Post-GWAS analysis of six substance use traits improves the identification and functional interpretation of genetic risk loci.
Post-GWAS analysis of six substance use traits improves the identification and functional interpretation of genetic risk loci.
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DOI：
10.1016/j.drugalcdep.2019.107703
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发表时间：
2020-01-01
影响因子：
4.2
通讯作者：
Derks, Eske M.
中科院分区：
文献类型：
--
作者：
Marees, Andries T.;Gamazon, Eric R.;Gerring, Zachary;Vorspan, Florence;Fingal, Josh;van den Brink, Wim;Smit, Dirk J. A.;Verweij, Karin J. H.;Kranzler, Henry R.;Sherva, Richard;Farrer, Lindsay;Stringer, Sven;Minica, Camelia C.;Mbarek, Hamdi;Bernard, Manon;Derringer, Jaime;van Eijk, Kristel R.;Isen, Joshua D.;Loukola, Anu;Maciejewski, Dominique F.;Mihailov, Evelin;van der Most, Peter J.;Sanchez-Mora, Cristina;Roos, Leonie;Walters, Raymond;Ware, Jennifer J.;Abdellaoui, Abdel;Bigdeli, Timothy B.;Branje, Susan J. T.;Brown, Sandra A.;Bruinenberg, Marcel;Casas, Miguel;Esko, Tonu;Garcia-Martinez, Iris;Gordon, Scott D.;Harris, Juliette M.;Hartman, Catharina A.;Henders, Anjali K.;Heath, Andrew C.;Hickie, Ian B.;Hickman, Matthew;Hopfer, Christian J.;Hottenga, Jouke Jan;Huizink, Anja C.;Irons, Daniel E.;Kahn, Rene S.;Korhonen, Tellervo;Krauter, Ken;van Lier, Pol A. C.;Lubke, Gitta H.;Madden, Pamela A. F.;Magi, Reedik;McGue, Matt K.;Medland, Sarah E.;Meeus, Wim H. J.;Miller, Michael B.;Montgomery, Grant W.;Nivard, Michel G.;Nolte, Ilja M.;Oldehinkel, Albertine J.;Pausova, Zdenka;Qaiser, Beenish;Quaye, Lydia;Ramos-Quiroga, Josep A.;Richarte, Vanesa;Rose, Richard J.;Shin, Jean;Stallings, Michael C.;Stiby, Alex I.;Wall, Tamara L.;Wright, Margaret J.;Koot, Hans M.;Paus, Tomas;Hewitt, John K.;Ribases, Marta;Kaprio, Jaakko;Boks, Marco P.;Snieder, Harold;Spector, Tim;Munafo, Marcus R.;Metspalu, Andres;Boomsma, Dorret I.;Iacono, William G.;Martini, Nicholas G.;Gillespie, Nathan A.;Vink, Jacqueline M.;Gelernter, Joel;Derks, Eske M.
人们对与物质使用特征相关的基因位点确定其影响的功能机制知之甚少。本研究旨在根据与物质使用特征相关的基因座在基因表达的遗传调控中的作用来识别和功能注释。我们评估了基因型组织表达 (GTEx) 数据库的 13 个脑区和全血以及抑郁基因和网络 (DGN) 数据库的全血的表达数量性状位点 (eQTL)。检查了单个 eQTL 在六种物质使用特征中的作用：饮酒量 (N=537,349)、每天吸烟量 (CPD；N=263,954)、以前吸烟者与当前吸烟者 (N=312,821)、开始吸烟年龄 (N=262,990)、曾经吸烟者 (N=632,802) 和可卡因依赖 (N=4,769)。随后，我们使用 S-PrediXcan 对这些物质使用特征的基因表达进行了基因水平分析。使用 q=0.05 的 FDR 阈值，我们发现了 2,976 个物质使用特征的新候选遗传位点，并确定了这些位点可能发挥其影响的基因和组织。使用 S-PrediXcan，我们鉴定了与所有物质性状显着相关的基因。基于转录组调控的基因注释可以改善物质使用特征的候选基因座和基因的识别和功能表征。
Little is known about the functional mechanisms through which genetic loci associated with substance use traits ascertain their effect. This study aims to identify and functionally annotate loci associated with substance use traits based on their role in genetic regulation of gene expression. We evaluated expression Quantitative Trait Loci (eQTLs) from 13 brain regions and whole blood of the Genotype-Tissue Expression (GTEx) database, and from whole blood of the Depression Genes and Networks (DGN) database. The role of single eQTLs was examined for six substance use traits: alcohol consumption (N=537,349), cigarettes per day (CPD; N=263,954), former vs. current smoker (N=312,821), age of smoking initiation (N=262,990), ever smoker (N=632,802), and cocaine dependence (N=4,769). Subsequently we conducted a gene level analysis of gene expression on these substance use traits using S-PrediXcan. Using an FDR threshold of q=0.05 we found 2,976 novel candidate genetic loci for substance use traits, and identified genes and tissues through which these loci potentially exert their effects. Using S-PrediXcan we identified significantly associated genes for all substance traits. Annotating genes based on transcriptomic regulation improves the identification and functional characterization of candidate loci and genes for substance use traits.
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影响因子：
4.8
作者：
Miguel-Hidalgo JJ
通讯作者：
Miguel-Hidalgo JJ
遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
2.7
作者：
McKenzie M;Henders AK;Caracella A;Wray NR;Powell JE
通讯作者：
Powell JE
DOI：
10.3109/00952991003736397
发表时间：
2010-05
期刊：
The American journal of drug and alcohol abuse
影响因子：
--
作者：
Hanson KL;Medina KL;Nagel BJ;Spadoni AD;Gorlick A;Tapert SF
通讯作者：
Tapert SF
影响因子：
7
作者：
Battle A;Mostafavi S;Zhu X;Potash JB;Weissman MM;McCormick C;Haudenschild CD;Beckman KB;Shi J;Mei R;Urban AE;Montgomery SB;Levinson DF;Koller D
通讯作者：
Koller D