Genetics Play a Role in Social Anxiety Disorder, Study Finds

The serotonin transporter gene “SLC6A4” is linked to social anxiety disorder.

Researchers at the Institute of Human Genetics at the University of Bonn in Germany recently discovered that a specific serotonin transporter gene called “SLC6A4” is strongly correlated with someone's odds of suffering from social anxiety disorder (SAD). The initial findings of this research were published online ahead of print March 9 in the journal Psychiatric Genetics.

Social anxiety disorder (or social phobia) is a common and heritable psychiatric disorder that is driven by a combination of genetic and environmental factors. Until now, genetic studies on SAD have been rare. According to the researchers, "This is the largest association study so far into social phobia."
For this study the German’s researcher genotyped 321 patients with SAD and 804 controls without social phobia. Then, they carried out a single-marker analysis to identify a quantitative association between SAD and avoidance behaviors. Their results provide evidence that the serotonin transporter gene SLC6A4 is frequently correlated with anxiety-related traits.

Notably, selective-serotonin reuptake inhibitors (SSRIs) are often prescribed to treat depression and anxiety disorders. SSRIs are believed to target the serotonin transporter gene SLC6A4.



People with social anxiety tend to avoid larger groups and situations in which they fearbeing judged by others. SAD is marked by symptoms such as increased heart rate, sweaty palms, shakiness, shortness of breath, etc.

The physiological discomfort of social anxiety reinforces avoidance behaviors and a withdrawal from face-to-face social contact. The fear of social encounters can lead to isolation and loneliness that snowballs. Unfortunately, people with social anxiety who rely excessively on social media to maintain a sense of connectedness may actually exacerbate their feelings of perceived social isolation, according to a recent study by researchers at the University of Pittsburgh, School of Medicine.

In 1948, when Maurice M. Rapport first isolated the chemical serotonin (5-hydroxytryptamine, 5-HT) in the human body and brain, serotonin was initially classified as a “serum agent that affected vascular tone.” Today, serotonin is commonly viewed as a neurotransmitter that helps to maintain mood balance.

Although there is a strong link between serotonin, depression, and social anxiety disorders; scientists remain uncertain about which comes first in terms of driving the correlation vs. causation dynamic between serotonin and psychiatric disorders. For example: Do low levels of serotonin contribute to social anxiety or does social phobia trigger a decrease in serotonin levels?

Interestingly, a 2015 study, "Serotonin Synthesis and Reuptake in Social Anxiety Disorder,“ published in JAMA Psychiatry reported that Individuals with social phobia have too much serotonin—not too little.

Surprisingly, the researchers found that the more serotonin someone with SAD self-produced, the more anxious he or she became in social situations. This raises doubt about the common assumption that selective serotonin reuptake inhibitor (SSRIs) help to lower social anxiety by keeping more serotonin in circulation.
In a statement, co-author Andreas Frick, a doctoral student at Uppsala University Department of Psychology said,



"Not only did individuals with social phobia make more serotonin than people without such a disorder, they also pump back more serotonin. We were able to show this in another group of patients using a different tracer which itself measures the pump mechanism.
We believe that this is an attempt to compensate for the excess serotonin active in transmitting signals. Serotonin can increase anxiety and not decrease it as was previously often assumed."

Taken together, all of this new research marks a significant leap forward when it comes to identifying changes in the brain's chemical messengers in people who suffer from social anxiety disorders. That said, much more research is needed to fully understand the enigmatic and complex workings of serotonin and transporter gene SLC6A4.

"There is still a great deal to be done in terms of researching the genetic causes of this illness," Andreas Forstner from the Institute of Human Genetics at the University of Bonn concluded.

