Genetic Risk for Psychiatric Disease Observed Early in Development


by Kayt Sukel

February 14, 2013

In the past few years, research into the origin and development of neuropsychiatric and neurodegenerative disorders has prompted doctors to rethink the best time to intervene. Instead of waiting for symptoms to show, they are seeking  to, wherever possible, prevent the start of the disease process. But a recent study by researchers at the University of North Carolina (UNC) suggests that clinicians may have to go back even further in life to successfully minister to these diseases, as many genetic variants and brain structure changes associated with disorders such as Alzheimer’s disease and schizophrenia can be observed even in newborns.

Going back in time

There is a great deal of evidence to suggest that prenatal, perinatal, and early childhood brain development is abnormal in people with schizophrenia. John Gilmore, a psychiatrist at the University of North Carolina, says that his interest in understanding the etiology of schizophrenia in young children led to a desire to better understand how genetic factors may be going awry in normal brain development.

“As we’ve learned more about schizophrenia, we keep moving further and further back into development. There’s been a lot of interest in treating 'first episode' patients and then even before the first episode, in prodromal phases,” he says. “But what we’re realizing is that if we want to make a real difference, we may have to intervene much, much earlier in life.”

To better understand where in the brain development timeline these disorders might take hold, Gilmore and fellow UNC researcher Rebecca Knickmeyer looked at whether genetic polymorphisms linked to diseases might show observable brain differences in neonates. Gilmore, Knickmeyer, and colleagues selected 10 versions of 7 genes, including several gene variants linked to schizophrenia as well as the ε4 version of the ApoE gene, a risk factor for Alzheimer’s.

“We’re not exactly sure why, but the ε4 variant of the ApoE gene, a gene that codes for the protein Apolipoprotein E, is a huge risk factor in any sort of situation where the brain sustains an insult or damage,” says Fiona Crawford, a neuroscientist at the Roskamp Institute who studies ApoE. “In Alzheimer’s disease, traumatic brain injury, or stroke, having the ε4 version not only increases your risk for those conditions dramatically but also increases your risk of a poor outcome once diagnosed.”

Looking for structure changes

Knickmeyer says that the ε4 variant is the best-replicated gene association seen in neurological disease—and, like the other genes selected, plays an important regulatory role in brain development.

“These genes all affect normal development, beyond being associated with disease,” he says. “But we chose this set also based on the fact that these genes are often related to a specific brain imaging genotype in older individuals.”  For example, ApoE ε4 has been linked to reduced volume in the medial temporal lobe in the elderly.

Gilmore, Knickmeyer, and colleagues used high resolution functional magnetic resonance imaging (fMRI) to scan the brains of 272 newborns, and also ran genetic profiles on the infants. They found associations between disease-related brain structure changes to gene variants like the rs821616 polymorphism of the gene DISC1 and the ε4 variant of ApoE. For example, DISC1’s rs821616 was linked to decreased volume in the frontal lobe and in the lateral temporal cortex in infants—the same type of brain structure differences seen in adults. Similarly, the ε4 variant of ApoE showed the reduced volume in the medial temporal lobe as observed in the elderly. The results were published in the Jan. 3 issue of Cerebral Cortex.

“The results were quite a surprise. You might think that these genes would change progression over development as they interact with the environment,” says Knickmeyer. “You might not expect to see the same brain changes in an infant that you see in an elderly person. It suggests there’s a heightened degree of stability in some of these relationships.”

But not all of the genes examined in this study showed the same brain associations. The rs6675281 variant of the DISC1 gene was not linked to a brain change in the newborns. Gilmore says that this suggests that not all risk genes may be activated on the same timeline—and there’s a lot more to understand about how—and when—they influence brain development.

Moving forward

Gilmore cautions that the development of any neuropsychiatric or neurodegenerative disorder is likely due to multiple genes. Yet this study suggests that it may be possible to prevent disorders like schizophrenia or Alzheimer’s in the future by focusing on early brain development.

Gilmore and Knickmeyer plan to follow the 272 infants in a longitudinal study and continue to track brain development, behavioral outcomes, fine motor skills, working memory, and language skills. Knickmeyer hopes that this emphasis on early development will provide new clues into the biological mechanisms behind neuropsychiatric disease and where clinicians can best intervene in the future.

Yet Gilmore cautions this study is just the first step in understanding how multiple genetic risk factors interact with each other through the course of brain development—and how that leads to an increased risk for neuropsychiatric disease.

The contribution of each of these risk genes is very small. They all have very small effects,” says Gilmore. “But if you could identify developmental mechanisms that multiple genes contribute to, the processes behind that abnormal development, you might be able to change that developmental trajectory—and prevent the disease.”