Koshiba Seizo, Motoike Ikuko, Kojima Kaname, Hasegawa Takanori, Shirota Matsuyuki, Saito Tomo, Saigusa Daisuke, Danjoh Inaho, Katsuoka Fumiki, Ogishima Soichi, Kawai Yosuke, Yamaguchi-Kabata Yumi, Sakurai Miyuki, Hirano Sachiko, Nakata Junichi, Motohashi Hozumi, Hozawa Atsushi, Kuriyama Shinichi, Minegishi Naoko, Nagasaki Masao, Takai-Igarashi Takako, Fuse Nobuo, Kiyomoto Hideyasu, Sugawara Junichi, Suzuki Yoichi, Kure Shigeo, Yaegashi Nobuo, Tanabe Osamu, Kinoshita Kengo, Yasuda Jun, Yamamoto Masayuki
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.
Sci Rep. 2016 Aug 16;6:31463. doi: 10.1038/srep31463.
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.
基于对来自一个人群队列的512名个体的全基因组序列数据与代谢物数量性状的关联研究，调查了人群中酶的结构变异与代谢表型之间的关系。我们鉴定出代谢物与非同义变异之间存在五个显著关联。这些非同义变异中的四个位于参与代谢紊乱的酶中，对这些中度非同义变异的结构分析表明，它们位于催化位点或相关调节域的外围区域。相比之下，还鉴定出两名代谢物水平变化较大的个体，这些个体保留了罕见变异，这些变异导致位于催化位点附近的非同义变异。这些结果首次证明了人群中变异频率、结构位置和对表型的影响相互关联，并且意味着代谢个体性和疾病易感性可能源于中度变异以及更具有害性但罕见的变异。
