HOW GENES TUNE THE BRAIN: THE BIOLOGY OF TEMPERAMENT
I’VE ALWAYS BEEN THIS WAY.” TIM CORNING WAS TRYING TO describe the roots of his social anxiety in our first meeting. He had come to see me because, after working for years as a computer programmer, he had decided to return to school for a master’s degree in education. But now his dream of becoming a science teacher was being hijacked by his anxiety around other people, and he wanted to reclaim it.
“As long as I can remember, I was shy.” He recalled his first day of school, feeling frozen amid the overwhelming buzz of new faces. “I don’t think I spoke all day. I remember asking the teacher if I could stay inside while the other kids went out for recess. But she said I had to go . . . so I went. And I stayed by the door while the other kids played.
“But I think I would have been okay if it wasn’t for that day a couple of months later when we went on a school trip to a museum. Before we got on the bus to go back to school, the teacher told all the kids to go to the bathroom so we wouldn’t have to stop on the way home.” As he recounted the story, his face began to flush. “We were lining up at the urinals and when my turn came, I couldn’t go. I felt like everyone was watching me. I stood there, waiting and praying that something would happen. One of the kids behind me laughed—I don’t even know if he was laughing at me, but I felt humiliated.” Ever since then, he was unable to urinate in a public bathroom, a condition known as paruresis, or “shy bladder.”
Things got worse for Tim. His father left the family when Tim was seven years old. Midway through second grade, he refused to go to school unless his mother chaperoned him to the classroom. Unfortunately for Tim, his mother went along with this. One of the fundamental principles about anxiety is that avoiding what causes it is the surest way to turn a fear into a phobia.
Tim recalled his mother’s own struggles with anxiety. “I don’t think she ever went out when I was a kid—she was too worried about me. I guess she was the classic overprotective mother.”
Over the years, Tim turned inward and focused on his studies. Schoolwork became one of the few areas that gave him a feeling of competence. In high school, he developed a fascination with science and engineering and managed to find a circle of friends who shared his interests. With a tentative self-confidence, he went off to college and studied computer science. But his social inhibition kept intruding. He recalled a job interview for a teaching position after college. He really wanted the job but, on the day of the interview, he started to imagine getting up in front of a class every day. Before the interviewer came out to greet him, he was gone. He took a job as a computer programmer, working mostly from home.
And now, ten years later, he was sitting in my office telling me he had come to a realization. He had set off in life with a sense of where he was heading, but so many times, he had taken slight turns to accommodate his shyness: declining an invitation to present his work at a scientific meeting, avoiding another party, or not quite feeling comfortable enough to call the woman who had given him her number. And now, suddenly, he looked up and realized he was miles from where he thought he would be.
How did Tim Corning end up where he did? How do any of us end up with the emotional and social lives we do? The answer has much to do with where we begin—the genes we inherit and the temperament we are born with. As every parent knows, children begin to signal their approach to life well before they can verbalize it. Walk into any preschool classroom and within minutes you can pick out the shy, inhibited kids who are wary of unfamiliar people. You can also spot the bold, uninhibited kids who are talking and playing with anyone who will oblige. What makes one child fearful and another gregarious or even aggressive?
As we’ll see, the foundations of our personalities can be traced to the genes and brain circuits that subtly shape temperament—the basic patterns of how we react to the world around us. We’ve known for some time that personality traits are influenced by genetic differences among people. But only recently have we begun to see how specific genes contribute to the development of these traits and how it all plays out in the brain.
The evolutionary history of our ancestors has selected suites of genes that “worked” for navigating the challenges of life. But we each inherit particular versions of these genes from the parents we happened to have. Our genetic differences bias our brains to be more or less sensitive to our environment, more or less emotional, more or less prone to behave in specific ways. They set our internal thresholds for reacting to our earliest experiences. Are we more likely to approach or avoid new situations and unfamiliar people? Are we prone to negative or positive emotions? Are we open to new experiences or wary of change? These subtle biases orient us to the world in different ways. We start life’s journey pointed in slightly different directions, and as we interact with our families, our social environments, and the stresses and opportunities that life throws our way, these differences are amplified and elaborated into distinctive personalities. Our genes can even influence what kind of experiences we have—nudging us to seek out risky situations or perhaps shy away from social connections. These temperamental styles are all well within the distribution of normal. But sometimes, when our innate biases collide with the demands of the world around us, we suffer. That seems to have been the story that played out for Tim Corning, who began his journey with a tendency to be wary and shy and ended up with a life constricted by what psychiatrists have called social phobia.
In this chapter and the next, we’ll explore the emerging picture of how nature and nurture interact to shape the trajectories of our life stories. The emphasis in this chapter is on the genetic roots of temperament and personality, how temperament is encoded in the brain, and how early differences in how our brains are tuned can have long-lasting effects on our emotional and social lives.
YOUR MIND: DAY ONE
THE MOST DRAMATIC TRANSITION ANY OF US MAKES IS ALSO ONE we all share. And none of us can remember a thing about it. I’m talking about the moment we travel from the secure and self-contained world of the womb into a new world of light, noise, and discomfort. Suddenly we have needs—and they are not being met. We’ve been thrust into a world of unforeseeable challenges and threats, and we have precious few resources of our own to draw on. Fortunately, we are not totally unprepared. Thanks to the trials and errors suffered by our evolutionary ancestors, we enter life with a rudimentary set of capacities that will help us negotiate the demands of this new world.
Imagine you are responsible for designing a mental survival kit for the newborn brain—a set of mental functions to ensure that this new visitor to our world will make it through the first months of life and meet the challenges of child development. Here are some constraints: the newborn can’t walk or talk and has had no experience of the outside world. And he hasn’t yet developed self-awareness or the concept of other people. What capacities would you pack into that little brain?
The most parsimonious answer would include at least three elements. First, you’d want to have built-in drives to satisfy immediate needs that are essential for survival—food, water, air. Next, you’d want a basic set of tools that could guide the infant brain to seek out helpful parts of the environment and avoid harmful ones, along with the capacity to control behavioral and emotional responses to the environment. This second part of the survival kit is the foundation of what we call temperament.
But of course, that’s not enough. You would also want to somehow equip the brain to respond to the infinite specific environmental contingencies that it may encounter. So the third element you’d want to include is what neuroscientists call plasticity. As experience presents novel challenges to the human brain, neural connections or synapses are formed and strengthened so that we can adapt and respond. (We’ll explore the biology of neural plasticity in more detail in the next chapter.) At the start of life, the nervous system is mainly a collection of possibilities. Only later will experience carve the detailed architecture of personality, desires, values, knowledge, and memories that make each of us unique. The adult mind reflects a record of the particular experiences that we encounter over a lifetime.
