title: Human variation in alcohol response is influenced by variation in neuronal signaling genes.
abstract: BACKGROUND
  Alcohol use disorders (AUD) exhibit the properties shared by common conditions and diseases classified as genetically complex. The etiology of AUDs is heterogeneous involving mostly unknown interactions of environmental and heritable factors. A person's level of response (LR) to alcohol is inversely correlated with a family history and the development of AUDs. As an AUD endophenotype, alcohol LR is hypothesized to be less genetically complex and closer to the primary etiology of AUDs.
  
  
  METHODS
  A genome wide association study (GWAS) was performed on subjects characterized for alcohol LR phenotypes. Gene Set Enrichment Analysis (GSEA) of the GWAS data was performed to determine whether, as a group, genes that participate in a common biological function (a gene set) demonstrate greater genetic association than would be randomly expected.
  
  
  RESULTS
  The GSEA analysis implicated variation in neuronal signaling genes, especially glutamate signaling, as being involved in alcohol LR variability in the human population.
  
  
  CONCLUSIONS
  These data, coupled with cell and animal model data implicating neuronal signaling in alcohol response, support the conclusion that neuronal signaling is mechanistically involved in alcohol's cellular and behavioral effects. Further, these data suggest that genetic variation in these signaling pathways contribute to human variation in alcohol response. Finally, this concordance of the cell, animal, and human findings supports neuronal signaling, particularly glutamate signaling, as a prime target for translational studies to understand and eventually modulate alcohol's effects.
authors.affiliation: Ernest Gallo Clinic and Research Center, Emeryville, California 94608, USA. gjoslyn@gallo.ucsf.edu <gjoslyn@gallo.ucsf.edu>
authors.forename: Geoff
authors.initials: G
authors.lastname: Joslyn
authors.forename: Ajay
authors.initials: A
authors.lastname: Ravindranathan
authors.forename: Gerry
authors.initials: G
authors.lastname: Brush
authors.forename: Marc
authors.initials: M
authors.lastname: Schuckit
authors.forename: Raymond L
authors.initials: RL
authors.lastname: White
mesh_terms: D000293:Adolescent; D000328:Adult; D000428:Alcohol Drinking / Q000235:genetics* / Q000523:psychology*; D000437:Alcoholism / Q000235:genetics / Q000523:psychology; D005260:Female; D020869:Gene Expression Profiling / Q000639:trends; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods / Q000639:trends; D006801:Humans; D008297:Male; D009474:Neurons / Q000502:physiology*; D035781:Siblings / Q000523:psychology; D015398:Signal Transduction / Q000235:genetics*; D011795:Surveys and Questionnaires; D055815:Young Adult