Characterization of ADME gene variation in 21 populations by exome sequencing

Daniel H. Hovelson, Zhengyu Xue, Matthew Zawistowski, Margaret G. Ehm, Elizabeth C. Harris, Sophie L. Stocker, Annette S. Gross, In Jin Jang, Ichiro Ieiri, Jong Eun Lee, Lon R. Cardon, Stephanie L. Chissoe, Gonçalo Abecasis, Matthew R. Nelson

研究成果: ジャーナルへの寄稿学術誌査読

32 被引用数 (Scopus)


Objective Proteins involving absorption, distribution, metabolism, and excretion (ADME) play a critical role in drug pharmacokinetics. The type and frequency of genetic variation in the ADME genes differ among populations. The aim of this study was to systematically investigate common and rare ADME coding variation in diverse ethnic populations by exome sequencing. Materials and methods Data derived from commercial exome capture arrays and next-generation sequencing were used to characterize coding variation in 298 ADME genes in 251 Northeast Asians and 1181 individuals from the 1000 Genomes Project. Results Approximately 75% of the ADME coding sequence was captured at high quality across the joint samples harboring more than 8000 variants, with 49% of individuals carrying at least one 'knockout' allele. ADME genes carried 50% more nonsynonymous variation than non-ADME genes (P=8.2×10-13) and showed significantly greater levels of population differentiation (P=7.6×10-11). Out of the 2135 variants identified that were predicted to be deleterious, 633 were not on commercially available ADME or general-purpose genotyping arrays. Forty deleterious variants within important ADME genes, with frequencies of at least 2% in at least one population, were identified as candidates for future pharmacogenetic studies. Conclusion Exome sequencing was effective in accurately genotyping most ADME variants important for pharmacogenetic research, in addition to identifying rare or potentially de novo coding variants that may be clinically meaningful. Furthermore, as a class, ADME genes are more variable and less sensitive to purifying selection than non-ADME genes.

ジャーナルPharmacogenetics and Genomics
出版ステータス出版済み - 2017

!!!All Science Journal Classification (ASJC) codes

  • 遺伝学(臨床)
  • 遺伝学
  • 分子医療
  • 分子生物学
  • 薬理学、毒性学および薬学(全般)


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