title: Genetic variability in the NMDA-dependent AMPA trafficking cascade is associated with alcohol dependence.
abstract: Model studies in mice indicate that the severity of alcohol withdrawal is associated with polymorphic variation and expression of the MPDZ gene. Current knowledge about variation in the human MPDZ gene is limited; however, our data indicate its potential association with alcohol dependence. The multi-PDZ protein is an important part of the N-methyl-D-aspartate (NMDA)-dependent α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor trafficking cascade that controls glutamate-related excitatory neurotransmission. To investigate association of variation in the NMDA-dependent AMPA trafficking cascade with alcohol dependence, we performed a gene-set (pathway) analysis using single nucleotide polymorphism (SNP) data from the Study of Addiction: Genetic and Environment. Rather than testing for association with each SNP individually, which typically has low power to detect small effects of multiple SNPs, gene-set analysis applies a single statistical test to evaluate whether variation in a set of genes is associated with the phenotype of interest. Gene-set analysis of 988 SNPs in 13 genes in the pathway demonstrated a significant association with alcohol dependence, with P < 0.01 for the global effect of variation in this pathway. The statistically significant association of alcohol dependence with genetic variation in the NMDA-dependent AMPA receptor trafficking cascade indicates a need for further investigation of the role of this pathway in alcohol dependence.
authors.affiliation: Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA. karpyak.victor@mayo.edu
authors.forename: Victor M
authors.initials: VM
authors.lastname: Karpyak
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Geske
authors.forename: Colin L
authors.initials: CL
authors.lastname: Colby
authors.forename: David A
authors.initials: DA
authors.lastname: Mrazek
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Biernacka
mesh_terms: D000437:Alcoholism / Q000235:genetics*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D008565:Membrane Proteins; D016202:N-Methylaspartate / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D021381:Protein Transport / Q000235:genetics; D018091:Receptors, AMPA / Q000235:genetics*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; C111442:MPDZ protein, human; D008565:Membrane Proteins; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C517657:CAMK2A protein, human; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2