Disentangling the consequences of type 2 diabetes on targeted metabolite profiles using causal inference and interaction QTL analyses

Circulating metabolite levels have been associated with type 2 diabetes (T2D), but the extent to which T2D affects metabolite levels and their genetic regulation remains to be elucidated. In this study, we investigate the interplay between genetics, metabolomics, and T2D risk in the UK Biobank dataset using the Nightingale panel composed of 249 metabolites, 92% of which correspond to lipids (HDL, IDL, LDL, VLDL) and lipoproteins. By integrating these data with large-scale T2D GWAS from the DIAMANTE meta-analysis through Mendelian randomization analyses, we find 79 metabolites with a causal association to T2D, all spanning lipid-related classes except for Glucose and Tyrosine. Twice as many metabolites are causally affected by T2D liability, spanning almost all tested classes, including branched-chain amino acids. Secondly, using an interaction quantitative trait locus (QTL) analysis, we describe four metabolites consistently replicated in an independent dataset from the Estonian Biobank, for which genetic loci in two different genomic regions show attenuated regulation in T2D cases compared to controls. The significant variants from the interaction QTL analysis are significant QTLs for the corresponding metabolites in the general population but are not associated with T2D risk, pointing towards consequences of T2D on the genetic regulation of metabolite levels. Finally, through differential level analyses, we find 165 metabolites associated with microvascular, macrovascular, or both types of T2D complications, with only a few discriminating between complication classes. Of the 165 metabolites, 40 are not causally linked to T2D in either direction, suggesting biological mechanisms specific to the occurrence of complications. Overall, this work provides a map of the consequences of T2D on Nightingale targeted metabolite levels and on their genetic regulation, enabling a better understanding of the T2D trajectory leading to complications.Author summary: Type 2 diabetes (T2D) is a complex disease that affects millions of people worldwide, with its progression to complications posing a significant health burden. While the genetics of the disease has been increasingly described through large efforts, the biological mechanisms behind these associations remain to be fully elucidated. Additionally, the consequences of the disease on molecular profiles, and how these changes could lead to further complications, remain poorly understood. Here, we have investigated the relationships between T2D, its complications and 249 targeted metabolites mostly focusing on lipids. We show a causal impact of 79 metabolites on T2D risk, while twice as many metabolites were causally affected by T2D liability. Further, we highlight four metabolites whose genetic regulation appears to be altered in T2D cases, which, along with additional lines of evidence, seems to be a consequence rather than a cause of T2D occurrence. Finally, we found that 165 metabolites were associated with the occurrence of T2D complications, with most also showing causal links to T2D, although 40 of them did not demonstrate such associations. Our study enhances our understanding of the metabolic pathways involved in the trajectory of T2D to complications and represents a first step towards the prevention of the development of complications in the future, a key public health priority.