The structural origin of metabolic quantitative diversity

Abstract

Relationship between structural variants of enzymes and metabolic phenotypes in human population was investigated based on the association study of metabolite quantitative traits with whole genome sequence data for 512 individuals from a population cohort. We identified five significant associations between metabolites and non-synonymous variants. Four of these non-synonymous variants are located in enzymes involved in metabolic disorders, and structural analyses of these moderate non-synonymous variants demonstrate that they are located in peripheral regions of the catalytic sites or related regulatory domains. In contrast, two individuals with larger changes of metabolite levels were also identified, and these individuals retained rare variants, which caused non-synonymous variants located near the catalytic site. These results are the first demonstrations that variant frequency, structural location, and effect for phenotype correlate with each other in human population, and imply that metabolic individuality and susceptibility for diseases may be elicited from the moderate variants and much more deleterious but rare variants.

jMorp: Japanese Multi Omics Reference Panel

“…In Japan, Tohoku University Tohoku Medical Megabank Organization (ToMMo) ( 6 ) conducted multi-omics (metabolome and proteome) analyses of 5093 plasma samples collected from Japanese (male: 2077, female: 3016) residents who participated in the Tohoku Medical Megabank Project Cohort Study. By using some of these data, Koshiba et al detected five interesting associations between the genome and plasma metabolome (TCN000004 formate, TCN000017 asparagine, TCN000019 phenylalanine, TCN000031 proline and TCN000033 glycine) ( 7 ). To share the data and promote the development of personalized healthcare, we created a new database known as jMorp for metabolome and proteome data in plasma obtained from 5,093 healthy volunteers in a Japanese population from the Tohoku Medical Megabank Cohort Study.…”

Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals

“…Thus, this data allows for genome-wide association studies aimed at finding disease-related variants by using phased variants for genotype imputation [4]. In addition to binary phenotypic traits, studying association with quantitative traits, such as metabolomics in plasma, is also valuable to reveal genetic susceptibility to proximal phenotypes at the molecular level [5]. Another important use of this data is to allow for detection of rare and pathogenic variants, and to estimate their population frequencies.…”

Omics research project on prospective cohort studies from the Tohoku Medical Megabank Project

“…However, as shown in Figure , two individuals with larger changes in the levels of the metabolite phenylalanine have also been identified; these individuals retained rare variants in the phenylalanine hydroxylase gene that cause nonsynonymous variations located near the catalytic sites. This observation indicates that these variations cause substantial changes in metabolite levels (Koshiba et al., ). These results demonstrate that variant frequency, structural location and phenotypic effect correlate with each other in human populations.…”

“…Before executing large‐scale omics analyses of cohort samples, we conducted a feasibility study using approximately 500 plasma samples collected in the TMM CommCohort Study (Koshiba et al., ; Saigusa et al., ). For the multi‐omics analysis, we selected samples whose whole‐genome sequences were already available in ToMMo (Nagasaki et al., ).…”

“…ToMMo has already released the first results of the association study between the plasma NMR metabolome data and the whole‐genome sequence data obtained from 512 participants (Koshiba et al., ). We identified five significant associations of metabolites with nonsynonymous variants, four of which were known to exist in enzymes involved in metabolic disorders (Figure ).…”