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Garrod’s concept of “chemical individuality” has contributed to comprehension of molecular origins of human diseases. Untargeted high throughput metabolomic technologies provide an in-depth snapshot of human metabolism at scale. Here we studied the genetic architecture of the human plasma metabolome using 913 metabolites assayed in 19,994 individuals. We identified 2,599 variant-metabolite associations (P

There is considerable interest in GIPR agonism to enhance the insulinotropic and extra-pancreatic effects of GIP, thereby improving glycaemic and weight control in type 2 diabetes (T2D) and obesity. Recent genetic epidemiological evidence has implicated higher GIPR-mediated GIP levels in raising coronary artery disease (CAD) risk, a potential safety concern for GIPR agonism. We therefore aimed to quantitatively assess whether the association between higher GIPR-mediated fasting GIP levels and CAD risk is mediated via GIPR or is instead the result of linkage disequilibrium (LD) confounding between variants at the GIPR locus. Using Bayesian multi-trait colocalisation, we identified a GIPR missense variant rs1800437 (G allele; E354) as the putatively causal variant shared between fasting GIP levels, glycaemic traits and adiposity-related traits (posterior probability for colocalisation, PPcoloc>0.97; PP explained by the candidate variant; PPexplained=1) that was independent from a cluster of CAD and lipid traits driven by a known missense variant in APOE (rs7412; distance to E354 ~770Kb; R2 with E354 = 0.004; PPcoloc>0.99; PPexplained=1). Further, conditioning the association between E354 and CAD on the residual LD with rs7412, we observed slight attenuation in association, but it remained significant (OR per copy of E354 after adjustment 1.03; 95% CI, 1.02, 1.04; P=0.003). Instead, E354’s association with CAD was completely attenuated when conditioning on an additional established CAD signal, rs1964272, (R2 with E354=0.27), an intronic variant in SNRPD2 (OR for E354 after adjustment for rs1964272: 1.01; 95% CI, 0.99, 1.03; P=0.06). We demonstrate that associations with GIP, anthropometric and glycaemic traits are driven by distinct genetic signals from those driving CAD and lipid traits in the GIPR region, and higher E354-mediated fasting GIP levels are not associated with CAD risk. These findings provide evidence that the inclusion of GIPR agonism in dual GIPR/GLP-1R agonists could potentiate the protective effect of GLP-1 agonists on diabetes without undue CAD risk, an aspect which has yet to be assessed in clinical trials.

In cross-platform analyses of 174 metabolites, we identify 499 associations (P < 4.9 × 10-10) characterized by pleiotropy, allelic heterogeneity, large and nonlinear effects and enrichment for nonsynonymous variation. We identify a signal at GLP2R (p.Asp470Asn) shared among higher citrulline levels, body mass index, fasting glucose-dependent insulinotropic peptide and type 2 diabetes, with β-arrestin signaling as the underlying mechanism. Genetically higher serine levels are shown to reduce the likelihood (by 95%) and predict development of macular telangiectasia type 2, a rare degenerative retinal disease. Integration of genomic and small molecule data across platforms enables the discovery of regulators of human metabolism and translation into clinical insights.

Circulating levels of small molecules or metabolites are highly heritable, but the impact of genetic differences in metabolism on human health is not well understood. In this cross-platform, genome-wide meta-analysis of 174 metabolite levels across six cohorts including up to 86,507 participants (70% unpublished data), we identify 499 (362 novel) genome-wide significant associations (p