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

Meyers JL, Salling MC, Almli LM, Ratanatharathorn A, Uddin M, Galea S, Wildman DE, Aiello AE, Bradley B, Ressler K, Koenen KC - Transl Psychiatry (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology, Columbia University, New York, NY, USA.

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.

No MeSH data available.


Related in: MedlinePlus

Increased methylation of cg12255298 (located in the 3′-UTR of EEF2 on Chr 19) for individuals with higher drinking days per month in the DNHS. Although alcohol consumption was analyzed continuously, it is presented dichotomously here for ease of presentation. Low alcohol consumption is defined as 1 s.d. below the mean value of alcohol consumption in the DNHS, whereas high alcohol consumption is defined as 1 s.d. above the mean value of alcohol consumption in the DNHS. Significant difference, *P<0.05. DNHS, Detroit Neighborhood Health Study; UTR, untranslated region.
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fig2: Increased methylation of cg12255298 (located in the 3′-UTR of EEF2 on Chr 19) for individuals with higher drinking days per month in the DNHS. Although alcohol consumption was analyzed continuously, it is presented dichotomously here for ease of presentation. Low alcohol consumption is defined as 1 s.d. below the mean value of alcohol consumption in the DNHS, whereas high alcohol consumption is defined as 1 s.d. above the mean value of alcohol consumption in the DNHS. Significant difference, *P<0.05. DNHS, Detroit Neighborhood Health Study; UTR, untranslated region.

Mentions: Of the eight CpG sites examined across the EEF2 region in the DNHS, one site (cg12255298), located in the 3'-untranslated region on the north shore of eEF2 (chromosome 19, BP: 3 976 193–3 976 193), was significantly and positively related to alcohol consumption (B=0.419, P=0.004) and withstood a multiple test correction (0.05/8=0.006). For individuals with higher drinking days per month (1 s.d. above the mean), cg12255298 was hypermethylated as compared with individuals with fewer drinking days per month (1 s.d. below the mean). This relationship is depicted in Figure 2.


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

Meyers JL, Salling MC, Almli LM, Ratanatharathorn A, Uddin M, Galea S, Wildman DE, Aiello AE, Bradley B, Ressler K, Koenen KC - Transl Psychiatry (2015)

Increased methylation of cg12255298 (located in the 3′-UTR of EEF2 on Chr 19) for individuals with higher drinking days per month in the DNHS. Although alcohol consumption was analyzed continuously, it is presented dichotomously here for ease of presentation. Low alcohol consumption is defined as 1 s.d. below the mean value of alcohol consumption in the DNHS, whereas high alcohol consumption is defined as 1 s.d. above the mean value of alcohol consumption in the DNHS. Significant difference, *P<0.05. DNHS, Detroit Neighborhood Health Study; UTR, untranslated region.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4490281&req=5

fig2: Increased methylation of cg12255298 (located in the 3′-UTR of EEF2 on Chr 19) for individuals with higher drinking days per month in the DNHS. Although alcohol consumption was analyzed continuously, it is presented dichotomously here for ease of presentation. Low alcohol consumption is defined as 1 s.d. below the mean value of alcohol consumption in the DNHS, whereas high alcohol consumption is defined as 1 s.d. above the mean value of alcohol consumption in the DNHS. Significant difference, *P<0.05. DNHS, Detroit Neighborhood Health Study; UTR, untranslated region.
Mentions: Of the eight CpG sites examined across the EEF2 region in the DNHS, one site (cg12255298), located in the 3'-untranslated region on the north shore of eEF2 (chromosome 19, BP: 3 976 193–3 976 193), was significantly and positively related to alcohol consumption (B=0.419, P=0.004) and withstood a multiple test correction (0.05/8=0.006). For individuals with higher drinking days per month (1 s.d. above the mean), cg12255298 was hypermethylated as compared with individuals with fewer drinking days per month (1 s.d. below the mean). This relationship is depicted in Figure 2.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology, Columbia University, New York, NY, USA.

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.

No MeSH data available.


Related in: MedlinePlus