CONSTITUTIONAL CONVENTIONS
BUT LET’S RETURN TO THE BEGINNING. WE ENTER THE WORLD with a set of cognitive, behavioral, and emotional biases that allow us to respond to general features of our physical and social environments. We call these biases “temperament.” The psychologist Jerome Kagan defines temperament as a profile of “stable behavioral and emotional reactions that appear early and are influenced in part by genetic constitution”(p. 40).1 The notion of temperament has a long and storied history dating at least to the Greek view that differences in behavior, rationality, and emotionality were due to a balance of the four essential humors: yellow bile, black bile, blood, and phlegm. Well before modern psychiatrists spoke of psychiatric disorders as “chemical imbalances,” the humoral theory was the prevailing view of mental health and disease from the time of Hippocrates to the Enlightenment.2 To the Greeks, disease occurred when there was an imbalance of the humors, but an excess of specific humors was also responsible for individual differences in mental traits. The Greek physician Hippocrates, and, later, the Roman physician Galen, recognized four temperaments corresponding to the effects of each humor. An excess of black bile (literally “melan” “cholic”) produced a depressive temperament. The choleric temperament, owing to an excess of yellow bile, was irascible, ambitious, and passionate; while the phlegmatic type was apathetic and calm, and the sanguine type, reflecting an excess of blood, was optimistic and hopeful.3
The modern study of childhood temperament began in 1956 when Stella Chess, Alexander Thomas, and their colleagues attempted something that no one had done before: instead of deducing the nature of temperament from preconceived theories, they decided to study it systematically. They began a long-term study of 133 infants. By interviewing parents, observing their children, and evaluating childcare practices and parenting attitudes, they identified three temperamental styles that characterized most children—the “easy child,” the “difficult child,” and the “slow-to-warm-up child.”4
About 40 percent of children could be classified as “the easy child.” These were kids who were regular in their bodily functions (sleeping, feeding), generally happy and smiling, easily approached new people and new situations, and adapted to change quickly.
Another 10 percent of children were at the other end of the spectrum: “the difficult child” was loud, moody, prone to tantrums, and didn’t take well to new situations or change. And the third temperamental category, dubbed “the slow-to-warm-up child” applied to about 15 percent of the children. These children were initially reserved and uncomfortable in new situations but would gradually adapt and engage.
By following the children over time, the researchers found that these early tendencies remained relatively stable into adulthood, and that temperament at age three was a significant predictor of behavioral traits in adulthood. But, crucially, Chess and Thomas also discovered that a child’s successful development depends not only on how the child responds to the world around it (temperament) but also on how that world responds to the child. They called this concept “goodness of fit”—or how well the child’s capacities and behaviors align with the expectations and demands of those around it.
For example, the “slow-to-warm-up child” whose parents express disappointment or anger at his shyness or difficulty making friends may have a troubled development. The same child born to parents who are accepting of his shyness is likely to do just fine.
In 2011 Yale law professor Amy Chua published a memoir that ignited a firestorm of controversy over parenting styles. The Battle Hymn of the Tiger Mother told the story of how Chua raised her two daughters, Sophia and Lulu, in the same way that her own Chinese immigrant parents had raised her: with love but also with a fierce commitment to excellence and hard work. In the popular press, the debate became a culture war: the uncompromising Chinese “tiger mother” versus the coddling Western style of indiscriminate praise and parental indulgence. In reality, the book was a brutally honest and often self-deprecating tale about the importance of knowing your child. And, in many ways, Tiger Mother was a book about “goodness of fit”: what happens when one style of parenting meets two very different temperaments. Of her elder daughter, Chua writes, “From the moment Sophia was born, she displayed a rational temperament and exceptional powers of concentration. . . . As an infant Sophia quickly slept through the night, and cried only if it achieved a purpose.” She was, from infancy, “calm and contemplative.” In short, Sophia was the paradigm of what Chess and Thomas called “the easy child.” Chua’s Chinese parenting fit seamlessly with Sophia’s easy temperament. She met her mother’s high standards and intense work ethic with equanimity and her own drive to exceed expectations. In an open letter to her mother that appeared in the New York Post, Sophia wrote, “Early on, I decided to be an easy child to raise.” By age fourteen, she was a model student and piano virtuoso with a Carnegie Hall debut under her belt.
But things were a little different with Chua’s younger daughter, Lulu: “From the day she was born, Lulu had a discriminating palate. She didn’t like the infant formula I fed her, and she was so outraged by the soy milk alternative suggested by our pediatrician that she went on a hunger strike. But unlike Mahatma Gandhi, who was selfless and meditative while he starved himself, Lulu had colic and screamed and clawed violently for hours every night.” From the start, Chua writes, Lulu was willful and hot-tempered—the type Chess and Thomas might have called “difficult.” Having known both Sophia and Lulu all their lives (my wife and I are their godparents), I think formidable would be a better word. Amy Chua describes how she was forced to adapt her cherished principles of child rearing to the vibrant reality of her younger daughter’s temperament. In the end, both daughters have grown to become remarkable young women with a deep love for their parents. Amy Chua’s ability to “fit” her parenting to the unique characters of her children was an example that Chess and Thomas would have advocated for mothers (and fathers) of all stripes.
REDISCOVERING OUR SENSE OF HUMORS
FOLLOWING CHESS AND THOMAS’S LANDMARK STUDIES, RESEARCHERS have highlighted different temperamental traits, but almost all of them have agreed that children differ from birth in how reactive (both physically and emotionally) they are to the environment. The temperamental difference between children who are predisposed to approach unfamiliar situations and those who tend to avoid the unfamiliar is commonly called “boldness vs. shyness,” and it has long-lasting effects on everything from our social relationships to our willingness to have unprotected sex.
Arguably, no one has taught us more about this temperamental difference than the psychologist Jerome Kagan, now an emeritus professor at Harvard, where he has been for more than forty years. In 2002 Kagan was ranked as one of the twenty-five most eminent psychologists of the twentieth century, just ahead of Carl Jung and Ivan Pavlov.5 But half a century ago, Kagan was a freshly minted PhD psychologist from Yale when he was offered a job at the Fels Research Institute, in Ohio. His Ivy League mentor told him, “Don’t take it, you’re going to isolate yourself on an island—you’ll never be heard from again.”
Kagan didn’t take that advice. At the Fels Institute, he was shown a room filled with piles and piles of notebooks containing the observations of children followed from birth through adolescence. Kagan reinterviewed the children as young adults, and when he and his colleague Howard Moss put the data together, they were struck by the fact that from early in life, a group of these children were passive and inhibited, and this trait seemed to follow them into adulthood. But when they wrote up their findings, they downplayed the possibility that biology played a role. This was an era when the two dominant strands of American psychology, Freudian psychoanalysis and behaviorism, had established the orthodoxy that child development was all about nurture.
“I was trained to believe in environment,” Kagan said, “that was my politics. I was against biology. So I didn’t pursue it—I didn’t pursue temperament.”
But by the late 1970s, having observed children across cultures and reading the latest research on the neurochemistry of behavior, Kagan was becoming increasingly convinced that temperament was rooted in our “constitution”—that is, our biological endowment. Modern psychology now seemed to be rediscovering the wisdom of the Greeks. “How amazing it is that Hippocrates and Galen got closer than Freud,” Kagan marveled. “Blood, bile, phlegm—those are neurotransmitters—how did they do that? How did they guess right? I think that is just extraordinary.”
ON THE SHY SIDE
KAGAN AND HIS COLLEAGUES PIONEERED THE STUDY OF SHYNESS and boldness by developing a method for picking up temperamental differences in the laboratory. In research that has spanned decades, they’ve found that differences in how children react to unfamiliar people and situations are evident as early as sixteen weeks of age. Kagan brought mothers and their four-month-old infants into the laboratory and observed them while the infants were exposed to a prespecified battery of events. The events were unfamiliar but not overtly threatening: mother stares at baby, a recording of an unfamiliar voice is played, a set of colorful mobiles are dangled in front of the baby, and so on.
Twenty percent of the infants exhibited behavior that Kagan called “high reactive”—they cried frequently and thrashed about, tensing their bodies and arching their backs when presented with the unfamiliar stimuli. Another 40 percent were low reactive: they seemed serene in the face of all these odd events. And that simple distinction turns out to tell you a lot about the developmental trajectory that these kids will take over the next twenty years. When the children were brought back to the laboratory at fourteen months and twenty-one months of age, they were again exposed to a series of unfamiliar events and people and objects. At one point, a woman dressed in a red clown costume and mask entered the room, talking and bearing toys, and invited the child to play with her. Next, the examiner brought in a radio-controlled metal robot. After a minute of silence, the robot began making noises, emitting lights, and moving, and the examiner invited the child to approach and touch the robot. Notice that these little challenges are subtle. Having a clown walk into the room is mildly stressful. If you had the clown burst into the room and yell “boo!” you’d get little or no information about individual differences because every kid would probably react the same way: scared out of their pants. The point is to elicit differences in how children react in unfamiliar situations by gently challenging their approach/avoidance systems.
The kids who had been high reactive at four months were much more likely to be behaviorally inhibited, that is, fearful and avoidant of these unfamiliar challenges. By age four, they were much more likely to be shy, quiet, and timid around unfamiliar peers.6 By age seven, children who were high reactive at four months or extremely inhibited at age two were more likely to be anxious, cautious, and socially avoidant,7 whereas those who were low reactive or had been uninhibited at age two were much more sociable, smiling and talking spontaneously with strangers. These differences were also seen when the children were studied at age eleven and age fifteen.8 Children who are inhibited in both infancy and later childhood are at increased risk for anxiety problems later in life. About a third of these children have significant problems with social anxiety in adolescence and adulthood.9 They followed the trajectory that Tim Corning had so poignantly described to me.
It may come as little surprise that people differ in how prone they are to approach or avoid life’s challenges or that inhibited children are more likely to become shy adults. The question is why? What determines where infants and young children fall on the shyness/boldness spectrum? The answer seems to involve subtle differences in how our brains are tuned to the world around us.
IT’S WRITTEN ALL OVER YOUR FACE
THE VARIATION IN HOW LIKELY WE ARE TO FEARFULLY AVOID NEW experiences or boldly seek them out is rooted in deep and evolutionarily older parts of the brain. The amygdala, an almond-shaped collection of brain cells, plays a key role in putting an emotional stamp on our experiences (“watch out, this guy is dangerous!”) and recognizing emotions in other people (“uh-oh, she’s angry”).
One of the major jobs of the amygdala seems to be evaluating the emotional expressions of other people—not a trivial assignment, since the face is the window through which we judge one another’s intentions and emotions. Facial expressions are a kind of social vocabulary. In 1872 Darwin wrote that our expressions “reveal the thoughts and intentions of others more truly than do words, which may be falsified” (p. 364).10 (I’ll have much more to say about this in Chapter 4.) The amygdala also plays a major role in our response to novelty, triggering behavioral responses that make us either approach or avoid unfamiliar people and situations. Emotional faces and unfamiliar faces have something important in common: they tell us that we’re in a situation that may be good or bad for us. Unfamiliar faces, like angry and frightened faces, signal potential threat.
Neuroimaging research has shown that one of the most reliable ways to fire up the amygdala is to show someone pictures of emotive or unfamiliar faces.11–13 My colleague Carl Schwartz and others at Harvard conducted a twenty-year follow-up study of children whose temperament previously had been observed in Kagan’s laboratory when they were only fourteen months old.14 The children had been exposed to unfamiliar people and situations, and while some responded to novel stimuli with fear and avoidance, others were quite uninhibited and unafraid of new people or surroundings. Twenty years later, these same subjects returned to the laboratory to undergo functional MRI (fMRI) studies.
Even though the subjects were all now healthy adult volunteers in their early twenties, their brain scans revealed a hidden signature of distinct childhood temperaments. When shown a series of unfamiliar faces, the adults who had been inhibited as infants had a much stronger amygdala response than those who had been uninhibited. This work has been confirmed in other studies that have shown that adolescents who were inhibited as infants have a heightened amygdala response to faces that evoke uncertainty or are expressing emotions.15
In another study, Schwartz and his team studied eighteen-year-olds who had been classified in Kagan’s lab as high or low reactive at four months of age.16 When he ran them through an MRI, he found something striking: their temperament as infants predicted differences in the actual structure of their brains at eighteen years of age. Those who had been high reactive had significantly thicker brain tissue in the right ventromedial prefrontal cortex, a region known to play an important role in regulating brain regions involved in fear and avoidance. On the other hand, adults who had been calm, low reactive infants had greater thickness in the left orbitofrontal cortex, a region involved in inhibiting fear reactions and suppressing unpleasant feelings. And when they were shown pictures of unfamiliar faces, the eighteen-year-olds who had been high reactive at four months had stronger amygdala responses compared to those who had a low reactive temperament in infancy.17
Infant temperament, it seems, leaves a “footprint” that can be seen in the brains of adults decades later—visible in the structure and sensitivity of emotion centers like the amygdala and prefrontal cortex.
Based on studies like Schwartz’s, Kagan and others have concluded that high reactivity in infancy and shyness/inhibition in childhood reflect an innate difference in how the brain reacts to novelty and threat. In shy, inhibited children, the emotional circuits of the brain (the “limbic system”) seem to have a lower threshold for detecting and responding to uncertainty and potential harm. The system is more excitable, more vigilant, like an amplifier with the gain turned up. Once activated, the amygdala, a key node in the limbic circuitry, sends signals to other centers that activate stress responses. The sympathetic nervous system prepares for “fight or flight” and the stress hormone axis releases cortisol, triggering a broad range of defensive reactions in the brain and body.
The evolutionary roots of shy and bold temperaments run deep: fear behavior in response to novelty are seen across the evolutionary tree of life. And in mammals from mice to monkeys, the biology of shy, inhibited temperament involves many of the same brain and hormone systems that we see in the human version.18, 19
TEMPERAMENT GROWN UP
SO THESE SUBTLE BIASES IN HOW WE APPROACH THE WORLD HAVE an underlying biology that follows us from infancy into adulthood. And they can leave more visible traces in our adult lives: our relationships, our work, even our mental health. Children who were temperamentally shy in early childhood are more likely to have smaller social networks as young adults20 and a greater risk of developing anxiety disorders,21 especially social phobia,9, 22, 23 in which fear of social and performance situations can be debilitating. That was the path that led Tim Corning to my door.
“It was like an out-of-body experience.” In our second meeting, Tim was describing what lunchtime was like at a software company where he’d worked after college. Every day, his team would go to the cafeteria for lunch. As they sat down to eat and began to banter, Tim’s mind went into overdrive. Instead of enjoying a casual lunch, Tim felt like he was onstage without a script, under a big spotlight, and playing to a crowd that was scrutinizing his every word and gesture. He was sure they could hear his heart pounding and his voice cracking, they could see his hand shake as he brought his fork to his mouth. After a few weeks of this, he stopped joining his colleagues for lunch, explaining that he needed to stay at his desk to catch up on work.
