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
Yonan AL; Alarcón M; Cheng R; Magnusson PKE; Spence SJ; Palmer AA; Grunn A; Juo SHH; Terwilliger JD; Liu J; Cantor RM; Geschwind DH; Gilliam TC A Genomewide Screen of 345 Families for Autism Susceptibility Loci. Am J Hum Genet, 2003, 73:886-97 PDF
The Complex Trait Consortium. The Nature and Identification of Quantitative Trait Loci: a Community’s View. Nature Rev Genet, 2003, 4:911-6 PDF
Yonan AL; Palmer AA; Smith KC; Feldman I; Lee HK; Yonan JM; Fischer SG; Pavlidis P; Gilliam TC Bioinformatic analysis of autism positional candidate genes using biological databases and computational gene network prediction. Genes Brain Behav, 2003, 2:303-20 PDF
Palmer AA; Printz DJ; Butler PD; Dulawa SC; Printz MP Prenatal Protein Deprivation in Rats Induces Changes in Prepulse Inhibition and NMDA Receptor Binding. Brain Res, 2004, 996:193-201 PDF
Palmer AA; Sharpe AL; Burkhart-Kasch S; McKinnon CS; Coste SC; Stenzel-Poore MP; Phillips TJ Corticotropin releasing hormone overexpression decreases ethanol drinking and increases sensitivity to the sedative effects of ethanol. Psychopharmacology, 2004, 176:386-97 PDF
The Complex Trait Consortium. The Collaborative Cross, a community resource for the genetic analysis of complex traits. Nature Genet, 2004, 36:1133-7 PDF
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
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, in press. 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, in press. PDF
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