You are diagnosed with a crippling illness. You lose your job. Someone close to you suddenly dies. Some people recover rapidly from life’s calamities and disappointments, whereas others are devastated by minor setbacks, becoming depressed and even suicidal.

The roots of such emotional differences have fascinated psychologists and nonspecialists alike. Environmental factors, such as a person’s upbringing, exert a tremendous influence on his or her resilience in the face of misfortune or failure. But as biologists (and parents) have long suspected, genes lay much of the groundwork for individual personality traits. Studies that compare the traits of identical twins, who have all the same genes, with those of fraternal twins, who share just half their DNA, suggest that genes account for 40 to 60 percent of the individual variation in anxiety levels and susceptibility to depression.

Recently scientists have begun to identify specific genes that shape facets of human personality. Based on an early understanding of the chemical underpinnings of mood and mood disorders, they have pinpointed genetic quirks that may contribute to curiosity, attention deficits and impulsive violence.

The roots of anxiety and emotional resilience reside partially in a gene that affects brain levels of serotonin—a chemical messenger that influences sleep, thought and mood, among other functions. The anxiety-provoking form of this gene is very common; more than half of the Caucasian population has inherited it from at least one parent. Recent work has not only connected this gene with anxiety-related personality traits but has also established a basis in the brain for the gene’s effects on anxiety.

This “anxiety gene” raises the risk of depression, however, only in the wake of very difficult life circumstances, the latest data show, illustrating the importance of an interaction between genes and particular life experiences in molding personality. Revealing such molecular ties to anxiety, along with their partners in the environment, may lead not only to a new understanding of human behavior but also to better treatments for—and possibly ways to prevent—mood disorders.

Anxiety Gene
Scientists have long speculated that problems with serotonin signaling underlie much of the pathology of mood disorders. A key molecule in this process is a protein called the serotonin transporter, which pumps serotonin from the space outside neurons, the synapse, back into neurons.

Indeed, research reported in the 1980s and 1990s hinted that people with depression and certain anxiety disorders bore either fewer or less efficient serotonin transporters than normal. Meanwhile scientists discovered an association between heightened anxiety levels in animals and people and increases in serotonin-induced communication between neurons. (Paradoxically, Prozac and similar antidepressants reduce anxiety and depression by inhibiting serotonin reuptake, and thus boosting levels of serotonin outside neurons—something scientists are still struggling to explain.)

Such observations led clinical psychiatrist Klaus-Peter Lesch of the University of Wuerzburg and his colleagues at the National Institute of Mental Health (NIMH) and the National Cancer Institute to wonder whether variations in the gene, or molecular blueprint, for the serotonin transporter might influence a person’s anxiety level and possibly his or her susceptibility to depression. Lesch and his colleagues discovered that the gene came in two lengths—long and short. Both produced functional proteins, but as the researchers reported in 1996, the long form of the gene causes a neuron to churn out more of the transporter than the short one does.

This quantitative difference does affect anxiousness, Lesch’s team found. Among 505 people who took a test for anxiety-associated traits, those who had inherited at least one copy of the short version of the serotonin transporter gene received higher scores than did those who inherited the long version of the gene from both parents. Lesch and his co-workers concluded that the serotonin transporter gene accounts for 3 to 4 percent of the total variation—and 7 to 9 percent of the inherited variation—in anxiety-related personality traits.

Angst in the Brain
Researchers have since identified a neurological basis for this effect: having a short serotonin transporter gene boosts the excitability of the amygdala, an almond-shaped group of neurons deep in the brain that processes fear and other emotions. In 2002 psychiatry researcher Ahmad R. Hariri, then at the NIMH, and his colleagues reported showing 28 healthy volunteers faces conveying fear or anger or bearing neutral expressions while they scanned their brains using functional magnetic resonance imaging (fMRI). They found that in the 14 people who had inherited at least one copy of the short transporter gene the amygdala was especially enlivened by the emotive faces. It was less active in the individuals with two long forms of the gene.

Additional studies have buttressed the theory that this genetic variant has consequences for the emotional brain. In a 2004 study a team led by psychologist Tomas Furmark of Uppsala University in Sweden showed that patients with social phobia who carried the short form of the serotonin transporter gene showed more activity in the amygdala during a public speaking task than did those with two long versions of the gene. Other researchers found that a part of the prefrontal cortex charged with the processing of risk and fear was also more aroused in response to negative images in bearers of the short transporter gene.

Research from my laboratory suggests, however, that the effect of this gene on brain activity may be more general; rather than controlling the response to negative stimuli, it may instead fine-tune the background level of neural activity in the emotional brain. Lesch and I, along with several colleagues, measured activation levels in the amygdala and other brain regions in 41 people while they viewed negative, neutral and positive words—or just stared at a spot on a computer screen.

Corroborating Hariri’s work, we found that the people with at least one short transporter gene showed higher activity in the amygdala in response to negative stimuli—words, in this case—than did the individuals carrying two long forms of the gene. More surprisingly, however, as we reported in 2005, the amygdala of those who had the short gene was unusually dynamic while the subjects were simply staring at the computer screen, and we discovered that this resting-state dynamism could account for the amygdala’s enhanced response to negative stimuli. We also observed greater neural activation in response to positive stimuli in other brain regions in the individuals carrying the short transporter gene.

