title: Dopamine transporter gene susceptibility to methylation is associated with impulsivity in nonhuman primates.
abstract: Impulsivity, the predisposition to act without regard for negative consequences, is a characteristic of several psychiatric disorders and is thought to result in part from genetic variation in the untranslated region of the dopamine transporter (DAT) gene. As the exact link between genetic mutations and impulsivity has not been established, we used oculomotor behavior to characterize rhesus monkeys as impulsive or calm and genetic/epigenetic analysis and positron emission tomography (PET) to correlate phenotype to DAT genotype, DAT gene methylation, and DAT availability. We found three single nucleotide polymorphisms (SNPs) in the 3'-UTR of the DAT gene, one of which provided a potential site for methylation in the impulsive group. Bisulfite analysis showed that the DNA of the impulsive but not the calm subjects was methylated at one SNP. Because genetic/epigenetic modifications could lead to differences in protein expression, we measured DAT availability using [(18)F]2β-carbomethoxy-3β-(4-chlorophenyl)-8-(2-fluoroethyl)-nortropane ([(18)F]FECNT) PET and found higher DAT availability in the internal globus pallidus, an output nucleus of the basal ganglia, of the impulsive group. Higher DAT availability lowers dopamine levels, potentially altering neuronal circuits involved in the initiation of action, thus contributing to the impulsive phenotype. The association between increased methylation in the DAT gene and greater DAT availability suggests that mutations to the regulatory portion of the DAT gene lead to a susceptibility to epigenetic modification resulting in a discrete behavioral phenotype.
authors.affiliation: Neuroscience Training Program, University of Wisconsin-Madison, Madison, Wisconsin;
authors.forename: Abigail Z
authors.initials: AZ
authors.lastname: Rajala
authors.affiliation: Department of Neuroscience, University of Wisconsin-Madison, Madison, Wisconsin;
authors.forename: Ismail
authors.initials: I
authors.lastname: Zaitoun
authors.affiliation: Department of Psychology, University of Wisconsin-Madison, Madison, Wisconsin;
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Henriques
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin;
authors.forename: Alexander K
authors.initials: AK
authors.lastname: Converse
authors.affiliation: Department of Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin; and.
authors.forename: Dhanabalan
authors.initials: D
authors.lastname: Murali
authors.affiliation: Department of Neuroscience, University of Wisconsin-Madison, Madison, Wisconsin;
authors.forename: Miles L
authors.initials: ML
authors.lastname: Epstein
authors.affiliation: Neuroscience Training Program, University of Wisconsin-Madison, Madison, Wisconsin; Department of Neuroscience, University of Wisconsin-Madison, Madison, Wisconsin; Department of Psychology, University of Wisconsin-Madison, Madison, Wisconsin; McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, Wisconsin lpopulin@wisc.edu.
authors.forename: Luis C
authors.initials: LC
authors.lastname: Populin
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D019175:DNA Methylation; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D005917:Globus Pallidus / Q000000981:diagnostic imaging / Q000378:metabolism; D007175:Impulsive Behavior; D008253:Macaca mulatta; D008297:Male; D009662:Nortropanes / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000494:pharmacology
chemical_list: C410211:2-carbomethoxy-3-(4-chlorophenyl)-8-(2-fluoroethyl)nortropane; D020413:3' Untranslated Regions; D050483:Dopamine Plasma Membrane Transport Proteins; D009662:Nortropanes; D019275:Radiopharmaceuticals
keywords: dopamine transporter; epigenetics; impulsivity; methylation; monkey