title: Characterization of ADME gene variation in 21 populations by exome sequencing.
abstract: 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.
  
  
  
  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.
  
  
  
  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) and showed significantly greater levels of population differentiation (P=7.6×10). 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.
  
  
  
  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.
authors.affiliation: aGlaxoSmithKline Research and Development, Durham, North Carolina bGlaxoSmithKline Research and Development, King of Prussia, Pennsylvania cDepartment of Biostatistics and/or Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA dGlaxoSmithKline Research and Development, Sydney, New South Wales, Australia eSeoul National University fDNA Link Inc., Seoul, Korea gKyushu University, Fukuoka, Japan.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Hovelson
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Xue
authors.forename: Matthew
authors.initials: M
authors.lastname: Zawistowski
authors.forename: Margaret G
authors.initials: MG
authors.lastname: Ehm
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Harris
authors.forename: Sophie L
authors.initials: SL
authors.lastname: Stocker
authors.forename: Annette S
authors.initials: AS
authors.lastname: Gross
authors.forename: In-Jin
authors.initials: IJ
authors.lastname: Jang
authors.forename: Ichiro
authors.initials: I
authors.lastname: Ieiri
authors.forename: Jong-Eun
authors.initials: JE
authors.lastname: Lee
authors.forename: Lon R
authors.initials: LR
authors.lastname: Cardon
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Chissoe
authors.forename: Gonçalo
authors.initials: G
authors.lastname: Abecasis
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Nelson
mesh_terms: D059472:Exome; D014644:Genetic Variation; D005828:Genetics, Population; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D020641:Polymorphism, Single Nucleotide; D044382:Population Groups / Q000208:ethnology / Q000235:genetics*; D025341:Principal Component Analysis; D017422:Sequence Analysis, DNA / Q000379:methods*