title: 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.
authors.affiliation: 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.
authors.forename: Seizo
authors.initials: S
authors.lastname: Koshiba
authors.affiliation: Tohoku Medical Megabank organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, 980-8573 Japan.|Graduate School of Information Sciences, Tohoku University, 6-3-09, Aramaki Aza-Aoba, Aoba-ku, Sendai, 980-8579 Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Motoike
authors.affiliation: 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.
authors.forename: Kaname
authors.initials: K
authors.lastname: Kojima
authors.affiliation: 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.
authors.forename: Takanori
authors.initials: T
authors.lastname: Hasegawa
authors.affiliation: 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.
authors.forename: Matsuyuki
authors.initials: M
authors.lastname: Shirota
authors.affiliation: 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.
authors.forename: Tomo
authors.initials: T
authors.lastname: Saito
authors.affiliation: 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.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Saigusa
authors.affiliation: 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.
authors.forename: Inaho
authors.initials: I
authors.lastname: Danjoh
authors.affiliation: 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.
authors.forename: Fumiki
authors.initials: F
authors.lastname: Katsuoka
authors.affiliation: 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.
authors.forename: Soichi
authors.initials: S
authors.lastname: Ogishima
authors.affiliation: 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.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kawai
authors.affiliation: 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.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Yamaguchi-Kabata
authors.affiliation: Tohoku Medical Megabank organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, 980-8573 Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Sakurai
authors.affiliation: Tohoku Medical Megabank organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, 980-8573 Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Hirano
authors.affiliation: Tohoku Medical Megabank organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, 980-8573 Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Nakata
authors.affiliation: Tohoku Medical Megabank organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, 980-8573 Japan.|Institute of Development, Aging and Cancer, Tohoku University, 4-1, Seiryo-machi, Aoba-ku, Sendai, 980-8575 Japan.
authors.forename: Hozumi
authors.initials: H
authors.lastname: Motohashi
authors.affiliation: 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.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hozawa
authors.affiliation: 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.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kuriyama
authors.affiliation: 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.
authors.forename: Naoko
authors.initials: N
authors.lastname: Minegishi
authors.affiliation: 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.
authors.forename: Masao
authors.initials: M
authors.lastname: Nagasaki
authors.affiliation: 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.
authors.forename: Takako
authors.initials: T
authors.lastname: Takai-Igarashi
authors.affiliation: 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.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Fuse
authors.affiliation: 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.
authors.forename: Hideyasu
authors.initials: H
authors.lastname: Kiyomoto
authors.affiliation: 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.
authors.forename: Junichi
authors.initials: J
authors.lastname: Sugawara
authors.affiliation: 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.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: 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.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kure
authors.affiliation: 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.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Yaegashi
authors.affiliation: 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.
authors.forename: Osamu
authors.initials: O
authors.lastname: Tanabe
authors.affiliation: Tohoku Medical Megabank organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, 980-8573 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.
authors.forename: Kengo
authors.initials: K
authors.lastname: Kinoshita
authors.affiliation: 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.
authors.forename: Jun
authors.initials: J
authors.lastname: Yasuda
authors.affiliation: 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.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto