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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">A translational systems biology approach in both animals and humans identifies a functionally related module of accumbal genes involved in the regulation of reward processing and binge drinking in males</title><author><name sortKey="Stacey, David" sort="Stacey, David" uniqKey="Stacey D" first="David" last="Stacey">David Stacey</name></author><author><name sortKey="Lourdusamy, Anbarasu" sort="Lourdusamy, Anbarasu" uniqKey="Lourdusamy A" first="Anbarasu" last="Lourdusamy">Anbarasu Lourdusamy</name></author><author><name sortKey="Ruggeri, Barbara" sort="Ruggeri, Barbara" uniqKey="Ruggeri B" first="Barbara" last="Ruggeri">Barbara Ruggeri</name></author><author><name sortKey="Maroteaux, Matthieu" sort="Maroteaux, Matthieu" uniqKey="Maroteaux M" first="Matthieu" last="Maroteaux">Matthieu Maroteaux</name></author><author><name sortKey="Jia, Tianye" sort="Jia, Tianye" uniqKey="Jia T" first="Tianye" last="Jia">Tianye Jia</name></author><author><name sortKey="Cattrell, Anna" sort="Cattrell, Anna" uniqKey="Cattrell A" first="Anna" last="Cattrell">Anna Cattrell</name></author><author><name sortKey="Nymberg, Charlotte" sort="Nymberg, Charlotte" uniqKey="Nymberg C" first="Charlotte" last="Nymberg">Charlotte Nymberg</name></author><author><name sortKey="Banaschewski, Tobias" sort="Banaschewski, Tobias" uniqKey="Banaschewski T" first="Tobias" last="Banaschewski">Tobias Banaschewski</name></author><author><name sortKey="Bhattacharyya, Sohinee" sort="Bhattacharyya, Sohinee" uniqKey="Bhattacharyya S" first="Sohinee" last="Bhattacharyya">Sohinee Bhattacharyya</name></author><author><name sortKey="Band, Hamid" sort="Band, Hamid" uniqKey="Band H" first="Hamid" last="Band">Hamid Band</name></author><author><name sortKey="Barker, Gareth" sort="Barker, Gareth" uniqKey="Barker G" first="Gareth" last="Barker">Gareth Barker</name></author><author><name sortKey="Bokde, Arun" sort="Bokde, Arun" uniqKey="Bokde A" first="Arun" last="Bokde">Arun Bokde</name></author><author><name sortKey="Buchel, Christian" sort="Buchel, Christian" uniqKey="Buchel C" first="Christian" last="Buchel">Christian Buchel</name></author><author><name sortKey="Carvalho, Fabiana" sort="Carvalho, Fabiana" uniqKey="Carvalho F" first="Fabiana" last="Carvalho">Fabiana Carvalho</name></author><author><name sortKey="Conrod, Patricia" sort="Conrod, Patricia" uniqKey="Conrod P" first="Patricia" last="Conrod">Patricia Conrod</name></author><author><name sortKey="Desrivieres, Sylvane" sort="Desrivieres, Sylvane" uniqKey="Desrivieres S" first="Sylvane" last="Desrivieres">Sylvane Desrivieres</name></author><author><name sortKey="Easton, Alanna" sort="Easton, Alanna" uniqKey="Easton A" first="Alanna" last="Easton">Alanna Easton</name></author><author><name sortKey="Fauth Buehler, Mira" sort="Fauth Buehler, Mira" uniqKey="Fauth Buehler M" first="Mira" last="Fauth-Buehler">Mira Fauth-Buehler</name></author><author><name sortKey="Fernandez Medarde, Alberto" sort="Fernandez Medarde, Alberto" uniqKey="Fernandez Medarde A" first="Alberto" last="Fernandez-Medarde">Alberto Fernandez-Medarde</name></author><author><name sortKey="Flor, Herta" sort="Flor, Herta" uniqKey="Flor H" first="Herta" last="Flor">Herta Flor</name></author><author><name sortKey="Frouin, Vincent" sort="Frouin, Vincent" uniqKey="Frouin V" first="Vincent" last="Frouin">Vincent Frouin</name></author><author><name sortKey="Gallinat, Jurgen" sort="Gallinat, Jurgen" uniqKey="Gallinat J" first="Jurgen" last="Gallinat">Jurgen Gallinat</name></author><author><name sortKey="Garavanh, Hugh" sort="Garavanh, Hugh" uniqKey="Garavanh H" first="Hugh" last="Garavanh">Hugh Garavanh</name></author><author><name sortKey="Heinz, Andreas" sort="Heinz, Andreas" uniqKey="Heinz A" first="Andreas" last="Heinz">Andreas Heinz</name></author><author><name sortKey="Ittermann, Bernd" sort="Ittermann, Bernd" uniqKey="Ittermann B" first="Bernd" last="Ittermann">Bernd Ittermann</name></author><author><name sortKey="Lathrop, Mark" sort="Lathrop, Mark" uniqKey="Lathrop M" first="Mark" last="Lathrop">Mark Lathrop</name></author><author><name sortKey="Lawrence, Claire" sort="Lawrence, Claire" uniqKey="Lawrence C" first="Claire" last="Lawrence">Claire