Research Description

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

• 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, 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, Skol AD, Palmer AA, de Wit H. Further evidence of association between amphetamine response and SLC6A2 gene variants. Psychopharmacology, 2009. PDF
• 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, 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, 2010. PDF
• Hamidovic A, Dlugos A, Skol A, Palmer AA, de Wit H. Evaluation of Genetic Variability in the Dopamine Receptor D2 in Relation to Behavioral Inhibition and Impulsivity/Sensation Seeking: An Exploratory Study With d-Amphetamine in Healthy Participants. Exp Clin Psychopharmacol, 2009 17:374. PDF
• McCloskey M, Palmer AA, de Wit H. Is self-reported liking of d-amphetamine related to impulsivity? Psychopharmacology, 2010 208:201. PDF Velez L, Sokoloff G, Miczek KA,
• Palmer AA, Dulawa SC. Differences in aggressive behavior and DNA copy number variants between BALB/cJ and BALB/cByJ substrains. Behav Genet, 2010 40:201. PDF
• Hamidovic A, Dlugos A, Palmer AA, de Wit H. Polymorphisms in Dopamine Transporter (SLC6A3) are Associated with Stimulant Effects of d-Amphetamine: An Exploratory Pharmacogenetic Study Using Healthy Volunteers. Behav Genet. 2010 40:255. PDF
• Palmer A.A. and Dulawa S.C. Murine warriors or worriers: The saga of comt1, b2 SINE elements, and the future of translational genetics. Front Neurosci, 4:177, 2010. (Link)
• Yang A., Childs E., Palmer A.A., and de Wit H. More on ADORA. Psychopharmacology (Berl), 212(4):699–700, Dec 2010. (Link)
• Dlugos A.M., Hamidovic A., Hodgkinson C., Shen P.H., Goldman D., Palmer A.A., and De Wit H. OPRM1 gene variants modulate amphetamine-induced euphoria in humans. Genes Brain Behav, Oct 2010. (Link)
• Samocha K.E., Lim J.E., Cheng R., Sokoloff G., and Palmer A.A. Fine mapping of QTL for prepulse inhibition in LG/j and SM/j mice using f(2) and advanced intercross lines. Genes Brain Behav, 9(7):759–767, Oct 2010. (PDF)
• Swaggart K.A., Heydemann A., Palmer A.A., and McNally E.M. Distinct genetic regions modify specific muscle groups in muscular dystrophy. Physiol Genomics, Oct 2010. (Link)
• Lionikas A., Cheng R., Lim J.E., Palmer A.A., and Blizard D.A. Fine-mapping of muscle weight QTL in LG/j and SM/j intercrosses. Physiol Genomics, 42A(1):33–38, Sep 2010. (PDF)
• Yang A., Palmer A.A., and de Wit H. Genetics of caffeine consumption and responses to caffeine. Psychopharmacology (Berl), 211(3):245–257, Aug 2010. (Link)
• Cheng R., Lim J.E., Samocha K.E., Sokoloff G., Abney M., Skol A.D., and Palmer A.A. Genome-wide association studies and the problem of relatedness among advanced intercross lines and other highly recombinant populations. Genetics, 185(3):1033–1044, Jul 2010. (PDF)
• Hamidovic A., Dlugos A., Palmer A.A., and de Wit H. Catechol-o-methyltransferase val158met genotype modulates sustained attention in both the drug-free state and in response to amphetamine. Psychiatr Genet, 20(3):85–92, Jun 2010. (PDF)
• Parker C.C., Cheng R., Sokoloff G., and Palmer A.A. Genome-wide association for methamphetamine sensitivity in an advanced intercross mouse line. Genes Brain Behav, 11(1):52–61, Feb 2012. (Link)
• Parker C.C., Sokoloff G., Cheng R., and Palmer A.A. Genome-wide association for fear conditioning in an advanced intercross mouse line. Behav Genet, Jan 2012. (Link)
• Cheng R., Abney M., Palmer A.A., and Skol A.D. QTLRel: an r package for genome-wide association studies in which relatedness is a concern. BMC Genet, 12:66, 2011. (Link)
• Savic D., Distler M.G., Sokoloff G., Shanahan N.A., Dulawa S.C., Palmer A.A., and Nobrega M.A. Modulation oftcf7l2 expression alters behavior in mice. PLoS One, 6(10):e26897, 2011. (Link)
• Palmer A.A. and de Wit H. Translational genetic approaches to substance use disorders: bridging the gap between mice and humans. Hum Genet, Dec 2011. (Link)
• Bryant C.D., Parker C.C., Zhou L., Olker C., Chandrasekaran R.Y., Wager T.T., Bolivar V.J., Loudon A.S., Vitaterna M.H., Turek F.W., and Palmer A.A. Csnk1e is a genetic regulator of sensitivity to psychostimulants and opioids. Neuropsychopharmacology, Nov 2011. (Link)
• Winawer M.R., Gildersleeve S.S., Phillips A.G., Rabinowitz D., and Palmer A.A. Mapping a mouse limbic seizure susceptibility locus on chromosome 10. Epilepsia, 52(11):2076–2083, Nov 2011. (Link)
• Karst S., Cheng R., Schmitt A.O., Yang H., de Villena F.P., Palmer A.A., and Brockmann G.A. Genetic determinants for intramuscular fat content and water-holding capacity in mice selected for high muscle mass. Mamm Genome, 22(9-10):530–543, Oct 2011. (Link)
• Parker C.C., Cheng R., Sokoloff G., Lim J.E., Skol A.D., Abney M., and Palmer A.A. Fine-mapping alleles for body weight in LG/j x SM/j f and f(34) advanced intercross lines. Mamm Genome, 22(9-10):563–571, Oct 2011. (Link)
• Philip V.M., Sokoloff G., Ackert-Bicknell C.L., Striz M., Branstetter L., Beckmann M.A., Spence J.S., Jackson B.L., Galloway L.D., Barker P., Wymore A.M., Hunsicker P.R., Durtschi D.C., Shaw G.S., Shinpock S., Manly K.F., Miller D.R., Donohue K.D., Culiat C.T., Churchill G.A., Lariviere W.R., Palmer A.A., O'Hara B.F., Voy B.H., and Chesler E.J. Genetic analysis in the collaborative cross breeding population. Genome Res, 21(8):1223–1238, Aug 2011. (Link)
• Johnson L.R., McGuire J., Lazarus R., and Palmer A.A. Pavlovian fear memory circuits and phenotype models of PTSD. Neuropharmacology, Jul 2011. (Link)
• Li D., Herrera S., Bubula N., Nikitina E., Palmer A.A., Hanck D.A., Loweth J.A., and Vezina P. Casein kinase 1 enables nucleus accumbens amphetamine-induced locomotion by regulating AMPA receptor phosphorylation. J Neurochem, 118(2):237–247, Jul 2011. (Link)
• Sokoloff G., Parker C.C., Lim J.E., and Palmer A.A. Anxiety and fear in a cross of C57BL/6j and DBA/2j mice: mapping overlapping and independent QTL for related traits. Genes Brain Behav, 10(5):604–614, Jul 2011. (Link)

Reviews

Tarantino LM, Reyes TM and Palmer AA. Animal Models of Prenatal Protein Malnutrition Relevant for Schizophrenia, (Patterson, Paul, Brown, Alan, Eds.), Columbia University Press, 2010. PDF

Yang A, Palmer AA, de Wit H. Role of Genetics in Caffeine Response and Its Implications for Health, Psychopharmacology, 2010 211:245. PDF