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Gene Variants Affect Human Stress Resilience

Inherited genetic variations that affect an anxiety-reducing molecule help explain why some people can withstand stress better than others, according to a new study.

Mood and anxiety disorders have been found by previous studies to have a genetic component. A nationwide team of researchers led by Dr. David Goldman of NIH's National Institute on Alcohol Abuse and Alcoholism (NIAAA) set out to investigate genetic variants of a signaling molecule called neuropeptide Y (NPY), which is induced by stress. Found in the brain and other tissues, NPY's release helps to reduce anxiety. It affects appetite, weight control and emotional responses. The researchers suspected that NPY variants might contribute to maladaptive stress responses that often underlie mood and anxiety disorders.

Analyses of human brain and other tissue samples allowed the research team to identify gene variants that affect the expression of NPY—that is, of how much of the protein is produced. The results were reported online in Nature on April 2, 2008.

To evaluate the gene variants' effects on brain responses to stress and emotion, the researchers used functional brain imaging to look at the amygdala, the brain's fear and anxiety center. They found that people with the variant yielding the lowest NPY levels reacted with heightened emotion to images of threatening facial expressions. “Metabolic activity in brain regions involved in emotional processing increased when these individuals were presented with the threatening images,” Dr. Goldman said.

Previous studies showed that NPY exerts its effects through interactions with opioid compounds. Opioids are produced by the body to help suppress pain, stress and anxiety. In another set of experiments, the researchers found that people with the low-level NPY variant were less able to tolerate moderate levels of sustained muscular pain. Brain imaging showed that they released less opioid neurotransmitter in response to the muscle discomfort than people with higher levels of NPY.

“Their emotional response to pain was also higher,” Dr. Goldman said, “showing the close tie between emotionality and resilience to pain and other negative stimuli.”

In a preliminary finding, the low-level NPY gene variant seemed to be more common than other variants among a small sample of people with anxiety disorders. Low-level NPY expression was also linked to high levels of anxiety.

This research supports the idea that NPY plays a role in reducing anxiety. It also helps explain why people vary in their resiliency to stress.

“Stress response is an important variable in vulnerability to alcohol dependence and other addictions, as well as other psychiatric disorders,” said NIAAA Director Dr. Ting-Kai Li. “This finding could help us understand individuals' initial vulnerability to these disorders.”