NEW YORK (GenomeWeb) – Genetic patterns detected in thousands of twins and unrelated individuals are revealing the wide range of genetic variants that can affect the metabolites found in an individual's blood.
Researchers from the US, the UK, and Singapore combined whole-genome sequencing with liquid chromatography and mass spectrometry-based metabolite profiling on nearly 2,000 individuals to look for genetic variants across the frequency spectrum — from common SNPs to rare variants — that impact blood metabolite patterns.
After filtering a list of more than 900 blood metabolites to 644 metabolites that appeared at relatively stable blood levels within individuals over time, the team tracked down 101 common and low-frequency variants with ties to 246 blood metabolites, along with more than a dozen rare loci that appeared to influence metabolite levels. Results from the analysis were described in Nature Genetics online yesterday.
"The collection of small molecules and chemicals in blood called the metabolome reflect the intimate workings of our body," co-senior author Amalio Telenti, chief scientific officer at the genomic company Human Longevity, said in a statement. "It was very surprising to us that so many adults would display abnormalities in blood metabolites, and that a high proportion would be the result of genetic defects."
For their analysis, Telenti and his colleagues focused on 1,960 individuals — a group that included 413 identical twin pairs and 552 non-identical sets of twins. Collaborators at Metabolon used that company's liquid chromatography and tandem mass spec to profile metabolite patterns in three samples each from the participants, which had been collected over a year and a half.
The team estimated that heritability ranged from 10 percent to 93 percent for the 644 most stable metabolites. Folding in whole-genome sequences for the participants made it possible to start picking out variants linked to levels of these metabolites.
The researchers' genome-wide association study — which considered nearly 6.7 million common variants and 4.7 million low-frequency variants present in 0.5 percent to 5 percent of the population — highlighted 233 variants with potential ties to 246 metabolites, traced back to 125 genes found at 101 loci.
Their search for blood metabolite-related rare variants took advantage of individuals with levels of 69 metabolites that were at the end of the spectrum, leading to 14 loci associated with abnormal metabolite profiles and a handful of rare regulatory variants expected to alter metabolite levels.
When they focused on 1,054 unrelated individuals, meanwhile, the researchers found that 113 individuals in that group had rare variants affecting 17 genes. These heterozygous changes, impacting one of the two gene copies each person carries, included rare variants in 13 genes linked to inborn errors of metabolism or other genetic conditions diagnosed in childhood.
Based on these and other results, Telenti said that the metabolome "should be a continued area of research, and our findings today highlight the importance of looking holistically at the human body and all the components that factor into our health and potential for disease."