David Stacey1, Anbarasu Lourdusamy1, Barbara Ruggeri1, Matthieu Maroteaux1, Tianye Jia1, Anna Cattrell1, Charlotte Nymberg1, Tobias Banaschewski1, Sohinee Bhattacharyya1, Hamid Band1, Gareth Barker1, Arun Bokde1, Christian Buchel1, Fabiana Carvalho1, Patricia Conrod1, Sylvane Desrivieres1, Alanna Easton1, Mira Fauth-Buehler1, Alberto Fernandez-Medarde1, Herta Flor1, Vincent Frouin1, Jurgen Gallinat1, Hugh Garavanh1, Andreas Heinz1, Bernd Ittermann1, Mark Lathrop1, Claire Lawrence1, Eva Loth1, Karl Mann1, Jean-Luc Martinot1, Frauke Nees1, Tomas Paus1, Zdenka Pausova1, Marcella Rietschel1, Andrea Rotter1, Eugenio Santos1, Michael Smolka1, Wolfgang Sommer1, Manuel Mameli1, Rainer Spanagel1, Jean-Antoine Girault1, Christian Mueller1, Gunter Schumann1. 1. 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, Mon
Abstract
BACKGROUND: 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 (RASGRF2) gene in the regulation of alcohol intake in men, we have recently shown that male Rasgrf2(-/-) 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. METHODS: Transcriptomic data from the nucleus accumbens (NAcc) of male Rasgrf2(-/-) 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 (n = 905) and ventral striatal activation during an fMRI reward task (n = 608). RESULTS: 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 Rasgrf2 knockout status: M5 (p < 0.001) and M6 (p < 0.001). In follow-up translational analyses we found that human orthologues for the M5 module were significantly (p < 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 (EHD4) gene (p < 0.001), was also significantly associated with altered ventral striatal activity in male adolescents performing an fMRI reward task (pempirical < 0.001). LIMITATIONS: It was not possible to determine the extent to which the M5 module was dysregulated in Rasgrf2(-/-) mice by perturbed mesolimbic dopamine signalling or by the loss of Rasgrf2 function in the NAcc. CONCLUSION: Taken together, our findings indicate that the accumbal M5 module, initially identified as being dysregulated in male Rasgrf2(-/-) 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.
BACKGROUND: 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 (RASGRF2) gene in the regulation of alcohol intake in men, we have recently shown that male Rasgrf2(-/-) 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. METHODS: Transcriptomic data from the nucleus accumbens (NAcc) of male Rasgrf2(-/-) 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 (n = 905) and ventral striatal activation during an fMRI reward task (n = 608). RESULTS: 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 Rasgrf2 knockout status: M5 (p < 0.001) and M6 (p < 0.001). In follow-up translational analyses we found that human orthologues for the M5 module were significantly (p < 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 (EHD4) gene (p < 0.001), was also significantly associated with altered ventral striatal activity in male adolescents performing an fMRI reward task (pempirical < 0.001). LIMITATIONS: It was not possible to determine the extent to which the M5 module was dysregulated in Rasgrf2(-/-) mice by perturbed mesolimbic dopamine signalling or by the loss of Rasgrf2 function in the NAcc. CONCLUSION: Taken together, our findings indicate that the accumbal M5 module, initially identified as being dysregulated in male Rasgrf2(-/-) 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.
Authors: Pamela Metten; Ovidiu D Iancu; Stephanie E Spence; Nicole A R Walter; Denesa Oberbeck; Christina A Harrington; Alexandre Colville; Shannon McWeeney; Tamara J Phillips; Kari J Buck; John C Crabbe; John K Belknap; Robert J Hitzemann Journal: Alcohol Clin Exp Res Date: 2014-12 Impact factor: 3.455
Authors: Andrew C Heath; John B Whitfield; Nicholas G Martin; Michele L Pergadia; Alison M Goate; Penelope A Lind; Brian P McEvoy; Andrew J Schrage; Julia D Grant; Yi-Ling Chou; Rachel Zhu; Anjali K Henders; Sarah E Medland; Scott D Gordon; Elliot C Nelson; Arpana Agrawal; Dale R Nyholt; Kathleen K Bucholz; Pamela A F Madden; Grant W Montgomery Journal: Biol Psychiatry Date: 2011-05-06 Impact factor: 13.382
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Authors: Kenneth Blum; Mark S Brodie; Subhash C Pandey; Jean Lud Cadet; Ashim Gupta; Igor Elman; Panayotis K Thanos; Marjorie C Gondre-Lewis; David Baron; Shan Kazmi; Abdalla Bowirrat; Marcelo Febo; Rajendra D Badgaiyan; Eric R Braverman; Catherine A Dennen; Mark S Gold Journal: J Pers Med Date: 2022-06-20
Authors: D Mielenz; M Reichel; T Jia; E B Quinlan; T Stöckl; M Mettang; D Zilske; E Kirmizi-Alsan; P Schönberger; M Praetner; S E Huber; D Amato; M Schwarz; P Purohit; S Brachs; J Spranger; A Hess; C Büttner; A B Ekici; F Perez-Branguli; B Winner; V Rauschenberger; T Banaschewski; A L W Bokde; C Büchel; P J Conrod; S Desrivières; H Flor; V Frouin; J Gallinat; H Garavan; P Gowland; A Heinz; J-L Martinot; H Lemaitre; F Nees; T Paus; M N Smolka; A Schambony; T Bäuerle; V Eulenburg; C Alzheimer; A Lourdusamy; G Schumann; C P Müller Journal: Mol Psychiatry Date: 2017-04-11 Impact factor: 15.992