Lawrence</name></author><author><name sortKey="Loth, Eva" sort="Loth, Eva" uniqKey="Loth E" first="Eva" last="Loth">Eva Loth</name></author><author><name sortKey="Mann, Karl" sort="Mann, Karl" uniqKey="Mann K" first="Karl" last="Mann">Karl Mann</name></author><author><name sortKey="Martinot, Jean Luc" sort="Martinot, Jean Luc" uniqKey="Martinot J" first="Jean-Luc" last="Martinot">Jean-Luc Martinot</name></author><author><name sortKey="Nees, Frauke" sort="Nees, Frauke" uniqKey="Nees F" first="Frauke" last="Nees">Frauke Nees</name></author><author><name sortKey="Paus, Tomas" sort="Paus, Tomas" uniqKey="Paus T" first="Tomas" last="Paus">Tomas Paus</name></author><author><name sortKey="Pausova, Zdenka" sort="Pausova, Zdenka" uniqKey="Pausova Z" first="Zdenka" last="Pausova">Zdenka Pausova</name></author><author><name sortKey="Rietschel, Marcella" sort="Rietschel, Marcella" uniqKey="Rietschel M" first="Marcella" last="Rietschel">Marcella Rietschel</name></author><author><name sortKey="Rotter, Andrea" sort="Rotter, Andrea" uniqKey="Rotter A" first="Andrea" last="Rotter">Andrea Rotter</name></author><author><name sortKey="Santos, Eugenio" sort="Santos, Eugenio" uniqKey="Santos E" first="Eugenio" last="Santos">Eugenio Santos</name></author><author><name sortKey="Smolka, Michael" sort="Smolka, Michael" uniqKey="Smolka M" first="Michael" last="Smolka">Michael Smolka</name></author><author><name sortKey="Sommer, Wolfgang" sort="Sommer, Wolfgang" uniqKey="Sommer W" first="Wolfgang" last="Sommer">Wolfgang Sommer</name></author><author><name sortKey="Mameli, Manuel" sort="Mameli, Manuel" uniqKey="Mameli M" first="Manuel" last="Mameli">Manuel Mameli</name></author><author><name sortKey="Spanagel, Rainer" sort="Spanagel, Rainer" uniqKey="Spanagel R" first="Rainer" last="Spanagel">Rainer Spanagel</name></author><author><name sortKey="Girault, Jean Antoine" sort="Girault, Jean Antoine" uniqKey="Girault J" first="Jean-Antoine" last="Girault">Jean-Antoine Girault</name></author><author><name sortKey="Mueller, Christian" sort="Mueller, Christian" uniqKey="Mueller C" first="Christian" last="Mueller">Christian Mueller</name></author><author><name sortKey="Schumann, Gunter" sort="Schumann, Gunter" uniqKey="Schumann G" first="Gunter" last="Schumann">Gunter Schumann</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26679926</idno><idno type="pmc">4853210</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4853210</idno><idno type="RBID">PMC:4853210</idno><idno type="doi">10.1503/jpn.150138</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000468</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000468</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A translational systems biology approach in both animals and humans identifies a functionally related module of accumbal genes involved in the regulation of reward processing and binge drinking in males</title><author><name sortKey="Stacey, David" sort="Stacey, David" uniqKey="Stacey D" first="David" last="Stacey">David Stacey</name></author><author><name sortKey="Lourdusamy, Anbarasu" sort="Lourdusamy, Anbarasu" uniqKey="Lourdusamy A" first="Anbarasu" last="Lourdusamy">Anbarasu Lourdusamy</name></author><author><name sortKey="Ruggeri, Barbara" sort="Ruggeri, Barbara" uniqKey="Ruggeri B" first="Barbara" last="Ruggeri">Barbara Ruggeri</name></author><author><name sortKey="Maroteaux, Matthieu" sort="Maroteaux, Matthieu" uniqKey="Maroteaux M" first="Matthieu" last="Maroteaux">Matthieu Maroteaux</name></author><author><name sortKey="Jia, Tianye" sort="Jia, Tianye" uniqKey="Jia T" first="Tianye" last="Jia">Tianye Jia</name></author><author><name sortKey="Cattrell, Anna" sort="Cattrell, Anna" uniqKey="Cattrell A" first="Anna" last="Cattrell">Anna Cattrell</name></author><author><name sortKey="Nymberg, Charlotte" sort="Nymberg, Charlotte" uniqKey="Nymberg C" first="Charlotte" last="Nymberg">Charlotte Nymberg</name></author><author><name sortKey="Banaschewski, Tobias" sort="Banaschewski, Tobias" uniqKey="Banaschewski T" first="Tobias" last="Banaschewski">Tobias Banaschewski</name></author><author><name sortKey="Bhattacharyya, Sohinee" sort="Bhattacharyya, Sohinee" uniqKey="Bhattacharyya S" first="Sohinee" last="Bhattacharyya">Sohinee Bhattacharyya</name></author><author><name