Genetic variation contributes to individual differences in the risk for a variety of psychiatric and other common diseases. For the common psychiatric diseases, multiple genes work in concert to confer risk, and interact with one another, as well as the environment, to produce the observed phenotype. Identifying these genes, as well as understanding their complex interactions, promises to revolutionize the diagnosis and treatment of psychiatric diseases. Our research uses mice as a model genetic system to identify specific genes that contribute to heritable disorders
Genetic determinants of sensitivity to methamphetamine (MA) in mice and humans. Individual differences in the sensitivity to drugs of abuse are controlled by both genetic and environmental factors. The genetic variants associated with differential sensitivity to abused drugs may partially underlie genetic liability for drug abuse. We have integrated QTL mapping with gene expression analysis and used these two approaches to identify genes that are associated with differential sensitivity to MA. Preliminary work with Harriet de Wit (Psychiatry) has established that at least one of these genes also regulates sensitivity to MA in human subjects who were administered MA in a controlled laboratory setting.
Translational genetic approach to fear and anxiety. Fear learning and anxiety disorders may be regulated by common genetic substrates. We selectively bred mice for high or low levels of fear learning to identify both QTLs for fear learning and gene-expression differences between the high and low selected lines. We have also shown that selection altered other aspects of fear and anxiety-like behavior. Candidate genes identified by this approach will be screened against several large human samples that have been phenotyped for fear and anxiety related traits.
Selected Publications
Meyer PC; Palmer AA; McKinnon CS; Phillips TJ Behavioral sensitization to ethanol is modulated by environmental conditions, but is not associated with cross-sensitization to allopregnanolone or pentobarbital in DBA/2J mice. Neuroscience, 2005, 131:263-73 PDF
Palmer AA; Verbitsky M; Suresh R; Kamens HM; Reed CL; Li N; Burkhart-Kasch S; McKinnon CS; Belknap JK; Gilliam TC; Phillips TJ Gene Expression Differences in Mice Divergently Selected for Methamphetamine Sensitivity. Mamm Genome, 2005, 16:291-305 PDF
Veenstra-Vanderweele J, Qaadir A, Palmer AA, Cook EH de Wit H Association between the Casein Kinase 1 Epsilon gene region and subjective response to D-amphetamine. Neuropsychopharm, 2006, 31:1056-63 PDF
Yonan AL; Palmer AA; Gilliam TC Hardy-Weinberg Disequilibrium Identified Genotyping Error of the Serotonin Transporter (SLC6A4) Promoter Polymorphism. Psychiatr Genet, 2006, 16:31-4 PDF
Palmer AA; Lessov-Schlaggar CN; Ponder CA; Phillips TJ Sensitivity to the locomotor stimulant effects of ethanol and allopregnanolone: a QTL study of common genetic influence. Genes Brain Behav, 2006, 5: 506-17 PDF
Winawer MR; Kuperman R; Niethammer M; Sherman S; Rabinowitz D; Guell IP; Ponder CA; Palmer AA Use of chromosome substitution strains to identify seizure susceptibility loci in mice, Mamm Genome, 2007, 18: 23-31 PDF
Ponder CA; Kliethermes CL; Drew MR; Muller J; Das K; Risbrough VB; Crabbe JC; Gilliam TC; Palmer AA Selection for contextual fear conditioning affects anxiety-like behaviors and gene expression. Genes Brain Behav, 2007, 6: 736–749 PDF
Ponder CA, Munoz M, Gilliam TC, Palmer AA Genetic architecture of fear conditioning in chromosome substitution strains: relationship to measures of innate (unlearned) anxiety-like behavior. Mammalian Genome, 2007, 18:221-8 PDF
Winawer MR, Makarenko N, Hintz TM, Kamel SM, McCloskey DP, Nair N, Palmer AA, Scharfman HE. Acute and chronic response to pilocarpine in DBA/2J and A/J mice: A foundation for mapping limbic seizure susceptibility genes in sequenced strains. Neuroscience, 2007, 149:465-75. PDF
Manichaikul A, Palmer AA, Saunak S, Broman KW. Significance thresholds for quantitative trait locus mapping under selective genotyping, Genetics, 2007, 177:1963-6. PDF
Ponder CA, Huded CP, Munoz MB, Gulden FO, Gilliam TC, Palmer AA. Rapid selection response for contextual fear conditioning in a cross between C57BL/6J and A/J: behavioral, QTL and gene expression analysis. Behav Genet, 2008, 38:277-91. PDF
Palmer AA, Brown, AS, Klugewicz D, DeSanti L, Rotrosen J, Butler PD. Prenatal Protein Deprivation Alters Dopamine-Mediated Behaviors and Dopaminergic and Glutamatergic Receptor Binding. Brain Res, 2008 1237:62-74. PDF
Bryant C, Graham M, Distler M, Munoz M, Li D, Vezina P, Sokoloff G, Palmer AA. Role for Casein Kinase 1 Epsilon in the Locomotor Stimulant Response to Methamphetamine. Psychopharmacology, 2009, 203:703-11. PDF
Bryant CD, Zhang NN, Sokoloff G, Fanselow MS, Ennes HS, Palmer AA, McRoberts JA. Behavioral differences among C57BL/6 substrains: Implications for transgenic and knockout studies. J Neurogenet, 2008, 22:315-31. PDF
Williams R, Lim JE, Harr B, Wing C, Walters R, Distler MG, Meike T, Wu C, Wiltshire T, Su AI, Sokoloff G, Tarantino LM, Borevitz JO, Palmer AA. A Common and Unstable Copy Number Variant is Associated with Differences in Glo1 Expression and Anxiety-Like Behavior. PLoS One, 2009, 4:e4649. PDF
Aldinger K, Sokoloff G, Rosenberg D, Palmer AA, Millen K. Genetic variation and population substructure in outbred CD-1 mice: implications for genome-wide association studies. PLoS One, 2009,4:e4729. PDF
Dlugos AM, Hamidovic A, Skol AD, Palmer AA, de Wit H. Further evidence of association between amphetamine response and SLC6A2 gene variants. Psychopharmacology, 2009. PDF
Dlugos AM, Badner J, Palmer AA, de Wit H. Negative emotionality: monoamine oxidase B gene variants modulate personality traits in healthy humans. Journal of Neural Transmission, 2009. PDF
Bryant CD, Chang HP, Zhang J, Tarantino LM, Palmer AA. A major QTL on chromosome 11 influences psychostimulant and opioid sensitivity in mice. Genes, Brain Behav, 2009. PDF
Dlugos AM, Hamidovic A, Hodgkinson CA, Goldman D, Palmer AA, de Wit H. More aroused, less fatigued: FAAH gene polymorphisms influence acute response to amphetamine. Neuropsychopharmacology, in press.
Heydemann A, Ceco E, Lim JE, Hadhazy M, Ryder P, Moran JL, Beier DR, Palmer AA, McNally EM. Latent transforming growth factor binding protein 4 modifies muscular dystrophy, J Clin Invest, in press.
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