Urban Upbringing Flips Genes’ Effects on Brain Activity
Tuesday, May 22, 2018
IRP researchers have found that being raised in a bustling metropolis changes the way certain genes affect the brain.
It might seem easy to blame your parents for the way you turned out; after all, they raised you and gave you all of your DNA. But, before throwing blame around, consider saving some for the place where you grew up. According to new IRP research, being raised in an urban environment can dramatically alter how your genes influence your brain.1
Scientists have identified a number of genes that affect the way our brains work, including some that appear to be linked to psychiatric illnesses. However, the influence of these genetic variants tends to be small, an observation known as ‘missing heritability’ because much of the variance in human traits appears to come from other, unknown sources. As a result, scientists are increasingly looking at how environmental factors like pollution and diet cooperate with genes to produce specific traits and diseases.
“Gene-environment interactions have been posited to play an important role in understanding missing heritability in disorders like schizophrenia,” says Joseph Callicott, M.D., an IRP staff clinician and the new study’s senior author. “In other words, you need to measure environmental variables and apply them to gene associations.”
One relationship that has been extensively studied is the effect of certain genes on the function of the brain’s prefrontal cortex (PFC). Much of the processing that occurs in the PFC depends on the chemical dopamine, and the way neurons in the PFC utilize dopamine is affected by variation in the COMT, DRD1, and DRD2 genes. These genes have also been linked to schizophrenia2,3, a disorder in which patients show distinct patterns of PFC activity when they perform certain tasks in functional magnetic resonance imaging (fMRI) scanners that measure neuronal activity.
Meanwhile, studies have shown that being raised in an urban environment — typically defined as an area with a population of more than 100,000 people — also influences the odds of developing schizophrenia4 and the way the PFC behaves. Consequently, Dr. Callicott and his colleagues wondered: If dopamine-related genes and an urban upbringing independently affect the PFC, might they also work together to determine the way that brain region works?
By having participants perform a PFC-based memory task in an fMRI scanner, Dr. Callicott’s team replicated prior findings showing that individuals raised in an urban environment tend to have less “efficient” prefrontal activation. In other words, urban-raised participants showed greater PFC activation compared to those raised in less populous towns or rural settings, even though they performed no better or faster on the task. This suggests their brains had to work harder to do the task as successfully as individuals raised in less populous areas, much like a gas-guzzling Hummer uses more gasoline to drive 40 miles per hour than a fuel-efficient hybrid does.
“People who are raised in an urban environment are inefficient because performance is held constant but they have to use more resources,” Dr. Callicott explains.
Even more interesting was the combined influence of participants’ dopamine-related genes and the places in which they grew up. For those raised in a town or rural area, the ‘Met’ form of the COMT1 gene was linked with greater PFC efficiency than the ‘Val’ form, but the opposite was seen in individuals raised in an urban environment. Similarly, forms of the DRD1 and DRD2 genes that were associated with greater PFC efficiency in town- or rural-raised participants were instead associated with lower efficiency in urban-raised individuals. The PFC tends to function best within a certain range of dopamine levels, so Dr. Callicott speculates that a gene variant that moves dopamine levels closer to that range when someone is raised in one environment might cause there to be too much or too little dopamine when someone is raised in a different setting.
Because PFC inefficiency is a hallmark of schizophrenia, Dr. Callicott’s findings provide a jumping-off point for future studies seeking to discern how the disorder develops. The research also highlights the importance of examining how our DNA interacts with our surroundings in order to influence our individual attributes.
“You can’t really understand the complete impact of certain genes until you figure out if they interact with environmental variables,” Dr. Callicott says, “so, in my mind, these results are really a call to collect those kinds of data.”
Subscribe to our weekly newsletter to stay up-to-date on the latest breakthroughs in the NIH Intramural Research Program.
 Interaction of childhood urbanicity and variation in dopamine genes alters adult prefrontal function as measured by functional magnetic resonance imaging. Reed JL, D'Ambrosio E, Marenco S, Ursini G, Zheutlin AB, Blasi G, Spencer BE, Romano R, Hochheiser J, Reifman A, Sturm J, Berman KF, Bertolino A, Weinberger DR, Callicott JH. PLoS One. 2018 Apr 10;13(4): e0195189. doi: 10.1371/journal.pone.0195189.
 Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Egan MF, Goldberg, TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE, et al. Proc Natl Acad Sci USA. 2001 May 29;98(12): 6917-6922. doi: 10.1073/pnas.111134598.
 Multivariate analyses suggest genetic impacts on neurocircuitry in schizophrenia. Tura E, Turner JA, Fallon JH, Kennedy JL, Potkin SG. Neuroreport. 2008 Apr 16;19(6): 603-607. doi: 10.1097/WNR.0b013e3282fa6d8d.
 Meta-analysis of the association of urbanicity with schizophrenia. Vassos E, Pedersen CB, Murray RM, Collier DA, Lewis CM. Schizophr Bull. 2012 Nov;38(6):1118-1123. doi: 10.1093/schbul/sbs096.