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RISS 인기검색어
- 검색키워드
- 저자 : Zawistowski, Matthew (검색결과 2 건)
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Evaluating the contribution of rare variants to type 2 diabetes and related traits using pedigrees
Jun, Goo,Manning, Alisa,Almeida, Marcio,Zawistowski, Matthew,Wood, Andrew R.,Teslovich, Tanya M.,Fuchsberger, Christian,Feng, Shuang,Cingolani, Pablo,Gaulton, Kyle J.,Dyer, Thomas,Blackwell, Thomas W. National Academy of Sciences 2018 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.115 No.2
<P>A major challenge in evaluating the contribution of rare variants to complex disease is identifying enough copies of the rare alleles to permit informative statistical analysis. To investigate the contribution of rare variants to the risk of type 2 diabetes (T2D) and related traits, we performed deep whole-genome analysis of 1,034 members of 20 large Mexican-American families with high prevalence of T2D. If rare variants of large effect accounted for much of the diabetes risk in these families, our experiment was powered to detect association. Using gene expression data on 21,677 transcripts for 643 pedigree members, we identified evidence for large-effect rare-variant c/s-expression quantitative trait loci that could not be detected in population studies, validating our approach. Flowever, we did not identify any rare variants of large effect associated with T2D, or the related traits of fasting glucose and insulin, suggesting that large-effect rare variants account for only a modest fraction of the genetic risk of these traits in this sample of families. Reliable identification of large-effect rare variants will require larger samples of extended pedigrees or different study designs that further enrich for such variants.</P>
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Characterization of ADME gene variation in 21 populations by exome sequencing
Hovelson, Daniel H.,Xue, Zhengyu,Zawistowski, Matthew,Ehm, Margaret G.,Harris, Elizabeth C.,Stocker, Sophie L.,Gross, Annette S.,Jang, In-Jin,Ieiri, Ichiro,Lee, Jong-Eun,Cardon, Lon R.,Chissoe, Stepha Lippincott WilliamsWilkins 2017 PHARMACOGENETICS AND GENOMICS Vol.27 No.3
<▼1><P>Supplemental Digital Content is available in the text.</P></▼1><▼2><P><B>Objective</B></P><P>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.</P><P><B>Materials and methods</B></P><P>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.</P><P><B>Results</B></P><P>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 (<I>P</I>=8.2×10<SUP>–13</SUP>) and showed significantly greater levels of population differentiation (<I>P</I>=7.6×10<SUP>–11</SUP>). 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.</P><P><B>Conclusion</B></P><P>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.</P></▼2>
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