sortKey="Band, Hamid" sort="Band, Hamid" uniqKey="Band H" first="Hamid" last="Band">Hamid Band</name></author><author><name sortKey="Barker, Gareth" sort="Barker, Gareth" uniqKey="Barker G" first="Gareth" last="Barker">Gareth Barker</name></author><author><name sortKey="Bokde, Arun" sort="Bokde, Arun" uniqKey="Bokde A" first="Arun" last="Bokde">Arun Bokde</name></author><author><name sortKey="Buchel, Christian" sort="Buchel, Christian" uniqKey="Buchel C" first="Christian" last="Buchel">Christian Buchel</name></author><author><name sortKey="Carvalho, Fabiana" sort="Carvalho, Fabiana" uniqKey="Carvalho F" first="Fabiana" last="Carvalho">Fabiana Carvalho</name></author><author><name sortKey="Conrod, Patricia" sort="Conrod, Patricia" uniqKey="Conrod P" first="Patricia" last="Conrod">Patricia Conrod</name></author><author><name sortKey="Desrivieres, Sylvane" sort="Desrivieres, Sylvane" uniqKey="Desrivieres S" first="Sylvane" last="Desrivieres">Sylvane Desrivieres</name></author><author><name sortKey="Easton, Alanna" sort="Easton, Alanna" uniqKey="Easton A" first="Alanna" last="Easton">Alanna Easton</name></author><author><name sortKey="Fauth Buehler, Mira" sort="Fauth Buehler, Mira" uniqKey="Fauth Buehler M" first="Mira" last="Fauth-Buehler">Mira Fauth-Buehler</name></author><author><name sortKey="Fernandez Medarde, Alberto" sort="Fernandez Medarde, Alberto" uniqKey="Fernandez Medarde A" first="Alberto" last="Fernandez-Medarde">Alberto Fernandez-Medarde</name></author><author><name sortKey="Flor, Herta" sort="Flor, Herta" uniqKey="Flor H" first="Herta" last="Flor">Herta Flor</name></author><author><name sortKey="Frouin, Vincent" sort="Frouin, Vincent" uniqKey="Frouin V" first="Vincent" last="Frouin">Vincent Frouin</name></author><author><name sortKey="Gallinat, Jurgen" sort="Gallinat, Jurgen" uniqKey="Gallinat J" first="Jurgen" last="Gallinat">Jurgen Gallinat</name></author><author><name sortKey="Garavanh, Hugh" sort="Garavanh, Hugh" uniqKey="Garavanh H" first="Hugh" last="Garavanh">Hugh Garavanh</name></author><author><name sortKey="Heinz, Andreas" sort="Heinz, Andreas" uniqKey="Heinz A" first="Andreas" last="Heinz">Andreas Heinz</name></author><author><name sortKey="Ittermann, Bernd" sort="Ittermann, Bernd" uniqKey="Ittermann B" first="Bernd" last="Ittermann">Bernd Ittermann</name></author><author><name sortKey="Lathrop, Mark" sort="Lathrop, Mark" uniqKey="Lathrop M" first="Mark" last="Lathrop">Mark Lathrop</name></author><author><name sortKey="Lawrence, Claire" sort="Lawrence, Claire" uniqKey="Lawrence C" first="Claire" last="Lawrence">Claire Lawrence</name></author><author><name sortKey="Loth, Eva" sort="Loth, Eva" uniqKey="Loth E" first="Eva" last="Loth">Eva Loth</name></author><author><name sortKey="Mann, Karl" sort="Mann, Karl" uniqKey="Mann K" first="Karl" last="Mann">Karl Mann</name></author><author><name sortKey="Martinot, Jean Luc" sort="Martinot, Jean Luc" uniqKey="Martinot J" first="Jean-Luc" last="Martinot">Jean-Luc Martinot</name></author><author><name sortKey="Nees, Frauke" sort="Nees, Frauke" uniqKey="Nees F" first="Frauke" last="Nees">Frauke Nees</name></author><author><name sortKey="Paus, Tomas" sort="Paus, Tomas" uniqKey="Paus T" first="Tomas" last="Paus">Tomas Paus</name></author><author><name sortKey="Pausova, Zdenka" sort="Pausova, Zdenka" uniqKey="Pausova Z" first="Zdenka" last="Pausova">Zdenka Pausova</name></author><author><name sortKey="Rietschel, Marcella" sort="Rietschel, Marcella" uniqKey="Rietschel M" first="Marcella" last="Rietschel">Marcella Rietschel</name></author><author><name sortKey="Rotter, Andrea" sort="Rotter, Andrea" uniqKey="Rotter A" first="Andrea" last="Rotter">Andrea Rotter</name></author><author><name sortKey="Santos, Eugenio" sort="Santos, Eugenio" uniqKey="Santos E" first="Eugenio" last="Santos">Eugenio Santos</name></author><author><name sortKey="Smolka, Michael" sort="Smolka, Michael" uniqKey="Smolka M" first="Michael" last="Smolka">Michael Smolka</name></author><author><name sortKey="Sommer, Wolfgang" sort="Sommer, Wolfgang" uniqKey="Sommer W" first="Wolfgang" last="Sommer">Wolfgang Sommer</name></author><author><name sortKey="Mameli, Manuel" sort="Mameli, Manuel" uniqKey="Mameli M" first="Manuel" last="Mameli">Manuel Mameli</name></author><author><name sortKey="Spanagel, Rainer" sort="Spanagel, Rainer" uniqKey="Spanagel