal through genome-wide association studies (GWAS) performed in the Netherlands Epidemiology of Obesity study (N=5,705). The metabolite response GWAS identified an association between glucose change and rs10830963:G in the melatonin receptor 1B (beta (SE): -0.23 (0.03), P-value: 2.15×10<sup>-19</sup>). In addition, <i>ANKRD55</i> locus led by rs458741:C showed strong associations to extremely large VLDL particle (XXLVLDL) response (with XXLVLDLC: beta (SE): 0.17 (0.03) P-value: 5.76×10<sup>-10 </sup>and with XXLVLDLCE: beta (SE): 0.17 (0.03), P-value: 9.74×10<sup>-10</sup>), which also revealed strong associations to body composition and diabetes in the UK Biobank (p-values<5×10<sup>-8</sup>). Furthermore, the associations between XXLVLDL response and insulinogenic index, HOMA-β, ISI matsuda index and HbA1c in the NEO study further implied the role of chylomicron synthesis in diabetes (with FDR corrected q-value<0.05). To conclude, genetic studies of metabolomics change after a liquid meal illuminate novel pathways for glucose and lipid metabolism. Further studies are warranted to corroborate biological pathways of <i>ANKRD55</i> locus underlying diabetes.