Tim’s mind seemed to be tuned with an exquisite sensitivity to social judgments, the core feature of social phobia. Indeed, the biology of social phobia seems to be an extension of the biology of normal shyness. Brain-imaging studies have found that people with social phobia have exaggerated responses of the amygdala or medial prefrontal cortex when they’re asked to get up in front of a group and give a speech,24 to think about embarrassing situations,25 or even just to look at faces of people expressing contempt.26, 27
What about children at the other end of the shyness/boldness spectrum—those who are temperamentally disinhibited early in life? These are the children who boldly approach unfamiliar situations. They tend to be impulsive and risk-taking. The trajectory for these children looks quite different from those who are temperamentally inhibited. One study that followed nearly one thousand children into adulthood found that those who were “undercontrolled” at age three were more likely to engage in risky or dangerous behaviors as adults—violent crime, alcoholism, unprotected sex, and drunk driving.28 They had difficulty forming intimate and trusting relationships and were more likely to be unemployed and to have been fired from a job. Temperamentally disinhibited children are also more prone to behavior problems including aggressive and antisocial behavior and to what child psychiatrists call “disruptive behavior disorders,” including attention deficit hyperactivity disorder (ADHD).29, 30
Just to be clear: when we talk about the spectrum of infant temperament, we’re talking about normal variation in how children approach the world from the first months of life. But for some children the extremes of shyness and boldness can set the stage for vulnerability to disorder.
So if you’re born with a nervous system that biases you toward high reactivity or inhibition, or toward disinhibition and boldness, has the story of your life been written? Of course not. It goes without saying that the world around you can shape the trajectory you take. Inhibited children whose mothers tend to be overprotective and intrusively controlling are more likely to remain inhibited and socially reticent. Children with less protective mothers and children placed in day care within the first two years of life appear to be less likely to remain inhibited by age four.31, 32
The interaction between temperament and the environment can be complex and subtle. For example, inhibited children are more likely to be bullied,33 and bullied children are more likely to become shy and withdrawn. Temperament is only the raw material. The family we are born into, the experiences we have, and the unique disappointments and windfalls that life brings sculpt the undifferentiated stuff of temperament into the textured contours of our adult personalities.
THE BIG FIVE
WHEN I TALK ABOUT PERSONALITY, I’M REFERRING TO THE ABIDING traits that give us our characteristic styles of operating in the world. They jell over time as our temperamental predispositions meet the specific conditions of life that we encounter. These are traits that allow us to make judgments about each other: “She’s a really friendly person,” or “He’s so hard to get to know,” or “He’s so conscientious.” We have an enormous variety of words like these that we use to characterize ourselves and others: selfish, gregarious, wimpy, cold, upbeat, and so on. The online dating site eHarmony markets their “29 Dimensions of Compatibility that are scientifically proven to predict happier, healthier relationships.” But how many varieties of personality traits or dimensions are there?
In 1936 psychologists Gordon Allport and H. S. Odbert34 set out to answer that question in a systematic way. They started with the premise that if a trait is recognizable enough to represent something real, there ought to be a word for it. Next, they undertook a project that one can only marvel at. They took the 1925 edition of Webster’s New Unabridged International Dictionary and looked for every word that described individual differences in human behavior. From more than half a million words in the dictionary, they identified 17,953 descriptors of human behavior. They whittled that number down to about 4,500 words that describe “real” personality traits.
But people who do personality research for a living will tell you that there are only a handful of stable personality domains that describe individual differences in our behavior. Based on massive amounts of data gathered over the past several decades, these researchers have shown that our personalities can be boiled down to how each of us varies along just five overarching domains: the “Big Five” as they are commonly called: neuroticism, extraversion, openness to experience, agreeableness, and conscientiousness. I’m going to bet that if I had asked you to name the five dimensions of personality, that’s not the list you would have come up with. But there they are—virtually all personality measures can be encompassed by these five factors, and they seem to be universal. The same domains emerge from studies in countries as diverse as Finland, Israel, Korea, Japan, China, Germany, and Portugal.35
Neuroticism refers to a tendency to experience worry, unstable moods, and negative emotions as opposed to being calm and emotionally stable. The extraversion factor captures the tendency to be active, enthusiastic, and to seek stimulation and the company of others. Those low in extraversion (i.e., high in introversion) tend to be quiet, reserved, shy, and withdrawn. Openness is a dimension that involves a tendency to be curious, creative, and open to new ideas and experiences. It correlates with aesthetic appreciation as well. Those low in openness are close-minded, conservative, and conventional in their tastes. Agreeableness indexes the tendency to be compassionate, empathic, and cooperative as opposed to being antagonistic, suspicious, and unfriendly. And, finally, conscientiousness refers to being self-disciplined and achievement-oriented as opposed to being disorganized and irresponsible.
Though these traits capture variation in personality across countries and cultures, there are still interesting differences in the personality profiles of people in different regions. In fact, the results of a survey of more than six hundred thousand Americans36 were oddly consistent with stereotypes we have about the personality profiles of different regions of the United States. Neuroticism tended to be high on the East Coast, while the outgoing positivity of extraversion was concentrated in the Midwest. Where are the friendly folks high in agreeableness? You guessed it: the Midwest and the South. But some states stand out. North Dakotans seem to be the most outgoing, friendly bunch of traditionalists you’d ever want to know: they topped the list of all states in agreeableness and extraversion but came in last on openness. On the other hand, Alaska scored at or near the bottom on all five traits, suggesting that the typical Alaskan is a calm but disagreeable and introverted slacker who doesn’t like unconventional ideas. If you’re looking for open-minded, enthusiastic, friendly neighbors who are emotionally stable and conscientious, your best bet is to move to Utah.
The geography of the Big 5 personality traits across the United States.
Studies of cultures around the world suggest that nations also differ in their personality profiles. In a study of data from fifty-one cultures across the globe, Brazilians reported the highest levels of neuroticism, the Northern Irish were the most extraverted, the German Swiss scored highest on openness, Czechs reported the highest levels of agreeableness, and Filipinos and German Swiss were tied for first place on conscientiousness.37
The Big 5 model is not without its critics. Some have pointed out that these traits are based on questionnaires that ask people how they typically behave, without addressing the fact that what’s “typical” in one situation may not apply in another. Nevertheless, these personality dimensions can even be found across the animal kingdom. The same dimensions have been observed in animals as diverse as guppies, octopus, cats, dogs, pigs, monkeys, and chimps. Even donkeys have a personality trait dubbed “vivacity” that closely resembles extraversion (though I must admit the notion of a vivacious donkey is a little disturbing).38
DIFFERENT STROKES
SO WHAT ACCOUNTS FOR INDIVIDUAL DIFFERENCES IN TEMPERAMENT and personality? Like everything else about our mental functioning, the answer is that it’s a combination of variations in our genes and our environments.*
The fact that genes can influence temperament and behavior is not controversial. Even if you are a skeptic about the importance of genes in human behavior, you’ve undoubtedly seen the phenomenon of genetic control of behavior. Dogs may be the “poster species” for behavior genetics in everyday life. It’s well known that different breeds of dogs have different behavioral specializations and temperaments. In fact, the hundreds of dog breeds currently in existence are basically the result of breeders using genetic selection to create animals that share specific temperaments and physical characteristics. The most popular dog breed in the United States year after year is the Labrador Retriever, and that’s not because most dog owners have unmet retrieval needs. The appeal of the dog is its temperament, which the American Kennel Club describes as “a kindly, outgoing, tractable nature; eager to please and nonaggressive toward man or animal.”39
But people aren’t bred for behavior, and so it may be less obvious that genes affect temperament in humans. Though the phrase “the apple doesn’t fall far from the tree” is a well-worn truism, the fact that traits run in families could in principle have little to do with genetics. Children observe their parents’ behavior throughout development. It’s entirely possible that any behavioral resemblance is simply a matter of this modeling effect. Siblings have many traits in common. But that could be entirely due to the fact that their family environments have been so similar.
So how can we find out whether genes affect human temperament and personality? One way to isolate the effect of genes would be to compare genetically identical clones who were raised in the same family environment to nonidentical siblings raised in the same family environment. If the clones are more similar in their behavior, you could conclude that this is due to their greater genetic similarity. This may sound like the musings of a mad scientist, but this very study has been done many times. It’s called a twin study.
In twin studies, researchers compare the trait similarities of pairs of identical twins (“monozygotic,” or MZ twins) to that of genetically nonidentical twins (“dizygotic,” or DZ twins). If the environment is not more similar for MZ twin pairs compared to DZ twin pairs, then the greater similarity among MZ twin pairs for, say, introversion, can be attributed, at least in part, to the fact that their genes are more similar.
Behavior geneticists measure the importance of genetic variation between people in terms of a number called heritability. The heritability of a trait is the proportion of variation in the trait within a population that is due to differences in people’s genes. It ranges from 0 percent (no influence of genetic differences) to 100 percent (completely due to genetic differences).
Because the concept of heritability will come up in many of the chapters in this book, let me clarify a couple of things.
First, heritability says nothing about the genetics of an individual. That’s because heritability is about how much variation in a trait is due to genetic differences in a population. So heritability is only meaningful when we talk about populations, not individual people. If the heritability of body weight is 70 percent, that doesn’t mean that 70 percent of your aunt Zelda’s obesity is genetic and 30 percent is environmental. It just means that 70 percent of the variation in body weight in the population is due to genetic variation. For an individual, we can’t tease apart nature and nurture in that way.
And, second, the heritability of a trait can vary depending on what population you’re talking about. Take the example of body weight again. In a population where there’s a lot of variation in what people eat, the environment may account for most of the differences in weight, whereas in a population where diet is more uniform, genetic differences may dominate. The heritability of weight would be smaller in the first group than in the second.
So the main value of heritability is that it gives us a measure of how strongly genetic variation influences trait differences in a population.
And twin studies have consistently shown that the heritability of the common temperamental and personality traits is in the range of 40 to 60 percent. That is, genetic differences account for about half of the variation in how shy or inhibited kids are in a population, how extraverted or neurotic adults are, and so on.40–47
One of the problems with heritability is that it tells us nothing about which genes influence temperament and personality. It also tells us nothing about how many such genes there are, how they act, and how big an effect each gene has. Until recently, scientists simply didn’t have the tools to identify the specific genetic variations that contribute to complex traits like personality. All that changed over the past two decades through a remarkable series of discoveries and scientific breakthroughs that have given us the ability to decipher and analyze the human genome. In recent years, scientists have applied the tools of molecular genetics to unravel which specific genes are involved and how they exert their influence on temperament and personality. If variations in our genes account for about 50 percent of the differences in temperament and personality, we can now ask, which genetic variations are they?
“PEOPLE” PEOPLE
SOME OF THE STRONGEST EVIDENCE THAT GENES CAN AFFECT human temperament and personality comes from rare syndromes where genes go missing.
When I met him for the first time, nineteen-year-old Greg Chislon fairly bounded forward with an outstretched hand and an exuberant “Hi, how are you?” It was the kind of greeting one might expect from an eager job applicant, but we were sitting in an exam room at my hospital. Greg was always drawn to people, his mother told me. On the first day of school, Greg would go up to other children in the class, ask their names, and try to engage them in conversation. The wariness that most kids experience when they encounter new people didn’t seem to register with Greg. If temperament depends in part on how the brain’s approach/avoidance systems are tuned, Greg’s seemed to be set all the way over to the “approach” side of the dial. Within minutes of meeting me, he was telling me about his love of music and asking me about my interests. His mother recalled that he would approach strangers in the supermarket and begin talking to them with a friendly smile. His eagerness to engage with other people was charming to his teachers and other adults, but sometimes made him the victim of teasing and practical jokes by his peers. There was a cost to his indiscriminate affability, and his mother frequently worried that he would be taken advantage of by some unscrupulous stranger. When he was seven, Greg was diagnosed with Williams syndrome. The diagnosis came as a shock, although in retrospect it made sense of a lot of Greg’s behavioral and medical history.
Williams syndrome is a genetic disorder that affects about 1 in 7,500 children who are born with a chunk of DNA missing from one copy of chromosome 7. Children born with Williams syndrome are typically missing about 1.6 million bases of DNA sequence, covering about twenty-five different genes. Not surprisingly, the loss of that many genes can have widespread effects. There can be abnormalities of the major blood vessels due to the absence of one copy of the gene that makes elastin, a protein needed for the strength and flexibility of connective tissues.48 There is increased risk of problems with blood calcium and hormonal systems, and just about everyone with Williams syndrome has a heightened sensitivity to sounds. Children with Williams syndrome are often described as having pixielike facial features, with a short upturned nose, and a wide mouth with full lips. They usually have some degree of intellectual disability, with an average IQ of 55.49
But the most remarkable characteristic of children with Williams syndrome is their intense interest in other people. It’s an interest that’s clear from infancy, when they become enraptured by faces. To meet a toddler with Williams can be intense—she may lock her gaze onto yours and hold it with a fascinated stare. As they grow, they become gregarious and exude a cheerful warmth and guileless affability.
Children with Williams are hypersociable. They’re “people” people. They seem to yearn to connect and affiliate. They’re often effortlessly good at small talk and unusually sensitive to other people’s feelings.
Somehow, the genes deleted in Williams syndrome affect how the brain’s emotional circuitry responds to the social world, resulting in nearly the opposite pattern seen in people who are shy and socially anxious. When presented with fearful or angry faces, they have a subdued amygdala response.50 But that’s only part of the story. It turns out that they have an increased amygdala response to happy faces.51 So the chromosomal deletion that causes Williams syndrome seems to shift the bias of the amygdala toward approaching others and processing positive emotions. And that may hold a key clue to the gregarious personality style of individuals with Williams. Where anxious, inhibited children are hypersensitive to threat, the Williams child is biased to see happiness.52 Not surprisingly, individuals with Williams syndrome seem to be relatively immune to social anxiety and social phobia.
THE LONG AND SHORT OF IT
WHEN IT COMES TO THE GENETIC BASIS OF TEMPERAMENT, THE example of Williams syndrome is an outlier. For most of us, our style of interacting with the world around us can’t be traced to a single stretch of DNA. The broad spectrum of temperament and personality reflects the action of many genes, each contributing a small amount to the overall picture and interacting with our environments and life experiences. This is why when you read headlines like SCIENTISTS FIND THE GENE FOR ANXIETY! or . . . THE GENE FOR BIPOLAR DISORDER or . . . THE GENE FOR almost anything, you should roll your eyes. There is no “the gene” for these kinds of complex traits. There are many genes, and they act like risk factors. Having a high cholesterol increases the risk of developing heart disease, but it doesn’t guarantee it. There are many people with elevated cholesterol who don’t go on to develop heart disease, and many people with heart disease who don’t have high cholesterol. So cholesterol is only one of many risk factors for heart disease, just like individual gene variations (alleles) can be risk factors for developing bipolar disorder.
