title: Frequency of alcohol consumption in humans; the role of metabotropic glutamate receptors and downstream signaling pathways.
abstract: Rodent models implicate metabotropic glutamate receptors (mGluRs) and downstream signaling pathways in addictive behaviors through metaplasticity. One way mGluRs can influence synaptic plasticity is by regulating the local translation of AMPA receptor trafficking proteins via eukaryotic elongation factor 2 (eEF2). However, genetic variation in this pathway has not been examined with human alcohol use phenotypes. Among a sample of adults living in Detroit, Michigan (Detroit Neighborhood Health Study; n = 788; 83% African American), 206 genetic variants across the mGluR-eEF2-AMPAR pathway (including GRM1, GRM5, HOMER1, HOMER2, EEF2K, MTOR, EIF4E, EEF2, CAMK2A, ARC, GRIA1 and GRIA4) were found to predict number of drinking days per month (corrected P-value < 0.01) when considered as a set (set-based linear regression conducted in PLINK). In addition, a CpG site located in the 3'-untranslated region on the north shore of EEF2 (cg12255298) was hypermethylated in those who drank more frequently (P < 0.05). Importantly, the association between several genetic variants within the mGluR-eEF2-AMPAR pathway and alcohol use behavior (i.e., consumption and alcohol-related problems) replicated in the Grady Trauma Project (GTP), an independent sample of adults living in Atlanta, Georgia (n = 1034; 95% African American), including individual variants in GRM1, GRM5, EEF2, MTOR, GRIA1, GRIA4 and HOMER2 (P < 0.05). Gene-based analyses conducted in the GTP indicated that GRM1 (empirical P < 0.05) and EEF2 (empirical P < 0.01) withstood multiple test corrections and predicted increased alcohol consumption and related problems. In conclusion, insights from rodent studies enabled the identification of novel human alcohol candidate genes within the mGluR-eEF2-AMPAR pathway.
authors.affiliation: Department of Epidemiology, Columbia University, New York, NY, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Meyers
authors.affiliation: Department of Anesthesiology, Columbia University, New York, NY, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Salling
authors.affiliation: Department of Veterans Affairs Medical Center, Mental Health Service Line, Atlanta, GA, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Almli
authors.affiliation: Department of Epidemiology, Columbia University, New York, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Ratanatharathorn
authors.affiliation: 1] Department of Psychology, University of Illinois-Urbana Champaign, Urbana, IL, USA [2] Institute for Genomic Biology, University of Illinois-Urbana Champaign, Champaign, IL, USA.
authors.forename: M
authors.initials: M
authors.lastname: Uddin
authors.affiliation: Department of Epidemiology, Columbia University, New York, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Galea
authors.affiliation: 1] Institute for Genomic Biology, University of Illinois-Urbana Champaign, Champaign, IL, USA [2] Department of Molecular and Integrative Physiology, University of Illinois-Urbana Champaign, Urbana, IL, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Wildman
authors.affiliation: Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: A E
authors.initials: AE
authors.lastname: Aiello
authors.affiliation: 1] Department of Veterans Affairs Medical Center, Mental Health Service Line, Atlanta, GA, USA [2] Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Bradley
authors.affiliation: 1] Department of Veterans Affairs Medical Center, Mental Health Service Line, Atlanta, GA, USA [2] Howard Hughes Medical Institute, Chevy Chase, MD, USA.
authors.forename: K
authors.initials: K
authors.lastname: Ressler
authors.affiliation: Department of Epidemiology, Columbia University, New York, NY, USA.
authors.forename: K C
authors.initials: KC
authors.lastname: Koenen
mesh_terms: D000328:Adult; D000368:Aged; D000428:Alcohol Drinking / Q000235:genetics*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics; D054736:Elongation Factor 2 Kinase / Q000235:genetics; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics*; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics; D005260:Female; D000072233:Homer Scaffolding Proteins; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D009473:Neuronal Plasticity / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D064529:Receptor, Metabotropic Glutamate 5 / Q000235:genetics; D018091:Receptors, AMPA / Q000235:genetics*; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics
chemical_list: D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D054736:Elongation Factor 2 Kinase; D015852:Eukaryotic Initiation Factor-2; D039561:Eukaryotic Initiation Factor-4E; D000072233:Homer Scaffolding Proteins; D009419:Nerve Tissue Proteins; D064529:Receptor, Metabotropic Glutamate 5; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; D058570:TOR Serine-Threonine Kinases; C578935:GRM5 protein, human; C000606614:HOMER1 protein, human; C092069:activity regulated cytoskeletal-associated protein; C104724:glutamate receptor ionotropic, AMPA 4; C104077:metabotropic glutamate receptor type 1; C546842:MTOR protein, human; C517689:EEF2K protein, human; C517657:CAMK2A protein, human