Frequency of alcohol consumption in humans; the role of metabotropic glutamate receptors and downstream signaling pathways

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 f...

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Published in:Translational psychiatry Vol. 5; no. 6; p. e586
Main Authors: Meyers, J L, Salling, M C, Almli, L M, Ratanatharathorn, A, Uddin, M, Galea, S, Wildman, D E, Aiello, A E, Bradley, B, Ressler, K, Koenen, K C
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 23.06.2015
Nature Publishing Group
Subjects:
38/43
49/39
631/208/212
Adult
Aged
Alcohol Drinking - genetics
Behavioral Sciences
Biological Psychology
Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics
Carrier Proteins - genetics
Cytoskeletal Proteins - genetics
Elongation Factor 2 Kinase - genetics
Eukaryotic Initiation Factor-2 - genetics
Eukaryotic Initiation Factor-4E - genetics
Female
Homer Scaffolding Proteins
Humans
Linear Models
Male
Medicine
Medicine & Public Health
Middle Aged
Nerve Tissue Proteins - genetics
Neuronal Plasticity - genetics
Neurosciences
Original
original-article
Pharmacotherapy
Polymorphism, Single Nucleotide
Psychiatry
Receptor, Metabotropic Glutamate 5 - genetics
Receptors, AMPA - genetics
Receptors, Metabotropic Glutamate - genetics
Signal Transduction - genetics
TOR Serine-Threonine Kinases - genetics
ISSN:2158-3188, 2158-3188
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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.
AbstractList 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[variant prime]-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.
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.
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.
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.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.
Author Ratanatharathorn, A
Wildman, D E
Aiello, A E
Galea, S
Almli, L M
Ressler, K
Salling, M C
Koenen, K C
Meyers, J L
Bradley, B
Uddin, M
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/26101849$$D View this record in MEDLINE/PubMed
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Snippet Rodent models implicate metabotropic glutamate receptors (mGluRs) and downstream signaling pathways in addictive behaviors through metaplasticity. One way...
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StartPage e586
SubjectTerms 38/43
49/39
631/208/212
Adult
Aged
Alcohol Drinking - genetics
Behavioral Sciences
Biological Psychology
Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics
Carrier Proteins - genetics
Cytoskeletal Proteins - genetics
Elongation Factor 2 Kinase - genetics
Eukaryotic Initiation Factor-2 - genetics
Eukaryotic Initiation Factor-4E - genetics
Female
Homer Scaffolding Proteins
Humans
Linear Models
Male
Medicine
Medicine & Public Health
Middle Aged
Nerve Tissue Proteins - genetics
Neuronal Plasticity - genetics
Neurosciences
Original
original-article
Pharmacotherapy
Polymorphism, Single Nucleotide
Psychiatry
Receptor, Metabotropic Glutamate 5 - genetics
Receptors, AMPA - genetics
Receptors, Metabotropic Glutamate - genetics
Signal Transduction - genetics
TOR Serine-Threonine Kinases - genetics
Title Frequency of alcohol consumption in humans; the role of metabotropic glutamate receptors and downstream signaling pathways
URI https://link.springer.com/article/10.1038/tp.2015.70
https://www.ncbi.nlm.nih.gov/pubmed/26101849
https://www.proquest.com/docview/1791130921
https://www.proquest.com/docview/1691285134
https://pubmed.ncbi.nlm.nih.gov/PMC4490281
Volume 5
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