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

Candidate gene studies of a promising intermediate phenotype: failure to replicate.

Hart AB, de Wit H, Palmer AA

(Apr 2013) Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 38(5):802-16 PMID:23303064

A simulation study of permutation, bootstrap, and gene dropping for assessing statistical significance in the case of unequal relatedness.

Cheng R, Palmer AA

(Mar 2013) Genetics 193(3):1015-8 PMID:23267053 (Full Text)

Psychopharmacology of theobromine in healthy volunteers.

Baggott MJ, Childs E, Hart AB, de Bruin E, Palmer AA, Wilkinson JE, de Wit H

(Feb 2013) Psychopharmacology PMID:23420115

Does COMT genotype influence the effects of d-amphetamine on executive functioning?

Wardle MC, Hart AB, Palmer AA, de Wit H

(Feb 2013) Genes, brain, and behavior 12(1):13-20 PMID:23231539 (Full Text)

Glyoxalase 1 and its substrate methylglyoxal are novel regulators of seizure susceptibility.

Distler MG, Gorfinkle N, Papale LA, Wuenschell GE, Termini J, Escayg A, Winawer MR, Palmer AA

(Feb 2013) Epilepsia PMID:23409935

Congenic dissection of a major QTL for methamphetamine sensitivity implicates epistasis.

Bryant CD, Kole LA, Guido MA, Sokoloff G, Palmer AA

(Jul 2012) Genes, brain, and behavior 11(5):623-32 PMID:22487465

Glyoxalase 1 increases anxiety by reducing GABAA receptor agonist methylglyoxal.

Distler MG, Plant LD, Sokoloff G, Hawk AJ, Aneas I, Wuenschell GE, Termini J, Meredith SC, Nobrega MA, Palmer AA

(Jun 2012) The Journal of clinical investigation 122(6):2306-15 PMID:22585572 (Full Text)

QTLs for murine red blood cell parameters in LG/J and SM/J F(2) and advanced intercross lines.

Bartnikas TB, Parker CC, Cheng R, Campagna DR, Lim JE, Palmer AA, Fleming MD

(Jun 2012) Mammalian genome : official journal of the International Mammalian Genome Society 23(5-6):356-66 PMID:22322356 (Full Text)

Translational genetic approaches to substance use disorders: bridging the gap between mice and humans.

Palmer AA, de Wit H

(Jun 2012) Human genetics 131(6):931-9 PMID:22170288 (Full Text)

Genome-wide association for fear conditioning in an advanced intercross mouse line.

Parker CC, Sokoloff G, Cheng R, Palmer AA

(May 2012) Behavior genetics 42(3):437-48 PMID:22237917 (Full Text)

Csnk1e is a genetic regulator of sensitivity to psychostimulants and opioids.

Bryant CD, Parker CC, Zhou L, Olker C, Chandrasekaran RY, Wager TT, Bolivar VJ, Loudon AS, Vitaterna MH, Turek FW, Palmer AA

(Mar 2012) Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 37(4):1026-35 PMID:22089318 (Full Text)

High-resolution genetic mapping using the Mouse Diversity outbred population.

Svenson KL, Gatti DM, Valdar W, Welsh CE, Cheng R, Chesler EJ, Palmer AA, McMillan L, Churchill GA

(Feb 2012) Genetics 190(2):437-47 PMID:22345611 (Full Text)

Pavlovian fear memory circuits and phenotype models of PTSD.

Johnson LR, McGuire J, Lazarus R, Palmer AA

(Feb 2012) Neuropharmacology 62(2):638-46 PMID:21782833

Genome-wide association for methamphetamine sensitivity in an advanced intercross mouse line.

Parker CC, Cheng R, Sokoloff G, Palmer AA

(Feb 2012) Genes, brain, and behavior 11(1):52-61 PMID:22032291 (Full Text)

Genome-wide association study of d-amphetamine response in healthy volunteers identifies putative associations, including cadherin 13 (CDH13).