R" first="Rainer" last="Spanagel">Rainer Spanagel</name></author><author><name sortKey="Girault, Jean Antoine" sort="Girault, Jean Antoine" uniqKey="Girault J" first="Jean-Antoine" last="Girault">Jean-Antoine Girault</name></author><author><name sortKey="Mueller, Christian" sort="Mueller, Christian" uniqKey="Mueller C" first="Christian" last="Mueller">Christian Mueller</name></author><author><name sortKey="Schumann, Gunter" sort="Schumann, Gunter" uniqKey="Schumann G" first="Gunter" last="Schumann">Gunter Schumann</name></author></analytic><series><title level="j">Journal of Psychiatry & Neuroscience : JPN</title><idno type="ISSN">1180-4882</idno><idno type="eISSN">1488-2434</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>The mesolimbic dopamine system, composed primarily of dopaminergic neurons in the ventral tegmental area that project to striatal structures, is considered to be the key mediator of reinforcement-related mechanisms in the brain. Prompted by a genome-wide association meta-analysis implicating the Ras-specific guanine nucleotide-releasing factor 2 (<italic>RASGRF2</italic>) gene in the regulation of alcohol intake in men, we have recently shown that male <italic>Rasgrf2</italic><sup>−/−</sup> mice exhibit reduced ethanol intake and preference accompanied by a perturbed mesolimbic dopamine system. We therefore propose that these mice represent a valid model to further elucidate the precise genes and mechanisms regulating mesolimbic dopamine functioning.</p></sec><sec><title>Methods</title><p>Transcriptomic data from the nucleus accumbens (NAcc) of male <italic>Rasgrf2</italic><sup>−/−</sup> mice and wild-type controls were analyzed by weighted gene coexpression network analysis (WGCNA). We performed follow-up genetic association tests in humans using a sample of male adolescents from the IMAGEN study characterized for binge drinking (<italic>n</italic> = 905) and ventral striatal activation during an fMRI reward task (<italic>n</italic> = 608).</p></sec><sec><title>Results</title><p>The WGCNA analyses using accumbal transcriptomic data revealed 37 distinct “modules,” or functionally related groups of genes. Two of these modules were significantly associated with <italic>Rasgrf2</italic> knockout status: M5 (<italic>p</italic> < 0.001) and M6 (<italic>p</italic> < 0.001). In follow-up translational analyses we found that human orthologues for the M5 module were significantly (<italic>p</italic> < 0.01) enriched with genetic association signals for binge drinking in male adolescents. Furthermore, the most significant locus, originating from the EH-domain containing 4 (<italic>EHD4</italic>) gene (<italic>p</italic> < 0.001), was also significantly associated with altered ventral striatal activity in male adolescents performing an fMRI reward task (<italic>p</italic><sub>empirical</sub> < 0.001).</p></sec><sec><title>Limitations</title><p>It was not possible to determine the extent to which the M5 module was dysregulated in <italic>Rasgrf2</italic><sup>−/−</sup> mice by perturbed mesolimbic dopamine signalling or by the loss of <italic>Rasgrf2</italic> function in the NAcc.</p></sec><sec><title>Conclusion</title><p>Taken together, our findings indicate that the accumbal M5 module, initially identified as being dysregulated in male <italic>Rasgrf2</italic><sup>−/−</sup> mice, is also relevant for human alcohol-related phenotypes potentially through the modulation of reinforcement mechanisms in the NAcc. We therefore propose that the genes comprising this module represent important candidates for further elucidation within the context of alcohol-related phenotypes.</p></sec></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Psychiatry Neurosci</journal-id><journal-id journal-id-type="iso-abbrev">J Psychiatry Neurosci</journal-id><journal-title-group><journal-title>Journal of Psychiatry & Neuroscience : JPN</journal-title></journal-title-group><issn pub-type="ppub">1180-4882</issn><issn pub-type="epub">1488-2434</issn><publisher><publisher-name>Joule Inc.