In fact, recent studies have convincingly identified specific genetic variants that increase risk for psychiatric disorders such as schizophrenia and bipolar disorder.53, 54 But doing so required very large studies involving thousands of subjects, because by themselves each of these genetic variants has a small effect.
So we know that variations in our DNA contribute to individual differences in behavior and risk for mental illness, but we also know that any single gene variant can have a subtle effect. Personality is “highly polygenic”—that is, there are hundreds or even thousands of individual genetic variations involved. Nevertheless, behavior geneticists have so far focused on only a few, and if they had a top ten list of favorite genes, SLC6A4 would be on it.
The SLC6A4 gene makes a protein called the serotonin transporter (also known as 5HTT). Serotonin is a neurotransmitter that has, for many years, been known to play a key role in the development and functioning of brain circuits involved in mood, anxiety, and aggression. Generally speaking, neurotransmitters act as chemical messengers, crossing the tiny junctions known as synapses between nerve cells. At a serotonin synapse, serotonin released from a neuron on one side of the synapse (the “presynaptic neuron”) crosses the submicroscopic divide and binds to receptors on a neighboring (“postsynaptic”) neuron. The neuron that released the serotonin quickly grabs any excess serotonin through its serotonin transporters, which act like little pumps that pick the serotonin up from the synapse and bring it back into the neuron. So the job of the serotonin transporter is “reuptake” of serotonin from the synapse.
This tiny molecular pump has been one of the pharmaceutical industry’s biggest cash cows. Based on the idea that depression involves a dysregulation of brain serotonin, the most widely used antidepressants—Prozac and its cousins Zoloft, Paxil, Lexapro, and others—were designed to block or inhibit the serotonin transporter. That’s why they’re called SSRIs: selective serotonin reuptake inhibitors.
Like other genes, the SLC6A4 gene includes a region called the promoter that regulates how active the gene is—that is, how much serotonin transporter protein it makes. In 1996 German scientists found a common variation (known as the 5HTTLPR) in the DNA sequence of the SLC6A4 gene promoter: the “long” variant, or allele, has an extra forty-four letters of DNA that are missing in the “short” allele. And that simple difference makes the gene carrying the “short” allele less active in making serotonin transporter. Neurons carrying one or two copies of the “short” allele make about half as much of the serotonin transporter as those without any short alleles.55
Variation in the serotonin transporter gene (SLC6A4) promoter (top) and its effects at a serotonin synapse (bottom). Genes carrying the “short” allele make fewer serotonin transporters, which are responsible for reuptake of serotonin into (presynaptic) neurons. SSRI antidepressants act by blocking serotonin transporters
As it turns out, about 75 percent of people with European-American ancestry carry at least one copy of the “short” allele and about 20 percent carry two copies. The lower levels of serotonin transporter made by the “short” allele seem to create a subtle bias in the way the brain responds to threatening or adverse experiences. Several—though not all—studies have shown that people carrying the “short” allele score higher on personality traits like neuroticism and harm avoidance that are related to anxious temperament.56–58
Does the DNA variation in the promoter of the SLC6A4 gene actually affect how our brains respond to threat? In a pioneering study, Ahmad Hariri and his colleagues divided a set of healthy volunteers into two groups: those carrying at least one “short” allele and those carrying two “long” alleles. Then they had them undergo a task similar to the one that Carl Schwartz used in his fMRI study of inhibited temperament. The researchers showed subjects a series of faces expressing emotions of anger or fear. Many neuroimaging studies have shown that exposure to emotional faces activates the amygdala and that people who are anxiety-prone tend to show a stronger amygdala response. Hariri and his colleagues found that indeed, those who carried the “short” allele had stronger amygdala reactions to angry and fearful faces.59 Immediately, groups around the world set out to replicate these findings, and putting these studies together, the results hold up.60 Further studies have shown that the “short” allele may weaken a brake on the amygdala from the brain’s prefrontal cortex.61 In people carrying the “short” allele, then, the amygdala is disinhibited, responding more intensely to signs of danger. They are primed to see threat in the faces of other people.
But genes do not act alone. Mounting evidence suggests that the serotonin transporter “short” allele operates differently depending on what life experiences you’ve had. The gene’s effect depends on the world you live in. For example, in one study, children carrying the “short” allele were more likely to be shy and behaviorally inhibited if their mothers had low levels of social support,62 and the activity of brain circuits involved in perceiving threat is greater among short allele carriers who have experienced more stressful life events.63
OF MICE AND MEN
EVEN IF THE SEROTONIN TRANSPORTER GENE TURNS OUT TO BE A gene that influences temperament, we know that it is not the gene. As I said before, the heritability of temperament involves many genes, each making a small contribution to how our brains interact with the world around us. So if these genes have such subtle effects, is there any way to find them? My laboratory has been pursuing this question for more than a decade. We reasoned that we could make use of the fact that shy, inhibited temperament is seen in many animal species, including mice. Mouse models can be very useful because they allow scientists to perform genetic studies that would be impossible in humans. And genetically, we’re a lot like mice. In fact, more than 99 percent of mouse genes have a counterpart in the human genome.64
The ability to breed and cross large numbers of mice provides a powerful way to rapidly map genes that affect behavior. And beyond that, using sophisticated “gene targeting” techniques, scientists can actually delete or insert specific genes in the genomes of mice. For example we can “knock out” a gene from a mouse embryo and see what effect deleting the gene has on the behavior of the mouse later in life. If mice missing the gene are more fearful, for example, we have evidence that the gene is somehow involved in fear behavior. And if we can find genes related to shy or fearful temperament in mice, we can see whether the same genes affect temperament in humans.
In 1995 a group of scientists at Oxford reported that a region on mouse chromosome 1 is linked to mouse fear behavior.65 Later studies replicated this finding, but the precise gene or genes involved remained a mystery. Then in 2004 the Oxford group seemed to have an answer. Using newer methods for mouse gene hunting, they fingered a gene called rgs2 as at least one of the culprits. Mice carrying one version of the gene were inhibited in a battery of fear behavior tests. Also, rgs2 “knockout mice”—mice born without the gene—are behaviorally inhibited and “anxious.”66, 67 Like temperamentally inhibited children, these mice also have an overactive sympathetic (“fight or flight”) nervous system.68
So what does the rgs2 gene do? Among other things, it makes a protein that controls how nerve cells respond to neurotransmitters like serotonin, norepinephrine, and dopamine—key players in the biology of temperament, anxiety, mood, and stress responses. When these neurotransmitters bind to their receptors on nerve cells, the receptors activate proteins (called G proteins) that set off a cascade of events within the cell. The rgs2 protein gloms onto the activated G proteins and shuts them down, providing an essential brake on the neurotransmitter signal. So a malfunctioning or missing rgs2 gene might leave brain cells vulnerable to overstimulation by neurotransmitters like serotonin. As you might expect, rgs2 is active in many of the key brain regions known to influence temperament and emotion, including the amygdala, hippocampus, and cerebral cortex.69–71
We humans have an RGS2 gene, too. If rgs2 contributes to anxious temperament in mice, could the human version play a similar role? Researchers at my lab studied children who had previously come to Jerry Kagan’s laboratory at Harvard and been exposed to unfamiliar people and situations in the battery of temperament measurements that I described earlier. Later, we had these children and their parents spit into a cup, allowing us to extract DNA from their saliva, which we then analyzed to find variations in the human RGS2 gene. We found that children with specific variants of the RGS2 gene were three times more likely to be shy and inhibited. And one of these variants had previously been shown to correlate with lower expression of the RGS2 gene. In other words, it appeared that having less RGS2 protein was associated with anxious temperament—just what we’d predict from the mouse studies.