Hart AB, Engelhardt BE, Wardle MC, Sokoloff G, Stephens M, de Wit H, Palmer AA

(2012) PloS one 7(8):e42646 PMID:22952603 (Full Text)

Role of Glyoxalase 1 (Glo1) and methylglyoxal (MG) in behavior: recent advances and mechanistic insights.

Distler MG, Palmer AA

(2012) Frontiers in genetics 3:250 PMID:23181072 (Full Text)

Methamphetamine-induced conditioned place preference in LG/J and SM/J mouse strains and an F45/F46 advanced intercross line.

Bryant CD, Kole LA, Guido MA, Cheng R, Palmer AA

(2012) Frontiers in genetics 3:126 PMID:22798962 (Full Text)

Assessment of behaviors modeling aspects of schizophrenia in Csmd1 mutant mice.

Distler MG, Opal MD, Dulawa SC, Palmer AA

(2012) PloS one 7(12):e51235 PMID:23284669 (Full Text)

Mapping a mouse limbic seizure susceptibility locus on chromosome 10.

Winawer MR, Gildersleeve SS, Phillips AG, Rabinowitz D, Palmer AA

(Nov 2011) Epilepsia 52(11):2076-83 PMID:21906048 (Full Text)

Genetic determinants for intramuscular fat content and water-holding capacity in mice selected for high muscle mass.

Kärst S, Cheng R, Schmitt AO, Yang H, de Villena FP, Palmer AA, Brockmann GA

(Oct 2011) Mammalian genome : official journal of the International Mammalian Genome Society 22(9-10):530-43 PMID:21732194 (Full Text)

Fine-mapping alleles for body weight in LG/J × SM/J F₂ and F(34) advanced intercross lines.

Parker CC, Cheng R, Sokoloff G, Lim JE, Skol AD, Abney M, Palmer AA

(Oct 2011) Mammalian genome : official journal of the International Mammalian Genome Society 22(9-10):563-71 PMID:21761260 (Full Text)

Genetic analysis in the Collaborative Cross breeding population.

Philip VM, Sokoloff G, Ackert-Bicknell CL, Striz M, Branstetter L, Beckmann MA, Spence JS, Jackson BL, Galloway LD, Barker P, Wymore AM, Hunsicker PR, Durtschi DC, Shaw GS, Shinpock S, Manly KF, Miller DR, Donohue KD, Culiat CT, Churchill GA, Lariviere WR, Palmer AA, O'Hara BF, Voy BH, Chesler EJ

(Aug 2011) Genome research 21(8):1223-38 PMID:21734011 (Full Text)

Anxiety and fear in a cross of C57BL/6J and DBA/2J mice: mapping overlapping and independent QTL for related traits.

Sokoloff G, Parker CC, Lim JE, Palmer AA

(Jul 2011) Genes, brain, and behavior 10(5):604-14 PMID:21554534

Casein kinase 1 enables nucleus accumbens amphetamine-induced locomotion by regulating AMPA receptor phosphorylation.

Li D, Herrera S, Bubula N, Nikitina E, Palmer AA, Hanck DA, Loweth JA, Vezina P

(Jul 2011) Journal of neurochemistry 118(2):237-47 PMID:21564097 (Full Text)

OPRM1 gene variants modulate amphetamine-induced euphoria in humans.

Dlugos AM, Hamidovic A, Hodgkinson C, Shen PH, Goldman D, Palmer AA, de Wit H

(Mar 2011) Genes, brain, and behavior 10(2):199-209 PMID:21029375 (Full Text)

Distinct genetic regions modify specific muscle groups in muscular dystrophy.

Swaggart KA, Heydemann A, Palmer AA, McNally EM

(Jan 2011) Physiological genomics 43(1):24-31 PMID:20959497 (Full Text)

Dark matter: are mice the solution to missing heritability?

