Pathologists and clinical laboratory professionals can expect to see new molecular test development as researchers develop new biomarkers in the wake of expanded knowledge of the genome-metabolome-diseasome correlates

One field of science that bears great potential for use in diagnostics and medical laboratory testing involves the human metabolome. Researchers are gaining more understanding of the genetic underpinnings of complex disease and drug response through metabolic pathways.

For example, scientists at the Wellcome Trust Sanger Institute (WTSI) in the United Kingdom have linked 145 genetic regions with more than 400 molecules involved in metabolism in human blood, a story in Genetic Engineering News recently reported. The resulting atlas of associations will enable identification of genes that could be targeted in the development of drugs and clinical laboratory test.

The study was published in the May 11 issue of Nature Genetics.

New Biological Information in Atlas of the Metabolome

“The sheer wealth of biological information we have uncovered is extraordinary,” declared Nicole Soranzo, Ph.D., Principal of Research at the Haematology Department at the University of Cambridge, United Kingdom. She also led the WTSI study and was senior author of the Nature Genetics’ paper. “[R]esearchers can now take this freely available information forward to better understand the molecular underpinnings of a vast range of metabolic associations.”

The WTSI researchers found 90 new genetic associations, which tripled the number of known genetic associations with metabolites. In the case of the already-known metabolites, they were able to link the molecule to gene function. Additionally, the researchers were able to map genes to their likely substrates or products. This allowed them to further link these metabolites to conditions, such as hypertension, cardiovascular disease, and diabetes.

Unprecedented Insights into Metabolomic Disorders

Increasingly, researchers, such as the WTSI team, are using network theory to analyze biological systems, wrote the authors of an article titled, “Networking metabolites and disease”. The article was published by PNAS, the scientific journal of the National Academy of Sciences of the United States. The field combines computer science, network science, and graph theory. Its various applications include biology and metabolic networks.

“This type of analysis is an increasingly important element of research, drug discovery and clinical testing worldwide,” observed Carl Hull, who is now CEO of Maravai Life Sciences. He was quoted in an Applied Imaging Corp. (Nasdaq: AICX) news release, when he served as that company’s CEO. Applied Imaging partnered with WTSI to provide imaging development for the institute’s Atlas of Gene Expression project.

Mapping the Body’s Network of Metabolites

Metabolic diseases were very poorly represented in the initial mapping of the “diseasome,” or human disease network. At the time, scientists hypothesized that metabolic diseases could, in fact, be connected via metabolites and common reactions.

The implications are significant. “Practically, alteration of one metabolite or one reaction can have numerous repercussions in the network, each of which can manifest as different diseases that frequently occur together in affected patients,” wrote the authors of the PNAS article.

By identifying such a large number of genetic, metabolic and disease associations, the WTSI study provided unprecedented insights into genetic links to metabolic disorders and complex disease.

Database Contains Genetic Variants Associated with Metabolism

The WTSI team reviewed two European population studies that involved 7, 824 adults, reported the authors in the Nature Genetics article. They looked at the genetic loci known to influence human metabolism. They used genome-wide association scans with high-throughput metabolic profiling.

“Our observations suggest widespread genetic control over a large range of different pathways and functions,” the authors wrote. “[These findings] support the notion of human metabolism as a complex continuum governed by genetic effects of variable intensity, complex regulatory influences, and nongenetic effects,” they added.

The WTSI findings are open data. “We developed an open-access database that allows researchers to easily search through the findings,” observed Gabi Kastenmüller, Ph.D., co-senior author from the Helmholtz Center Munich in Germany. “[This allows them] to understand genetic variants associated with metabolism one metabolite at a time and in the context of the complete metabolic network. This database will facilitate drug discovery for metabolic disorders and also help researchers to understand the biology behind disease,” she explained.

Geneticist Laura Reed, Ph.D., noted that emphasizing more research into the role of metabolites in various human diseases will be essential, since a strictly genetic-centered approach to understanding disease will limit innovation. Reed is a Professor at the University of Alabama. She was quoted in Science Daily. (Photo copyright University of Alabama.)

Geneticist Laura Reed, Ph.D., noted that emphasizing more research into the role of metabolites in various human diseases will be essential, since a strictly genetic-centered approach to understanding disease will limit innovation. Reed is a Professor at the University of Alabama. She was quoted in Science Daily. (Photo copyright University of Alabama.)

Could Be Used in Drug and Diagnostic Test Development

According to some scientists, more focus on the role of metabolites in understanding disease is important. “Over-reliance on genetic-centered approaches in predicting, diagnosing and treating disease will lead to few future scientific breakthroughs,” cautioned Laura Reed, Ph.D., a geneticist and Professor at the University of Alabama. Reed was lead author a paper published on March 25, 2014 by Science Daily.

“To augment the value of genetic data, the scientific community needs to add additional information from things like metabolomics—the analysis of metabolites within an organism,” stated Reed. “[P]erhaps, a more expedient approach would be analyzing higher level traits, like metabolites, that might summarize what’s occurring in the genome in ways more useful for diagnostic or treatment purposes.”

Such Research Can Lead to New Medical Laboratory Tests

Pathologists and clinical laboratory managers can view the published study of the “Atlas of Genetic Influences on Human Blood Metabolites” at this URL: It is expected that research teams like the one at WTSI will continue to add new information about the human metabolome at a fast pace. The discoveries of researchers like the  WTSI team can be expected to support the development of new therapeutic drugs and clinical laboratory tests.

—by Pamela Scherer McLeod

Related Information:

An atlas of genetic influences on human blood metabolites

System-Wide Map of Genetic/Metabolomic Connections Released

Ideogram of metabolomic associations

New Study in Nature Genetics Reveals Interplay between Genetics and Metabolism in Complex Disease

Metabolites’ role in understanding disease emphasized

Redefining Disease, Genes and All