Through a series of genome-wide association studies and Mendelian randomization (MR) analyses, a team of researchers at McGill University identified dozens of blood metabolites that influence a number of common disease and traits linked to aging, inflammation, and metabolism.

The research was published online in Nature Genetics.

Q&A with Yiheng Chen, M.Sc
PhD Student in Human Genetics, McGill University 

What are blood metabolites?  

Blood metabolites are small molecules in the blood that are the intermediate or end products of metabolic reactions. Examples of metabolites include lipids, amino acids, and vitamins. 

How does the introduction of metabolomics into the Canadian Longitudinal Study of Aging (CLSA) provide unique research opportunities? 

Amongst the cohorts with the largest collection of metabolomics data in the world, the CLSA provides many unique research opportunities. Since metabolites are influenced by both internal factors (e.g., genetics and disease conditions) and external factors (e.g., environment exposure, dietary patterns, and lifestyle), CLSA data allows the study of specific factors that influence metabolism and disease-related risks for Canadians. Additionally, the collection of longitudinal data in an aging population allows the identification of metabolites that can predict aging-related diseases and phenotypes (observable traits that result from the interaction of genes with environmental factors).

What question(s) did you set out to answer with this research?  

We set out to answer which genetic variants can influence blood metabolite levels and what metabolites influence aging-, metabolism- and immune-related diseases and traits. 

What did you find? 

By conducting genome-wide association studies of 1,091 blood metabolites and 309 metabolite ratios, we identified associations with 690 metabolites at 248 genetic loci and associations with 143 metabolite ratios at 69 genetic loci. Integrating metabolite-gene and gene expression information, we identified 94 effector genes for 109 metabolites and 48 metabolite ratios.   

Using MR, a statistical tool for an inferring causal relationship between risk factors and disease outcomes using genetic data, we identified 22 metabolites and 20 metabolite ratios having estimated causal effects on 12 traits and diseases, including orotate for estimated bone mineral density from ultrasound measurements, alpha-hydroxyisovalerate for body mass index and ergothioneine for inflammatory bowel disease and asthma. We further measured the orotate level in a separate cohort and demonstrated that, consistent with MR, orotate levels were positively associated with incident hip fractures. 

In other words, we found certain metabolites or metabolite ratios influence diseases or disease traits. For example, orotate was linked to a lower bone-mineral density and associated with a higher risk of hip fractures. Another metabolite, alpha-hydroxyisovalerate, was associated with lower body mass index and ergothioneine with inflammatory bowel disease and asthma.

What is the significance of these findings? 

The results from this study provide a valuable resource describing the genetic architecture of metabolites and deliver insights into their roles in common diseases, thereby offering opportunities for therapeutic targets.