title: Common Variation in the DOPA Decarboxylase (DDC) Gene and Human Striatal DDC Activity In Vivo.
abstract: The synthesis of multiple amine neurotransmitters, such as dopamine, norepinephrine, serotonin, and trace amines, relies in part on DOPA decarboxylase (DDC, AADC), an enzyme that is required for normative neural operations. Because rare, loss-of-function mutations in the DDC gene result in severe enzymatic deficiency and devastating autonomic, motor, and cognitive impairment, DDC common genetic polymorphisms have been proposed as a source of more moderate, but clinically important, alterations in DDC function that may contribute to risk, course, or treatment response in complex, heritable neuropsychiatric illnesses. However, a direct link between common genetic variation in DDC and DDC activity in the living human brain has never been established. We therefore tested for this association by conducting extensive genotyping across the DDC gene in a large cohort of 120 healthy individuals, for whom DDC activity was then quantified with [(18)F]-FDOPA positron emission tomography (PET). The specific uptake constant, Ki, a measure of DDC activity, was estimated for striatal regions of interest and found to be predicted by one of five tested haplotypes, particularly in the ventral striatum. These data provide evidence for cis-acting, functional common polymorphisms in the DDC gene and support future work to determine whether such variation might meaningfully contribute to DDC-mediated neural processes relevant to neuropsychiatric illness and treatment.
authors.affiliation: Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, NIH, DHHS, Bethesda, MD, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Eisenberg
authors.affiliation: Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, NIH, DHHS, Bethesda, MD, USA.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Kohn
authors.affiliation: Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, NIH, DHHS, Bethesda, MD, USA.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Hegarty
authors.affiliation: Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, NIH, DHHS, Bethesda, MD, USA.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Ianni
authors.affiliation: Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, NIH, DHHS, Bethesda, MD, USA.
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Kolachana
authors.affiliation: Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, NIH, DHHS, Bethesda, MD, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Gregory
authors.affiliation: Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, NIH, DHHS, Bethesda, MD, USA.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Masdeu
authors.affiliation: Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, NIH, DHHS, Bethesda, MD, USA.
authors.forename: Karen F
authors.initials: KF
authors.lastname: Berman
mesh_terms: D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging / Q000201:enzymology; D004296:Dopa Decarboxylase / Q000235:genetics* / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D005260:Female; D019788:Fluorodeoxyglucose F18; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D049268:Positron-Emission Tomography; D066328:Ventral Striatum / Q000000981:diagnostic imaging / Q000201:enzymology*; D055815:Young Adult
chemical_list: D019788:Fluorodeoxyglucose F18; D004296:Dopa Decarboxylase; D004298:Dopamine