</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26679926</article-id><article-id pub-id-type="pmc">4853210</article-id><article-id pub-id-type="doi">10.1503/jpn.150138</article-id><article-id pub-id-type="publisher-id">jpn-41-192</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Paper</subject></subj-group></article-categories><title-group><article-title>A translational systems biology approach in both animals and humans identifies a functionally related module of accumbal genes involved in the regulation of reward processing and binge drinking in males</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Stacey</surname><given-names>David</given-names></name><degrees>PhD</degrees><xref ref-type="author-notes" rid="fn1-jpn-41-192">*</xref><xref ref-type="corresp" rid="c1-jpn-41-192"></xref></contrib><contrib contrib-type="author"><name><surname>Lourdusamy</surname><given-names>Anbarasu</given-names></name><degrees>PhD</degrees><xref ref-type="author-notes" rid="fn1-jpn-41-192">*</xref></contrib><contrib contrib-type="author"><name><surname>Ruggeri</surname><given-names>Barbara</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Maroteaux</surname><given-names>Matthieu</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Jia</surname><given-names>Tianye</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Cattrell</surname><given-names>Anna</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Nymberg</surname><given-names>Charlotte</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Banaschewski</surname><given-names>Tobias</given-names></name><degrees>MD, PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Bhattacharyya</surname><given-names>Sohinee</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Band</surname><given-names>Hamid</given-names></name><degrees>MD, PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Barker</surname><given-names>Gareth</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Bokde</surname><given-names>Arun</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Buchel</surname><given-names>Christian</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type="author"><name><surname>Carvalho</surname><given-names>Fabiana</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Conrod</surname><given-names>Patricia</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Desrivieres</surname><given-names>Sylvane</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Easton</surname><given-names>Alanna</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Fauth-Buehler</surname><given-names>Mira</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Fernandez-Medarde</surname><given-names>Alberto</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Flor</surname><given-names>Herta</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Frouin</surname><given-names>Vincent</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Gallinat</surname><given-names>Jurgen</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type="author"><name><surname>Garavanh</surname><given-names>Hugh</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Heinz</surname><given-names>Andreas</given-names></name><degrees>MD, PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Ittermann</surname><given-names>Bernd</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Lathrop</surname><given-names>Mark</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Lawrence</surname><given-names>Claire</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Loth</surname><given-names>Eva</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Mann</surname><given-names>Karl</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type="author"><name><surname>Martinot</surname><given-names>Jean-Luc</given-names></name><degrees>MD, PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Nees</surname><given-names>Frauke</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Paus</surname><given-names>Tomas</given-names></name><degrees>MD, PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Pausova</surname><given-names>Zdenka</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type="author"><name><surname>Rietschel</surname><given-names>Marcella</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type="author"><name><surname>Rotter</surname><given-names>Andrea</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Santos</surname><given-names>Eugenio</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Smolka</surname><given-names>Michael</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type="author"><name><surname>Sommer</surname><given-names>Wolfgang</given-names></name><degrees>MD, PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Mameli</surname><given-names>Manuel</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Spanagel</surname><given-names>Rainer</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Girault</surname><given-names>Jean-Antoine</given-names></name><degrees>MD, PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Mueller</surname><given-names>Christian</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Schumann</surname><given-names>Gunter</given-names></name><degrees>MD</degrees></contrib><on-behalf-of>on behalf of the IMAGEN consortium</on-behalf-of><xref ref-type="author-notes" rid="fn2-jpn-41-192">†</xref><aff id="af1-jpn-41-192">From the Discipline of Psychiatry, University of Adelaide, Australia (Stacey); the Institute of Psychiatry, King’s College, London, UK (Lourdusamy, Ruggeri, Maroteaux, Jia, Cattrell, Nymberg, Barker, Carvalho, Conrod, Desrivières, Easton, Loth, Müller, Schumann); the MRC Social, Genetic and Developmental Psychiatry (SGDP) Centre, London, UK (Lourdusamy, Ruggeri, Jia, Nymberg, Carvalho, Desrivières, Easton, Loth, Müller, Schumann); the Institut du Fer à Moulin, UMR-S 839, INSERM and Université Pierre et Marie Curie, Paris, France (Maroteaux, Mameli, Girault); the Department of Child and Adolescent Psychiatry, Central Institute of Mental Health, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Germany (Banaschewski); the University of Nebraska Medical Center, Omaha, USA (Bhattacharyya, Band); the Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland (Bokde, Garavan); the Institute for Systemic Neuroscience, UMC Hamburg Eppendorf, Hamburg, Germany (Büchel); the Department of Psychiatry, Université de Montreal, CHU Ste Justine Hospital, Montreal, Canada (Conrod); the Department of Addiction Medicine, Central Institute of Mental Health, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Germany (Fauth-Buehler, Mann); the CIC-IBMCC, University of Salamanca – CSIC, Spain (Fernandez-Medarde, Santos); Department of Neuropsychiatry and Cognitive Psychology, Central Institute of Mental Health, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Germany (Flor, Nees); the CEA, DSV, I2BM, Neurospin Bât 145 Gif-sur-Yvette, France (Frouin); the Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité – Universitätsmedizin Berlin, Germany (Gallinat); the Departments of Psychiatry and Psychology, University of Vermont, Burlington, USA (Garavan); the Physikalisch-Technische Bundesanstalt (PTB), Braunschweig and Berlin, Germany (Ittermann); the McGill University and Genome Quebec Innovation Centre, Montreal, Canada (Lathrop); the School of Psychology, University of Nottingham, UK (Lawrence, Paus); the Institut National de la Santé et de la Recherche Médicale, INSERM Unit 1000 “Neuromaging & Psychiatry”, University Paris Sud, Orsay, and University Paris Descartes, Paris, France (Martinot); the Rotman Research Institute, University of Toronto, Toronto, Canada (Paus); the Montreal Neurological Institute, McGill University, Montreal, Canada (Paus); the Hospital for Sick Children, University of Toronto, Toronto, Canada (Pausova); the Department of Genetic Epidemiology, Central Institute of Mental Health, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Germany (Rietschel); the Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany (Rotter, Müller); the Department of Psychiatry and Psychotherapy, Technische Universität Dresden, Germany (Smolka); the Neuroimaging Center, Department of Psychology, Technische Universität Dresden, Germany (Smolka); and the Deptartment of Psychopharmacology, Central Institute of Mental Health, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Germany (Sommer, Spanagel)</aff></contrib-group><author-notes><corresp id="c1-jpn-41-192">Correspondence to: D. Stacey, Discipline of Psychiatry, Level 4, Eleanor Harrald Building, Frome Road, University of Adelaide, Adelaide, 5005, Australia; <email>david.stacey@adelaide.edu.au</email></corresp><fn id="fn1-jpn-41-192"><label>*</label><p>These authors contributed equally to this work.