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

David Stacey, Anbarasu Lourdusamy, Barbara Ruggeri, Matthieu Maroteaux, Tianye Jia, Anna Cattrell, Charlotte Nymberg, Tobias Banaschewski, Sohinee Bhattacharyya, Hamid Band, Gareth Barker, Arun Bokde, Christian Büchel, Fabiana Carvalho, Patricia Conrod, Sylvane Desrivières, Alanna Easton, Mira Fauth-Buehler, Alberto Fernandez-Medarde, Herta Flor & 23 others Vincent Frouin, Jurgen Gallinat, Hugh Garavanh, Andreas Heinz, Bernd Ittermann, Mark Lathrop, Claire Lawrence, Eva Loth, Karl Mann, Jean Luc Martinot, Frauke Nees, Tomas Paus, Zdenka Pausova, Marcella Rietschel, Andrea Rotter, Eugenio Santos, Michael Smolka, Wolfgang Sommer, Manuel Mameli, Rainer Spanagel, Jean Antoine Girault, Christian Müller, Gunter Schumann

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 maleRasgrf2–/– 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.

Original languageEnglish (US)
Pages (from-to)192-202
Number of pages11
JournalJournal of Psychiatry and Neuroscience
Volume41
Issue number3
DOIs
StatePublished - May 1 2016

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Binge Drinking
Systems Biology
Gene Regulatory Networks
Reward
Corpus Striatum
Dopamine
Nucleus Accumbens
Alcohols
Genes
Guanine Nucleotide-Releasing Factor 2
ras-GRF1
Magnetic Resonance Imaging
Phenotype
Ventral Tegmental Area
Genome-Wide Association Study
Dopaminergic Neurons
Meta-Analysis
Ethanol
Brain

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Biological Psychiatry
  • Pharmacology (medical)

Cite this

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. / Stacey, David; Lourdusamy, Anbarasu; Ruggeri, Barbara; Maroteaux, Matthieu; Jia, Tianye; Cattrell, Anna; Nymberg, Charlotte; Banaschewski, Tobias; Bhattacharyya, Sohinee; Band, Hamid; Barker, Gareth; Bokde, Arun; Büchel, Christian; Carvalho, Fabiana; Conrod, Patricia; Desrivières, Sylvane; Easton, Alanna; Fauth-Buehler, Mira; Fernandez-Medarde, Alberto; Flor, Herta; Frouin, Vincent; Gallinat, Jurgen; Garavanh, Hugh; Heinz, Andreas; Ittermann, Bernd; Lathrop, Mark; Lawrence, Claire; Loth, Eva; Mann, Karl; Martinot, Jean Luc; Nees, Frauke; Paus, Tomas; Pausova, Zdenka; Rietschel, Marcella; Rotter, Andrea; Santos, Eugenio; Smolka, Michael; Sommer, Wolfgang; Mameli, Manuel; Spanagel, Rainer; Girault, Jean Antoine; Müller, Christian; Schumann, Gunter.

In: Journal of Psychiatry and Neuroscience, Vol. 41, No. 3, 01.05.2016, p. 192-202.

