Genome Wide Association Study Published in Nature

This groundbreaking Genome Wide Association Study (GWAS) establishes the strong association of biochemical levels with the genetics of an individual and illustrates the power of combining metabolomics with genomics analyses. The study was carried out by researchers at Helmholtz Zentrum Munchen Institute in Munich, Germany, the Wellcome Trust/Sanger Centre, King’s College and Metabolon, Inc.

Historically, GWAS have identified risk loci for some diseases but studies have been limited in size, the effect size of the associations have typically been relatively small, and an immediate biological linkage or understanding is often missing. The newly published study overcomes many of these limitations.

“This is by far the most comprehensive GWAS to investigate the association of biochemical levels in blood with human genetics,” said Dr. John Ryals, President and CEO of Metabolon. “The associations uncovered in this work provide new functional insights for many disease-related associations that have been reported in previous studies, including cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, venous thromboembolism, and Crohn’s disease.”

Metabolomic profiling was performed on fasting serum collected from 2,820 individuals who were participants in the German KORA F4 study (n=1,768) or the British TwinsUK study (n=1,052). As such, it is the most comprehensive evaluation of genetic variance in human metabolism to date, combining genetics and metabolomics for hypothesis generation in a GWAS. The researchers identified 37 genetic loci associated with blood metabolite concentrations, of which 25 exhibit effect sizes that are unusually high for GWAS, accounting for 10-60% of metabolite levels per allele copy. Further, 23 of these loci describe new genetic associations with metabolic traits and 14 replicate and extend our knowledge of known associations. In one example, the function for the locus SLC16A9 as a carnitine efflux transporter, suggested by the association between the gene and metabolites, was experimentally validated.

“Using Metabolon’s technology platform we measured more than 250 metabolites covering over 60 biochemical pathways, analyzing a total of 2820 individual blood samples from two separate cohorts rapidly (24 minutes/sample) and with low median process variability (<12%),” emphasized Dr. Mike Milburn, Metabolon’s Chief Scientific Officer.

This study establishes biochemistry, perhaps the most easily measured genetic trait, as an intermediate to provide a biological link that contributes to the understanding of the genetic effects and more effectively impacts discovery and development of individualized biomarkers and therapies.

“The exceptionally large effect sizes of 10-60% per allele copy for 25 specific loci suggests that testing biochemical levels—beyond inborn errors of metabolism—is likely an excellent way of understanding individual uniqueness and can potentially increase the development of personalized medicine,” said Dr. Craig Venter, Founder and President of the J. Craig Venter Institute and a Scientific Advisor to Metabolon.

The article has been published in the journal Nature and may be accessed below.