Interaction of childhood urbanicity and variation in dopamine genes alters adult prefrontal function as measured by functional magnetic resonance imaging (fMRI)

PLoS One. 2018 Apr 10;13(4):e0195189. doi: 10.1371/journal.pone.0195189. eCollection 2018.


Brain phenotypes showing environmental influence may help clarify unexplained associations between urban exposure and psychiatric risk. Heritable prefrontal fMRI activation during working memory (WM) is such a phenotype. We hypothesized that urban upbringing (childhood urbanicity) would alter this phenotype and interact with dopamine genes that regulate prefrontal function during WM. Further, dopamine has been hypothesized to mediate urban-associated factors like social stress. WM-related prefrontal function was tested for main effects of urbanicity, main effects of three dopamine genes-catechol-O-methyltransferase (COMT), dopamine receptor D1 (DRD1), and dopamine receptor D2 (DRD2)-and, importantly, dopamine gene-by-urbanicity interactions. For COMT, three independent human samples were recruited (total n = 487). We also studied 253 subjects genotyped for DRD1 and DRD2. 3T fMRI activation during the N-back WM task was the dependent variable, while childhood urbanicity, dopamine genotype, and urbanicity-dopamine interactions were independent variables. Main effects of dopamine genes and of urbanicity were found. Individuals raised in an urban environment showed altered prefrontal activation relative to those raised in rural or town settings. For each gene, dopamine genotype-by-urbanicity interactions were shown in prefrontal cortex-COMT replicated twice in two independent samples. An urban childhood upbringing altered prefrontal function and interacted with each gene to alter genotype-phenotype relationships. Gene-environment interactions between multiple dopamine genes and urban upbringing suggest that neural effects of developmental environmental exposure could mediate, at least partially, increased risk for psychiatric illness in urban environments via dopamine genes expressed into adulthood.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Brain / diagnostic imaging*
  • Brain Mapping
  • Catechol O-Methyltransferase / genetics*
  • Child
  • Dopamine / physiology
  • Female
  • Gene-Environment Interaction
  • Genotype
  • Humans
  • Intelligence Tests
  • Italy
  • Magnetic Resonance Imaging
  • Male
  • Memory, Short-Term
  • Phenotype
  • Prefrontal Cortex / diagnostic imaging*
  • Receptors, Dopamine D1 / genetics*
  • Receptors, Dopamine D2 / genetics*
  • Social Behavior
  • Social Class
  • United States
  • Urban Population*


  • DRD1 protein, human
  • DRD2 protein, human
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • COMT protein, human
  • Catechol O-Methyltransferase
  • Dopamine

Grant support

This work was funded as part of the Division of Intramural Research Program of the National Institute of Mental Health and the Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs of University of Bari Aldo Moro. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.