Research output: Contribution to journalArticle

Stacey, D, Lourdusamy, A, Ruggeri, B, Maroteaux, M, Jia, T, Cattrell, A, Nymberg, C, Banaschewski, T, Bhattacharyya, S, Band, H, Barker, G, Bokde, A, Büchel, C, Carvalho, F, Conrod, P, Desrivières, S, Easton, A, Fauth-Buehler, M, Fernandez-Medarde, A, Flor, H, Frouin, V, Gallinat, J, Garavanh, H, Heinz, A, Ittermann, B, Lathrop, M, Lawrence, C, Loth, E, Mann, K, Martinot, JL, Nees, F, Paus, T, Pausova, Z, Rietschel, M, Rotter, A, Santos, E, Smolka, M, Sommer, W, Mameli, M, Spanagel, R, Girault, JA, Müller, C & Schumann, G 2016, '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', Journal of Psychiatry and Neuroscience, vol. 41, no. 3, pp. 192-202. https://doi.org/10.1503/jpn.150138
Stacey, David ; Lourdusamy, Anbarasu ; Ruggeri, Barbara ; Maroteaux, Matthieu ; Jia, Tianye ; Cattrell, Anna ; Nymberg, Charlotte ; Banaschewski, Tobias ; Bhattacharyya, Sohinee ; Band, Hamid ; Barker, Gareth ; Bokde, Arun ; Büchel, Christian ; Carvalho, Fabiana ; Conrod, Patricia ; Desrivières, Sylvane ; Easton, Alanna ; Fauth-Buehler, Mira ; Fernandez-Medarde, Alberto ; Flor, Herta ; Frouin, Vincent ; Gallinat, Jurgen ; Garavanh, Hugh ; Heinz, Andreas ; Ittermann, Bernd ; Lathrop, Mark ; Lawrence, Claire ; Loth, Eva ; Mann, Karl ; Martinot, Jean Luc ; Nees, Frauke ; Paus, Tomas ; Pausova, Zdenka ; Rietschel, Marcella ; Rotter, Andrea ; Santos, Eugenio ; Smolka, Michael ; Sommer, Wolfgang ; Mameli, Manuel ; Spanagel, Rainer ; Girault, Jean Antoine ; Müller, Christian ; Schumann, Gunter. / 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. In: Journal of Psychiatry and Neuroscience. 2016 ; Vol. 41, No. 3. pp. 192-202.
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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 maleRasgrf2–/– 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.",
author = "David Stacey and Anbarasu Lourdusamy and Barbara Ruggeri and Matthieu Maroteaux and Tianye Jia and Anna Cattrell and Charlotte Nymberg and Tobias Banaschewski and Sohinee Bhattacharyya and Hamid Band and Gareth Barker and Arun Bokde and Christian B{\"u}chel and Fabiana Carvalho and Patricia Conrod and Sylvane Desrivi{\`e}res and Alanna Easton and Mira Fauth-Buehler and Alberto Fernandez-Medarde and Herta Flor and Vincent Frouin and Jurgen Gallinat and Hugh Garavanh and Andreas Heinz and Bernd Ittermann and Mark Lathrop and Claire Lawrence and Eva Loth and Karl Mann and Martinot, {Jean Luc} and Frauke Nees and Tomas Paus and Zdenka Pausova and Marcella Rietschel and Andrea Rotter and Eugenio Santos and Michael Smolka and Wolfgang Sommer and Manuel Mameli and Rainer Spanagel and Girault, {Jean Antoine} and Christian M{\"u}ller and Gunter Schumann",
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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

AU - Stacey, David

AU - Lourdusamy, Anbarasu

AU - Ruggeri, Barbara

AU - Maroteaux, Matthieu

AU - Jia, Tianye

AU - Cattrell, Anna

AU - Nymberg, Charlotte

AU - Banaschewski, Tobias

AU - Bhattacharyya, Sohinee

AU - Band, Hamid

AU - Barker, Gareth

AU - Bokde, Arun

AU - Büchel, Christian

AU - Carvalho, Fabiana

AU - Conrod, Patricia

AU - Desrivières, Sylvane

AU - Easton, Alanna

AU - Fauth-Buehler, Mira

AU - Fernandez-Medarde, Alberto

AU - Flor, Herta

AU - Frouin, Vincent

AU - Gallinat, Jurgen

AU - Garavanh, Hugh

AU - Heinz, Andreas

AU - Ittermann, Bernd

AU - Lathrop, Mark

AU - Lawrence, Claire

AU - Loth, Eva

AU - Mann, Karl

AU - Martinot, Jean Luc

AU - Nees, Frauke

AU - Paus, Tomas

AU - Pausova, Zdenka

AU - Rietschel, Marcella

AU - Rotter, Andrea

AU - Santos, Eugenio

AU - Smolka, Michael

AU - Sommer, Wolfgang

AU - Mameli, Manuel

AU - Spanagel, Rainer

AU - Girault, Jean Antoine

AU - Müller, Christian

AU - Schumann, Gunter

PY - 2016/5/1

Y1 - 2016/5/1

N2 - 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 maleRasgrf2–/– 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.

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 maleRasgrf2–/– 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.

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