Then, in a collaboration with my colleagues Murray Stein and Martin Paulus, at the University of California–San Diego, and Joel Gelernter, at Yale, we asked whether the RGS2 gene might also affect introversion in adults (since introverted adults, like inhibited children, are often shy and wary of unfamiliar people). We analyzed the DNA of nearly 750 adults who had completed a personality assessment and found, indeed, that the same RGS2 variants that predicted childhood shyness were associated with adult introversion.
The key question, though, was whether we could see the effect of this gene in the brain centers that regulate temperament and social anxiety. To answer this, we looked at the RGS2 variants in a cohort of adults who underwent fMRI scans while being shown emotional faces. Sure enough, those carrying the variants associated with inhibited temperament and introverted personality had a substantially stronger response to emotional faces in two key areas of the brain’s emotion (limbic) circuitry: the amygdala and the insula.72
A WINNING PERSONALITY?
THE RGS2 STORY IS NOTABLE FOR TWO REASONS. FOR ONE, IT provided one of the first demonstrations of how a specific gene’s effect on temperament and personality can be seen at both a behavioral and a neurobiological level. But secondly, the RGS2 story provides key evidence that at least some of the genetic influences on temperament and anxiety are evolutionarily conserved. Here’s an example where the same gene seems to affect anxiety-related behavior and brain function from mice to humans. The serotonin transporter short/long variation also points to our evolutionary history, though a more recent one. That variation seems to have arisen about forty million years ago because it is present in monkeys and apes but not in earlier mammals.73 Interestingly, the frequency of the short and long alleles in rhesus monkeys is quite similar to our own. That raises an interesting question—why?
Why would natural selection maintain a common variation like the “short” allele that seems to make animals more timid and “neurotic”? There are several possible explanations, including the possibility that the variation is “invisible” to natural selection—that is, it doesn’t really affect a primate’s reproductive fitness and so natural selection leaves it alone. But if that were true, it’s hard to explain how a mutation in the serotonin transporter gene that apparently arose as a onetime event forty million years ago became so common. It’s also possible that variation in genes that affect temperament and personality is not just evolutionary “noise.” It could be that natural selection might favor certain temperaments. It might seem obvious that a trait like extraversion could provide selective advantages. Individuals who are more social and outgoing might have more opportunities to find mates, for example. But even behavioral inhibition could be a good strategy from a reproductive standpoint: being wary of new situations or people could prevent someone from being preyed on or from engaging in fatal conflict.
So gene variations that contribute to these traits could easily be promoted by natural selection. But if you think about it further, there’s a problem. Remember, these traits are heritable—that means that individuals differ in these traits, and we’re trying to explain the genetic differences that underlie the trait differences. If one temperament or personality type is clearly advantageous, shouldn’t natural selection cause it to become a fixed part of universal human nature? If being shy or avoidant protected our ancestors from harm, the shy ones should have had a reproductive advantage and gradually replaced all the risk-taking types in the human population. Alleles that promoted shy, inhibited behavior would be selected and become “fixed” at high frequencies. So, we’d expect that there would be very little, if any, genetic variation in genes that shape personality. With no individual differences or genetic variation, the heritability of temperament and personality would gradually approach zero. But we know that’s not the case.
EVERYTHING IN MODERATION
ONE EXPLANATION FOR HOW NATURAL SELECTION MIGHT MAINTAIN variation in personality involves something called “balancing selection.” The idea is that personality traits, like everything else in life, involve trade-offs. Agreeableness is great when it allows you to form alliances, but not so great when you need to fight to defend your interests or your family. One form of balancing selection, called “heterozygote advantage”—an advantage that comes with carrying one copy of a mutation—is widely known in medicine. For example, people who carry two copies of a mutation in the β-globin gene, which encodes a protein essential for making hemoglobin, develop the painful and devastating disease called sickle cell anemia. The sickle cell mutation interferes with the flexibility of red blood cells, causing them to assume a rigid “sickle” shape when oxygen levels become low. Sickled red blood cells can get stuck in capillaries, cutting off blood supply and oxygen delivery to the tissues, which in turn can cause excruciating pain and even death.
So why hasn’t natural selection gotten rid of this deadly mutation? It turns out that carrying one copy of the sickle cell mutation results in a mild form of sickling that can reduce the risk of malaria, one of the world’s biggest killers. Because sickle cell anemia only occurs if there are two copies of the mutation, people who carry only one copy of the mutation (heterozygotes) are protected from both sickle cell disease and malaria. That trade-off has allowed the sickle cell mutation to persist in areas where malaria is common. A similar phenomenon could balance out the effects of natural selection on alleles that contribute to personality traits.
Of course, temperamental styles and personality traits come in many flavors, each of which entails trade-offs alone and in combination with other traits. Different combinations of extraversion, neuroticism, openness, and so on may each have their own risks and benefits. So if we have a situation where each trait is affected by many genes, and the advantages of each trait vary over time and context, the alleles that influence that trait may not be eliminated by natural selection, even if they sometimes have disadvantages.74
OUT OF AFRICA
IN THE CASE OF TEMPERAMENT, WE CAN ACTUALLY BEGIN TO SEE the faint footprint of natural selection on human behavior. For example, there is evidence that a gene variant related to personality may have become more common as humans migrated across the globe by subtly enhancing the fitness of those who explored new environments.75
Many studies have pointed to the neurotransmitter dopamine as a key player in regulating how eager we are to seek out new experiences. Dopamine receptors are located in brain regions involved in motivation, exploration, and reward. Just as the amygdala and related fear circuits stamp certain stimuli as dangerous threats to be avoided, these regions mark other stimuli as rewarding opportunities to be approached.
Variations in the gene that makes one of the dopamine receptors (the dopamine receptor D4 or DRD4) have been associated with boldness, novelty-seeking, and high levels of activity and exploration in humans as well as birds, dogs, and horses.76–81 One of these variations involves repeated DNA sequences in part of the gene that determines how the DRD4 receptor responds to dopamine. People differ in how many copies of the repeated DNA sequence they carry. Many people have four copies of this repeated sequence (the “four-repeat allele”), but there are other variants, including a seven-repeat form that appears to make less efficient DRD4 receptors. This seven-repeat allele has been linked to novelty-seeking and may be a risk factor for attention deficit hyperactivity disorder (ADHD).82
With detailed knowledge about the structure of the genome, researchers can now conduct evolutionary detective work (think CSI-meets-Darwin) to track down the history of genetic variations that influence behavior. Using clues from the patterns of variation in the DRD4 gene, a team of geneticists was able to date the origin of the novelty-seeking seven-repeat allele to a mutation that occurred in Africa about fifty thousand years ago (relatively recently in the history of human evolution and around the time of the last major human exodus from Africa).83 Somehow, this recent mutation became common in human populations throughout the world. Rather than remaining rare or disappearing, it actually flourished.