If you would like to get involved in the genetic research on social anxiety disorder, Forstner and colleagues are encouraging the general public to participate in their research online by visiting their website: Social Phobia Research. The more people that get involved in the study of social anxiety disorder, serotonin, and SLC6A4, the more precisely the researchers will be able to decode these complex mechanisms.
References: Psychology Today
Andreas J. Forstner, Stefanie Rambau, Nina Friedrich, Kerstin U. Ludwig, Anne C. Böhmer, Elisabeth Mangold, Anna Maaser, Timo Hess, Alexandra Kleiman, Antje Bittner, Markus M. Nöthen, Jessica Becker, Franziska Geiser, Johannes Schumacher, Rupert Conrad.

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New roots discovered in the psychiatric field

Newborns whose mothers were exposed during pregnancy to any one of a variety of environmental stressors — such as trauma, illness, and alcohol or drug abuse — become susceptible to various psychiatric disorders that frequently arise later in life. However, it has been unclear how these stressors affect the cells of the developing brain prenatally and give rise to conditions such as schizophrenia, post-traumatic stress disorder, and some forms of autism and bipolar disorders.

*Important Note: The research is in press, corrected proof. Please see below for more information.*

Now, Yale University researchers have identified a single molecular mechanism in the developing brain that sheds light on how cells may go awry when exposed to a variety of different environmental insults. The findings, to be published in the May 7 issue of the journal Neuron, suggest that different types of stressors prenatally activate a single molecular trigger in brain cells that may make exposed individuals susceptible to late-onset neuropsychiatric disorders.

The researchers found that mouse embryos exposed to alcohol, methyl-mercury, or maternal seizures all activate in the developing brain cells a single gene — HSF1 or heat shock factor — which protects and enables some of the brain cells to survive prenatal insult. Mice lacking the HSF1 gene showed structural brain abnormalities and were prone to seizures after birth, even after exposure to very low levels of the toxins.

In addition, researchers created stem cells — which are capable of becoming many different tissue types, including neurons — from biopsies of individuals diagnosed with schizophrenia. Genes from these “schizophrenic” stem cells responded more dramatically when exposed to environmental insults than stem cells obtained from non-schizophrenic individuals. The findings provide support to the thesis that stress induces vulnerable cells to malfunction.

“It appears that different types of environmental stressors can trigger the same condition if they occur at the same period of prenatal development,” said Yale’s Pasko Rakic, senior author of the study. “Conversely, the same environmental stressor may cause different pathologies, if it occurs at different times during pregnancy.”

Since HSF1 activation can potentially serve as a permanent marker of the stressed/damaged cell, it opens the possibility of identifying these cells in adults in order to explore the pathogenesis of postnatal disorders and how to protect vulnerable cells.

Notes about this neuropsychology research

Rakic is the Dorys McConnell Duberg Professor of Neuroscience and Professor of Neurology and Director of the Yale Kavli Institute for Neuroscience and corresponding author. Kazue Hashimoto-Torii formerly of Yale and now at the Center for Neuroscience, Children’s National Medical Center, Washington, DC is lead author of the paper.

The research was funded primarily though grants R01 NS014841, R01 DA023999 and K99/R00-AA018387 from the National Institutes of Health.

Contact: Bill Hathaway – Yale
Source: Yale press release
Image Source: The image is credited Michael Helfenbein and is adapted from the Yale press release
Original Research: Abstract for “Roles of Heat Shock Factor 1 in Neuronal Response to Fetal Environmental Risks and Its Relevance to Brain Disorders” by Kazue Hashimoto-Tori, Masaaki Torii, Mitsuaki Fujimoto, Akira Nakai, Rachid El Fatimy, Valerie Mezger, Min J. Ju, Seiji Ishii, Shih-hui Chao, Kristen J. Brennand11, Fred H. Gage, Pasko Rakic in Neuron. Published online April 10 2014 doi:10.1016/j.neuron.2014.03.002

Important disclaimer: The abstract page offers this notice: “Note to users: Uncorrected proofs are Articles in Press that have been copy edited and formatted, but have not been finalized yet. They still need to be proof-read and corrected by the author(s) and the text could still change before final publication.”