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.

Trial registration: ClinicalTrials.gov NCT00024622.

Figures

Figure 1

DDC haplotype 4 effects. The graph shows region of interest (ROI) analyses with mean DDC activity values and standard errors for each ROI by haplotype 4 status. Multivariate Pillai's trace=0.1; F(3, 116)=4.31; p=0.006. Asterisks indicate p<0.05 for univariate comparisons. Coronal slices show results of post hoc voxel-wise analysis indicating locations of DDC effects in the striatum (at MNI Y=9 for ventral striatum and Y=−6 for caudate). Colored clusters represent areas where more copies of the DDC haplotype predicted greater DDC activity. Color bar indicates t-values, and data are displayed by radiological convention at a voxel-wise, uncorrected threshold of p<0.005.