RT Journal Article
SR Electronic
T1 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
JF Journal of Psychiatry and Neuroscience
JO J Psychiatry Neurosci
FD Canadian Medical Association
SP 192
OP 202
DO 10.1503/jpn.150138
VO 41
IS 3
A1 David Stacey
A1 Anbarasu Lourdusamy
A1 Barbara Ruggeri
A1 Matthieu Maroteaux
A1 Tianye Jia
A1 Anna Cattrell
A1 Charlotte Nymberg
A1 Tobias Banaschewski
A1 Sohinee Bhattacharyya
A1 Hamid Band
A1 Gareth Barker
A1 Arun Bokde
A1 Christian Buchel
A1 Fabiana Carvalho
A1 Patricia Conrod
A1 Sylvane Desrivieres
A1 Alanna Easton
A1 Mira Fauth-Buehler
A1 Alberto Fernandez-Medarde
A1 Herta Flor
A1 Vincent Frouin
A1 Jurgen Gallinat
A1 Hugh Garavanh
A1 Andreas Heinz
A1 Bernd Ittermann
A1 Mark Lathrop
A1 Claire Lawrence
A1 Eva Loth
A1 Karl Mann
A1 Jean-Luc Martinot
A1 Frauke Nees
A1 Tomas Paus
A1 Zdenka Pausova
A1 Marcella Rietschel
A1 Andrea Rotter
A1 Eugenio Santos
A1 Michael Smolka
A1 Wolfgang Sommer
A1 Manuel Mameli
A1 Rainer Spanagel
A1 Jean-Antoine Girault
A1 Christian Mueller
A1 Gunter Schumann
A1 ,
YR 2016
UL http://jpn.ca/content/41/3/192.abstract
AB 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.