</p></fn><fn id="fn2-jpn-41-192"><label>†</label><p><bold>Members of the IMAGEN consortium:</bold> Gunter Schumann, Anna Cattrell, Herta Flor, Frauke Nees, Tobias Banaschewski, Arun Bokde, Rob Whelan, Christian Buechel, Uli Bromberg, Patricia Conrod, Vincent Frouin, Dimitri Papadoulos, Juergen Gallinat, Hugh Garavan, Andreas Heinz, Henrik Walter, Bernd Ittermann, Penny Gowland, Tomáš Paus, Luise Poustka, Jean-Luc Martinot, Herve Lemaitre, Eric Artiges, or Marie-Laure Paillère Martinot, Michael N. Smolka, Eva Mennigen, Nora C. Vetter and Sarah Rodehacke.</p></fn></author-notes><pub-date pub-type="ppub"><month>5</month><year>2016</year></pub-date><pub-date pub-type="epub"><day>15</day><month>12</month><year>2015</year></pub-date><volume>41</volume><issue>3</issue><fpage>192</fpage><lpage>202</lpage><history><date date-type="received"><day>22</day><month>4</month><year>2015</year></date><date date-type="rev-recd"><day>23</day><month>7</month><year>2015</year></date><date date-type="rev-recd"><day>26</day><month>7</month><year>2015</year></date><date date-type="accepted"><day>01</day><month>8</month><year>2015</year></date></history><permissions><copyright-statement>© 2016 Joule Inc.</copyright-statement><copyright-year>2016</copyright-year></permissions><abstract><sec><title>Background</title><p>The mesolimbic dopamine system, composed primarily of dopaminergic neurons in the ventral tegmental area that project to striatal structures, is considered to be the key mediator of reinforcement-related mechanisms in the brain. Prompted by a genome-wide association meta-analysis implicating the Ras-specific guanine nucleotide-releasing factor 2 (<italic>RASGRF2</italic>) gene in the regulation of alcohol intake in men, we have recently shown that male <italic>Rasgrf2</italic><sup>−/−</sup> mice exhibit reduced ethanol intake and preference accompanied by a perturbed mesolimbic dopamine system. We therefore propose that these mice represent a valid model to further elucidate the precise genes and mechanisms regulating mesolimbic dopamine functioning.</p></sec><sec><title>Methods</title><p>Transcriptomic data from the nucleus accumbens (NAcc) of male <italic>Rasgrf2</italic><sup>−/−</sup> mice and wild-type controls were analyzed by weighted gene coexpression network analysis (WGCNA). We performed follow-up genetic association tests in humans using a sample of male adolescents from the IMAGEN study characterized for binge drinking (<italic>n</italic> = 905) and ventral striatal activation during an fMRI reward task (<italic>n</italic> = 608).</p></sec><sec><title>Results</title><p>The WGCNA analyses using accumbal transcriptomic data revealed 37 distinct “modules,” or functionally related groups of genes. Two of these modules were significantly associated with <italic>Rasgrf2</italic> knockout status: M5 (<italic>p</italic> < 0.001) and M6 (<italic>p</italic> < 0.001). In follow-up translational analyses we found that human orthologues for the M5 module were significantly (<italic>p</italic> < 0.01) enriched with genetic association signals for binge drinking in male adolescents. Furthermore, the most significant locus, originating from the EH-domain containing 4 (<italic>EHD4</italic>) gene (<italic>p</italic> < 0.001), was also significantly associated with altered ventral striatal activity in male adolescents performing an fMRI reward task (<italic>p</italic><sub>empirical</sub> < 0.001).</p></sec><sec><title>Limitations</title><p>It was not possible to determine the extent to which the M5 module was dysregulated in <italic>Rasgrf2</italic><sup>−/−</sup> mice by perturbed mesolimbic dopamine signalling or by the loss of <italic>Rasgrf2</italic> function in the NAcc.</p></sec><sec><title>Conclusion</title><p>Taken together, our findings indicate that the accumbal M5 module, initially identified as being dysregulated in male <italic>Rasgrf2</italic><sup>−/−</sup> mice, is also relevant for human alcohol-related phenotypes potentially through the modulation of reinforcement mechanisms in the NAcc. We therefore propose that the genes comprising this module represent important candidates for further elucidation within the context of alcohol-related phenotypes.</p></sec></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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