Parker CC, Palmer AA

(2011) Frontiers in genetics 2:32 PMID:22303328 (Full Text)

QTL Analysis of Type I and Type IIA Fibers in Soleus Muscle in a Cross between LG/J and SM/J Mouse Strains.

Carroll AM, Palmer AA, Lionikas A

(2011) Frontiers in genetics 2:99 PMID:22303393 (Full Text)

QTLRel: an R package for genome-wide association studies in which relatedness is a concern.

Cheng R, Abney M, Palmer AA, Skol AD

(2011) BMC genetics 12:66 PMID:21794153 (Full Text)

Modulation ofTcf7l2 expression alters behavior in mice.

Savic D, Distler MG, Sokoloff G, Shanahan NA, Dulawa SC, Palmer AA, Nobrega MA

(2011) PloS one 6(10):e26897 PMID:22046400 (Full Text)

Animal Models of Prenatal Protein Malnutrition Relevant for Schizophrenia(Patterson, Paul, Brown, Alan, Eds.)

Tarantino LM, Reyes TM, Palmer AA.

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Role of Genetics in Caffeine Response and Its Implications for Health

Yang A, Palmer AA, de Wit H.

(2010) 211:245. Psychopharmacology (PDF)

More on ADORA.

Yang A, Childs E, Palmer AA, de Wit H

(Dec 2010) Psychopharmacology 212(4):699-700 PMID:20802997

Fine mapping of QTL for prepulse inhibition in LG/J and SM/J mice using F(2) and advanced intercross lines.

Samocha KE, Lim JE, Cheng R, Sokoloff G, Palmer AA

(Oct 2010) Genes, brain, and behavior 9(7):759-67 PMID:20597988

Fine-mapping of muscle weight QTL in LG/J and SM/J intercrosses.

Lionikas A, Cheng R, Lim JE, Palmer AA, Blizard DA

(Sep 2010) Physiological genomics 42A(1):33-8 PMID:20627939 (Full Text)

Genetics of caffeine consumption and responses to caffeine.

Yang A, Palmer AA, de Wit H

(Aug 2010) Psychopharmacology 211(3):245-57 PMID:20532872

Genome-wide association studies and the problem of relatedness among advanced intercross lines and other highly recombinant populations.

Cheng R, Lim JE, Samocha KE, Sokoloff G, Abney M, Skol AD, Palmer AA

(Jul 2010) Genetics 185(3):1033-44 PMID:20439773 (Full Text)

Catechol-O-methyltransferase val158met genotype modulates sustained attention in both the drug-free state and in response to amphetamine.

Hamidovic A, Dlugos A, Palmer AA, de Wit H

(Jun 2010) Psychiatric genetics 20(3):85-92 PMID:20414144 (Full Text)

Differences in aggressive behavior and DNA copy number variants between BALB/cJ and BALB/cByJ substrains.

Velez L, Sokoloff G, Miczek KA, Palmer AA, Dulawa SC

(Mar 2010) Behavior genetics 40(2):201-10 PMID:20033273

Polymorphisms in dopamine transporter (SLC6A3) are associated with stimulant effects of D-amphetamine: an exploratory pharmacogenetic study using healthy volunteers.

Hamidovic A, Dlugos A, Palmer AA, de Wit H

(Mar 2010) Behavior genetics 40(2):255-61 PMID:20091113

Are attention lapses related to d-amphetamine liking?

McCloskey M, Palmer AA, de Wit H

(Feb 2010) Psychopharmacology 208(2):201-9 PMID:19936714

More aroused, less fatigued: fatty acid amide hydrolase gene polymorphisms influence acute response to amphetamine.

Dlugos AM, Hamidovic A, Hodgkinson CA, Goldman D, Palmer AA, de Wit H

(Feb 2010) Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 35(3):613-22 PMID:19890266 (Full Text)

Murine Warriors or Worriers: The Saga of Comt1, B2 SINE Elements, and the Future of Translational Genetics.

Palmer AA, Dulawa SC

(2010) Frontiers in neuroscience 4:177 PMID:20976038 (Full Text)