Our data thus suggest that the amygdala and other parts of the emotional brain are naturally more aroused in people who have inherited the short serotonin transporter gene. We hypothesize that this chronic arousal may lead to anxiety, fearfulness and, possibly, a predisposition to mood disorders such as depression.

Surviving Stress
But carrying this genetic variant is unlikely to beget depression unless your environment also conspires against you. Studies show that the gene variant boosts depression risk only in the presence of significant stress from misfortune or failure. In 2003 psychiatry researcher Avshalom Caspi of King’s College London and his colleagues reported analyzing the serotonin transporter gene in 847 New Zealanders whom they also surveyed about stressful life events such as illness, financial difficulties and romantic disappointments that had occurred between ages 21 and 26.

Although a person’s transporter gene did not budge depression risk in the absence of stress, it did influence his or her tendency toward gloominess in response to adversity. The risk of depression and suicidal thoughts rose as the number of stressful events mounted—but only in those with at least one short copy of the transporter gene. And after four or more traumatic occurrences, 33 percent of the subjects who carried at least one short transporter gene became depressed as compared with just 17 percent of those who bore two copies of the lengthier blueprint, suggesting that the long gene protects against depression in the wake of acutely negative experiences.

In 2005 psychiatric geneticist Kenneth S. Kendler and his colleagues at Virginia Commonwealth University replicated this finding in 549 twins whom they interviewed about signs of major depression and anxiety within the past year, along with the occurrence—dated to the nearest month—of 15 types of stressful life events, including divorce, job loss, robbery and illness in the family. The researchers found that individuals with two short forms of the serotonin transporter gene were more likely to become depressed after mild stressors than were those with one or two long forms. The next year geneticist Peter R. Schofield of the Prince of Wales Medical Research Institute in Sydney and his co-workers reported that serious adversity was more likely to produce a bout of major depression within five years in those carrying two short transporter genes, as compared with those who had at least one long transporter gene.

Lesch and I, along with several colleagues, observed these differing vulnerabilities to life’s misfortunes in the brain. We surveyed 48 healthy volunteers to determine how many times they had experienced significant tension from, say, work, relationships, finances or illness; some of them were also assessed for their tendency to ruminate, a risk factor for depression. We then used noninvasive imaging techniques such as fMRI to measure brain activity while the subjects focused on various facial expressions or just stared at a spot on a computer screen.

In the individuals carrying a short serotonin transporter gene, life stress was not associated with a boost in brain activation in response to moody facial expressions but did lead to a higher resting level of activity in the amygdala and hippocampus—a memory-processing region that is vulnerable to stress—and to a greater tendency to ruminate. The opposite was true for people who carried two long forms of the gene: the more crises these people had faced, the lower the background level of activity in their amygdala and hippocampus—and the less they dwelled on things, we reported in 2006. These results support the theory that stress interacts with a short serotonin transporter gene to produce a highly vigilant emotional brain that predisposes a person toward depression.

Stress that is combined with a deficit in the serotonin transporter protein perturbs the emotional brains of mice as well. In a study published in 2007 geneticist Andrew Holmes of the National Institute on Alcohol Abuse and Alcoholism and his colleagues deleted the serotonin transporter gene in mice, creating a lack of the transporter protein meant to mimic the less pronounced deficit in people who inherit the abbreviated transporter gene.

The genetically altered mice showed signs of depression—they stood still more than normal mice—after several stressful swim tests. The animals also had unusual difficulty getting over a fear of a sound the researchers had instilled in them—by pairing the sound with a shock to the foot—and then subsequently tried to extinguish. The DNA disruption also affected the rodents’ brains: in the genetically manipulated mice, the researchers found structural oddities in the amygdala and in an area of the prefrontal cortex that plays a role in stress and fear.

Molecules of the Mind
Despite such findings, variation in the serotonin transporter gene is thought to explain only a small part of people’s differing sensitivities to the stresses of life. Geneticists estimate that at least 15 genes, along with various environmental factors, most likely contribute to anxiety and a person’s susceptibility to stress. Only if researchers can complete this genetic and environmental mosaic will they be able to confidently gauge the propensity to develop anxiety and depression in each of us—or to pinpoint the causes of such disorders in those who have them.

Moreover, with a more complete picture, those of us at high risk might be able to act to prevent the emergence of such mood disorders. And an ability to home in on a molecular cause of anxiety or depression in psychiatric patients might enable doctors to select the treatment most likely to work for each patient.

Meanwhile the unraveling of the entire human genetic code under the auspices of the Human Genome Project and of human genetic variation in the so-called Human HapMap Project is expected to accelerate the outing of genes that work in the brain to shape our personalities. As these genes come to light, psychologists will have to increasingly incorporate these molecules of inheritance into their explanations of human behavior, mental illness and temperament.