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

• Published in: PloS one Vol. 13; no. 4; p. e0195189
• Main Authors: Reed, Jessica L., D’Ambrosio, Enrico, Marenco, Stefano, Ursini, Gianluca, Zheutlin, Amanda B., Blasi, Giuseppe, Spencer, Barbara E., Romano, Raffaella, Hochheiser, Jesse, Reifman, Ann, Sturm, Justin, Berman, Karen F., Bertolino, Alessandro, Weinberger, Daniel R., Callicott, Joseph H.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 10.04.2018; Public Library of Science (PLoS)
• Subjects: Activation; Adult; Adults; Biology and Life Sciences; Brain; Brain - diagnostic imaging; Brain Mapping; Catechin; Catechol; Catechol O-methyltransferase; Catechol O-Methyltransferase - genetics; Child; Childhood; Children; Cognition & reasoning; Dependent variables; Dopamine; Dopamine - physiology; Dopamine D1 receptors; Dopamine D2 receptors; Dopamine receptors; Ecological risk assessment; Ecology and Environmental Sciences; Environmental effects; Exposure; Female; Functional magnetic resonance imaging; Gene-Environment Interaction; Genes; Genomics; Genotype; Genotype-environment interactions; Genotypes; Humans; Independent variables; Intelligence Tests; Italy; Magnetic resonance; Magnetic Resonance Imaging; Male; Medicine and Health Sciences; Memory, Short-Term; Mental health; Meta-analysis; Methyltransferase; Neuroimaging; Neurosciences; NMR; Nuclear magnetic resonance; People and Places; Phenotype; Phenotypes; Physical Sciences; Population; Prefrontal cortex; Prefrontal Cortex - diagnostic imaging; Psychiatry; Receptors, Dopamine D1 - genetics; Receptors, Dopamine D2 - genetics; Research and Analysis Methods; Rural environments; Schizophrenia; Short term memory; Social Behavior; Social Class; Social interactions; Stress; Studies; United States; Urban areas; Urban environment; Urban environments; Urban Population; Italy; United States > US; Maryland; Baltimore Maryland
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0195189

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.