title: The impact of common dopamine D2 receptor gene polymorphisms on D2/3 receptor availability: C957T as a key determinant in putamen and ventral striatum.
abstract: Dopamine function is broadly implicated in multiple neuropsychiatric conditions believed to have a genetic basis. Although a few positron emission tomography (PET) studies have investigated the impact of single-nucleotide polymorphisms (SNPs) in the dopamine D2 receptor gene (DRD2) on D2/3 receptor availability (binding potential, BPND), these studies have often been limited by small sample size. Furthermore, the most commonly studied SNP in D2/3 BPND(Taq1A) is not located in the DRD2 gene itself, suggesting that its linkage with other DRD2 SNPs may explain previous PET findings. Here, in the largest PET genetic study to date (n=84), we tested for effects of the C957T and -141C Ins/Del SNPs (located within DRD2) as well as Taq1A on BPNDof the high-affinity D2 receptor tracer18F-Fallypride. In a whole-brain voxelwise analysis, we found a positive linear effect of C957T T allele status on striatal BPNDbilaterally. The multilocus genetic scores containing C957T and one or both of the other SNPs produced qualitatively similar striatal results to C957T alone. The number of C957T T alleles predicted BPNDin anatomically defined putamen and ventral striatum (but not caudate) regions of interest, suggesting some regional specificity of effects in the striatum. By contrast, no significant effects arose in cortical regions. Taken together, our data support the critical role of C957T in striatal D2/3 receptor availability. This work has implications for a number of psychiatric conditions in which dopamine signaling and variation in C957T status have been implicated, including schizophrenia and substance use disorders.
authors.affiliation: Department of Psychology, Vanderbilt University, Nashville, TN, USA.
authors.forename: C T
authors.initials: CT
authors.lastname: Smith
authors.affiliation: Department of Psychology, Vanderbilt University, Nashville, TN, USA.
authors.forename: L C
authors.initials: LC
authors.lastname: Dang
authors.affiliation: Department of Psychology, Harvard University, Cambridge, MA, USA.|Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Buckholtz
authors.affiliation: Department of Psychology, Vanderbilt University, Nashville, TN, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Tetreault
authors.affiliation: Department of Psychology, Vanderbilt University, Nashville, TN, USA.|Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Cowan
authors.affiliation: Department of Radiology, UAB School of Medicine, Birmingham, AL, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Kessler
authors.affiliation: Department of Psychology, Vanderbilt University, Nashville, TN, USA.|Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: D H
authors.initials: DH
authors.lastname: Zald
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D001549:Benzamides; D004298:Dopamine / Q000502:physiology; D005260:Female; D005462:Fluorine Radioisotopes; D033141:Genetic Determinism; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D049268:Positron-Emission Tomography; D011699:Putamen / Q000000981:diagnostic imaging / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000235:genetics* / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D066328:Ventral Striatum / Q000000981:diagnostic imaging / Q000378:metabolism*; D055815:Young Adult
chemical_list: D001549:Benzamides; C581293:DRD2 protein, human; C493593:DRD3 protein, human; D005462:Fluorine Radioisotopes; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C574003:fallypride; C000615276:Fluorine-18; D004298:Dopamine