But why would natural selection preserve a genetic risk factor for ADHD? One possibility is that those carrying the seven-repeat allele had an advantage under some circumstances. In an environment where the availability of food or other resources might suddenly change or disappear, people who were able to rapidly respond, move, and seek out new resources might have done better than those who were slower to respond. These were the people whose credo was WHEN THE GOING GETS TOUGH, THE TOUGH GET GOING. As you would expect for a genetic variant that promotes novelty-seeking, the seven-repeat allele becomes more common at the farthest distances from Africa. In South America, which is the endpoint of migrations that would have had to span Africa, Europe, Asia, and North America, the seven-repeat is actually the most common form.84 Perhaps those carrying the genetic form of DRD4 were “bold enough to go where no man had gone before.”
Again, it’s clear that one or two genes don’t tell the whole story of how shy, extraverted, fearful, or aggressive we are. Rather, many genes contribute small amounts to the development and functioning of brain circuits that underlie how we feel about and interact with the outside world. Your 5HTTLPR genotype or DRD4 repeats don’t determine what kind of person you will be. But there is growing evidence that common genetic variation between people may contribute to slight shifts or biases in brain function that influence how we respond to the world around us.
The subtlety of these effects has recently been brought home by very large studies that have used newer DNA chip technology to scan the whole genome for variants affecting the Big 5 personality traits. These “genomewide association studies” are able to examine genetic variations across the entire genome and typically use very large sample sizes. And yet these studies have been unable to find many specific variants related to personality traits, despite the fact that we know these traits are substantially heritable. In other words, we know there are variants to be found, but the vast majority have effects that are too subtle to be picked up even in powerful studies. One meta-analysis of these studies that surveyed more than 2.4 million genetic variations across the genome in more than 17,000 subjects was only able to find two genetic regions that were strongly associated with Big 5 traits—one for openness and the other for conscientiousness.85 In another study that included thousands of people, my colleagues and I found another genetic region associated with excitement-seeking, a central feature of extraversion.86 Finding all of the genetic differences that account for the heritability of personality traits (which you’ll recall is about 50 percent of the total variation in these traits) will probably require massive studies. That’s the lesson emerging from other genetic studies of “complex traits” like obesity. The heritability of obesity is similar to personality traits, but it took a genomewide study of nearly 250,000 people to pick out genetic variations that together account for about 2 percent of the individual differences in body mass index.87 If personality is anything like body weight, you might need to study millions of people to find all of the genes involved.
SHADES OF THINGS TO COME
THERE’S ANOTHER IMPORTANT LESSON IN ALL OF THIS. BY CREATING subtle biases in how we approach life, temperament and its underlying neurocircuitry can sometimes have long-lasting and cascading effects that set us on a troubled trajectory. Children who are extremely inhibited are much more likely to develop significant problems with social anxiety later in life. A temperamental bias toward impulsivity and distractibility can evolve into attention deficits and hyperactivity. And an early tendency to refract one’s experience through the lens of negative emotionality can produce a vulnerability to depression, especially when someone faces adversity. So we begin to see how our temperamental approach to life, itself the reflection of how our neural systems are calibrated, can evolve into symptoms and syndromes that appear as disorders. Not surprisingly, then, genetic variation that underlies temperament and personality seems to account for much of the genetic component of common disorders, including depression and anxiety disorders.88, 89 The biology of normal shades into the biology of disorder.
And that may provide a clue to how treatments for depression and anxiety work.
At the end of my first meeting with Tim Corning, I suggested that we try treating his social anxiety with cognitive-behavioral therapy (CBT), a proven therapy for treating a wide range of anxiety disorders. In CBT, clients learn to recognize and overcome the cognitive biases that exaggerate their social fears. And by gradually exposing themselves to social situations, they become desensitized to the fear that they will do something embarrassing or that other people will judge them harshly. Unfortunately, after twelve weeks of therapy, Tim felt that he wasn’t making enough progress, and he wanted to try something else. And so we agreed to start an SSRI. We began with 25 mg of sertraline (Zoloft) and worked our way up to 100 mg per day. Eight weeks went by with little change. As we continued to increase the dose, Tim began to notice something: he was starting to feel more comfortable eating at the local diner. After two weeks at 200 mg, he told me he’d surprised himself by accepting an invitation to go to a party thrown by his former coworkers. “I could never have done that a year ago. I thought I’d just stand around and watch, but I actually talked to people.” A month later, he went on his first job interview in two years. “I’m a different person,” he said.
Tim may have been on to something. Recent research suggests that SSRIs like sertraline may work in part by subtly changing personality itself. People with depression and anxiety disorders like social phobia tend to be high in neuroticism and introversion (low extraversion). In a placebo-controlled study of the SSRI paroxetine (Paxil) for depression, researchers found that the SSRI “normalized” neuroticism and introversion whether or not their depression improved. And when they controlled for changes in these personality traits, there was no independent effect of the drug on depression. In other words, the antidepressant effect of the SSRI seemed to depend on its ability to recalibrate personality.
Psychological and neuroimaging research has shown that anxiety- and depression-prone people have emotional circuitry that tends to process the world as “a glass half-empty”—a bias toward registering negative emotional and social features of the environment and away from seeing and feeling the positive side of things.
So here’s the emerging picture. Variations in genes make some people more prone to shyness, anxiety, and negative emotions, in part by creating an amygdala-prefrontal cortex circuit that is oversensitive to threat and biased toward negative thoughts and emotions. SSRIs, and perhaps CBT, seem to retune that circuitry, damping down a sensitive emotional system and shifting its bias toward a more “glass half-full” approach to life.90 When people with depression or anxiety and even healthy volunteers are given SSRIs, MRI scans show a cooling down of emotional circuits that have been linked to inhibited, anxious temperament and neuroticism.91–93 So perhaps for Tim Corning, whose genetic endowment and life experiences had amplified his inhibited temperament into debilitating social anxiety, medication offered a way to nudge him back toward the middle of the normal distribution.
Evidence from both psychological and genetic studies points to the notion that the most common psychiatric disorders are really the extremes of normal, quantitative traits that all of us share. And like other quantitative traits—blood pressure, body weight, cholesterol levels, for example—where we draw the line between normal variation and dysfunction may be a pragmatic decision. Some experts have gone so far as to say that “what we call common disorders are, in fact, the quantitative extremes of continuous distributions of genetic risk . . . there are no common disorders—just the extremes of quantitative traits” (p. 877).94
We enter life with brains that have been tuned by our genes and the environment of the womb. Temperament shapes the timbre of our earliest notes and probably constrains our dynamic range throughout life. But as we will see in the next chapter, early experience can profoundly alter the path we take in life. The picture emerging from neuroscience and genetic research is one of continual dialogue between the brain and experience, each modifying the other throughout development. As Tim Corning found, the people we become, our personalities, are the product of the small adjustments we make and the imperceptible turns we take as our innate temperaments encounter our own particular world.
* By the environment, I mean everything that isn’t encoded in the sequence of our DNA. That includes the natural environment (the availability of food, weather patterns), the social environment (interactions with other people, the size of our families and communities), and even the gestational environment (the womb).