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Sci Rep. 2016 Aug 16;6:31463. doi: 10.1038/srep31463.

The structural origin of metabolic quantitative diversity.

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Tohoku Medical Megabank organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, 980-8573 Japan.
Graduate School of Medicine, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, 980-8575 Japan.
Graduate School of Information Sciences, Tohoku University, 6-3-09, Aramaki Aza-Aoba, Aoba-ku, Sendai, 980-8579 Japan.
Institute of Development, Aging and Cancer, Tohoku University, 4-1, Seiryo-machi, Aoba-ku, Sendai, 980-8575 Japan.


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.

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