Newly Identified Genes Linking Environment to Risk of Anxiety Disorders
Madison, Wisconsin - A genome-wide study in young primates with anxious temperament has yielded two candidate genes that may convey the effects of environmental experience on developmental brain alterations that underlie the childhood risk to develop anxiety and depressive disorders.
In a study published this week in the Journal of Neuroscience, Dr. Reid Alisch, Dr. Ned Kalin, and collaborators identify a number of genes that are different in the brains of anxious young monkeys, two of which are particularly interesting.
In the anxious monkeys, these genes show the addition of a methyl group – called DNA methylation – which turns genes on or off and is a mark of an epigenetic change that is often caused by environmental stimuli. The methylation pattern of these genes may have been changed by environmental stimuli in early life or could have been passed down by previous generations of anxious monkeys.
Because these genes regulate neural development, methylation related changes in their activity may help explain the overactivity of specific brain regions that in previous work by Kalin’s lab have been identified to underlie the early childhood risk to develop anxiety and depression.
It is well known that early life stress is a risk factor for the later development of anxiety and depressive disorders. “This could explain how early environmental events can influence some primates to display an anxious temperament early in life,” says Alisch, assistant professor of psychiatry in the University of Wisconsin School of Medicine and Public Health.
To do the study, Alisch relied on earlier studies by senior author Dr. Ned Kalin, chair of psychiatry, which showed that anxious young monkeys have differences in the brain circuits that comprise the amygdala. The amygdala is important in the adaptive response to fear and its level of activity differs from individual to individual.
Kalin’s lab determined that anxious young monkeys have increased amygdala activity, which in large part seems to be determined by environmental factors. Young monkeys are a well-established model for anxiety in children because of their similar brain development and social behaviors.
Alisch specifically used tissue from the central nucleus of the amygdala, a region of the brain important in fear response and anxiety. The brain tissue came from 23 young rhesus monkeys with a range of anxious temperament levels. Alisch was trying to find the epigenotype that underlies the anxious temperament phenotype and to search for changes in the function of amygdala genes that may have been brought about by the environment.
Researchers analyzed the entire genome for genes in the central nucleus of the amygdala that had been changed by the addition or subtraction of a methyl group. Initially, the study yielded 1,363 genes with methylation patterns associated with anxious temperament, many of them clustered on chromosomes one and 19.
They narrowed this list of genes down to 22 genes that had methylation changes correlated to the expression level of each gene. Of these twenty-two genes, BCL11A and JAG1 are among the most interesting in thinking about how environmental factors might influence the development of a vulnerable brain.
“This finding gives us two really good candidates for follow-up work in both monkeys and humans,” Alisch says. “This could lead to earlier diagnosis and a target for treatment that ultimately could prevent children with an extreme anxious temperament from developing full blown anxiety and depression.”
A next step is to see if the methylation differences found also are evident in blood samples collected from monkeys and humans, Alisch says, which could lead to a blood test for early identification of youngsters who have a molecular risk to develop anxiety and depressive disorders.
“Anxiety and depressive disorders are among the most common of all illnesses that result in marked disability, medical morbidity, and tragically suicide,” says Kalin, a clinician and neuroscientist. “They frequently begin early in life and with the current findings from primate studies we now have clues about which genes might be the best targets for designing interventions aimed at disrupting the marked negative impact of childhood trauma and adversity on the later development of stress-related psychopathology.”
Other researchers on the study include Andrew Fox, Kailei Chen, Andrew White, Patrick Roseboom and Sunduz Keles of the University of Wisconsin-Madison, and Pankaj Chopra of Emory University. The work was supported by grants from the Conti Center, the National Institutes of Health and the UW Department of Psychiatry.
Date Published: 11/21/2014