Metabolon Elucidates Novel Biomarkers of Human Disease

The Challenge: Understanding the Causal Role of Metabolites in Human Disease

Metabolites are small molecules that are produced as a result of biochemical reactions. The dysregulation of certain metabolites can contribute to the development of human diseases. Understanding the causal role of metabolites in disease etiology could provide tractable points for therapeutic intervention. Metabolomics can help identify causal influences of metabolites upon diseases. The heritability of many metabolite levels is high, allowing the use of a genome-wide association study (GWAS), which identifies genetic variations associated with a particular disease. When combined, metabolomics and GWAS can provide a more comprehensive understanding of the genetic and metabolic basis of human diseases. By combining GWAS and metabolomics, researchers can identify genetic variants associated with changes in specific metabolic pathways and gain insights into how these pathways contribute to the development of human diseases.

Metabolon Insight: Elucidating Metabolite-Gene Associations Related to Human Disease

In this study, the Global Discovery Panel was used to profile the plasma of 8,299 individuals of European ancestry who had also been genotyped.¹ The panel’s unrivaled coverage of up to 5,400 metabolites offered this group the most comprehensive solution to elucidate metabolite-gene associations related to human disease. Plasma orotate levels from hip fracture cases (n = 2,225) and controls (n = 2,225) were also quantified by Metabolon using the panel.

The Solution: Metabolon Helped Identify Metabolites Associated with Human Disease

GWAS of plasma metabolites identified associations for 690 metabolites at 248 loci. Many metabolites are substrates and products of enzymatic reactions. Identifying genetic determinants of substrate-to-product ratios can offer insights into biological processes that are not apparent when studying individual metabolites. Undertaking GWAS for metabolite ratios identified associations for 143 metabolite ratios across 69 loci. The researchers then used bioinformatics approaches and identified 94 effector genes for 109 metabolites and 48 metabolite ratios. Elucidating the specific genes, rather than genomic loci, that regulate metabolites and their ratios can aid in identifying potential targets for therapeutic interventions. Next, the researchers applied the newly identified gene-metabolite associations to Mendelian randomization (MR)—a method used to investigate the causal relationship between an exposure (eg, metabolites) and disease outcomes. Using MR, they identified 22 metabolites and 20 metabolite ratios to have an estimated causal effect on 12 traits and diseases that are influenced by aging, metabolism, and immune response. These causal effects included orotate for estimated bone mineral density (eBMD), α-hydroxy isovalerate for body mass index, and ergothioneine for inflammatory bowel disease (IBD) and asthma. Prior to this study, the relationship between orotate and bone traits had never been reported. To validate this finding, the Global Discovery Panel was used to measure the plasma orotate levels of a separate cohort. The results showed that consistent with MR, orotate levels were positively associated with incident hip fractures.

The Outcome: Identifying Targets for Pharmaceutical Intervention

The Global Discovery Panel helped identify novel gene-metabolite associations.  These findings provide insights into the genetic architecture of metabolites and show how these data can be used to identify metabolites as biomarkers for increased risk of disease.  The findings may assist in understanding the genetic regulation of human metabolism and provide a valuable resource for identifying targets for pharmaceutical intervention.