A Violence in the Blood

Five generations of aggressive men in a Dutch family have led researchers to a gene that seems to lie at the root of the violence.  One day in 1978 a woman walked into University Hospital in Nijmegen, the Netherlands, with a problem: the men in her family. Many of them--including several of her brothers and a son--seemed to have some sort of mental debility. Gradually, as the clinical geneticists who counseled the woman got to know her and her family, the details of the strange behavior of the woman’s male kin emerged. One had tried to rape his sister; another had tried to run his boss down with a car; a third had forced his sisters to undress at knife point. Furthermore, the violent streak had a long history. In 1962 the woman’s granduncle had prepared a family tree that identified nine other males with the same disorder, tracing it as far back as 1870. The granduncle, who was not violent himself--he worked in an institution for the learning disabled--had apparently come to suspect that something was terribly wrong with his family.  Three decades later, and 15 years after the woman’s first office visit, geneticist Han Brunner and his colleagues at the Nijmegen hospital think they’ve figured out what that something is. Some of the men in the woman’s family, they say, suffer from a genetic defect on the X chromosome- -a defect that cripples an enzyme that may help regulate aggressive behavior. If Brunner and his colleagues are right, it would be the first time a specific gene has been linked to aggression. That means their finding cannot fail to be controversial.  The geneticists’ first clue to the origin of the aggressive behavior in the Dutch family was simply that all the violent family members were men; moreover, the trait seemed to be handed down from mother to son. That pattern immediately suggested that the root of the disorder was a defect on the X chromosome. Men are vulnerable to such a defect because they only have one X chromosome. Women have two X chromosomes, so as long as the second one is normal they don’t feel the effects of a defect on the first. But they can carry the defect and pass it on to their sons.  The second clue to the nature of the disorder came from the IQs of the affected men, which were typically about 85, on the border of what is considered mental retardation. (Only one of the five men examined by the geneticists had even completed primary school.) X-linked mental retardation is a well-known phenomenon; it comes in many forms and is caused by many different genetic defects, but aggressive behavior is one of its more common symptoms. The Nijmegen geneticists had often seen X-linked retardation. At first, all they could do for the worried woman who had walked into their office was tell her that her male relatives appeared to have a mild form of it, traceable to a defect on the X chromosome--precise location unknown.  By 1988, though, two things had happened to change the situation. The men in the family were continuing to be violent in a way that didn’t seem mild and that frightened the women enough to seek help again. The youngest generation of women were reaching their twenties, says Brunner, who joined the Nijmegen group in 1984, and they wanted to know if they were carriers. By then, a key gene-mapping technique had improved enough to allow the geneticists to tell them.  The technique is called genetic linkage analysis. It consists essentially in analyzing a chromosome to find an identifiable stretch of DNA that is always inherited along with a still-unidentified genetic defect--to find, that is, a genetic marker that lies near the defect on the chromosome. Over the course of four years, Brunner and his colleagues analyzed the X chromosomes of 28 members of the Dutch family. Finally they found a marker. It was on the short arm of the X chromosome, says Brunner, and the match with the clinical condition was absolutely perfect. The violent men examined by the researchers all had the marker, and so did some of the women--they, presumably, were carriers of the genetic defect. None of the nonviolent men had it. The chance of such a coincidence occurring randomly, says Brunner, is about 1 in 5,000.  The researchers still did not know the nature of the genetic defect itself, but now they had a clue. Although hundreds of genes, most of them unidentified, lay in the vicinity of the marker, one was of particular interest. It was known to code for an enzyme called monoamine oxidase A, or MAOA. MAOA’s job is to break down three important neurotransmitters-- chemicals that trigger or inhibit the transmission of nerve impulses. One of the three is norepinephrine, which raises blood pressure and increases alertness as part of the body’s fight or flight response. The other two neurotransmitters that MAOA breaks down are serotonin and dopamine, which are also involved in regulating mood and alertness, and imbalances of which are often found in patients with psychiatric disorders. The MAOA gene thus seemed like a good place to look for a defect associated with mental retardation and aggressive behavior.  If the violent men were suffering from defective MAOA, Brunner and his colleagues reasoned, excess levels of the neurotransmitters would accumulate in their bodies and in their urine. So the researchers tested the men’s urine. They found excess levels of all three neurotransmitters. They also found extraordinarily low levels of breakdown products--the substances normally left over after MAOA has done its work.  Brunner and his colleagues don’t know how MAOA deficiency might result in a lower IQ, but they think the excess neurotransmitters may amount to a kind of biochemical hair trigger that predisposes the men to violence when they are under stress. (Two of the men, for example, committed arson following the death of a close relative.) We can’t say a genetic defect causes the behavior, says Brunner. It is only one element. What we observe in these men is a lowered threshold for this type of behavior.  Even that seemingly measured conclusion is likely to excite controversy, however; the very notion that there might be biological roots to aggression carries such emotional freight these days that last year the National Institutes of Health was forced by a public outcry to cancel a conference on the subject. Skeptics point out that even though the Dutch study was confined to one family--which may limit its significance, they say--Brunner’s group did not attempt to measure the influence of a shared environment on the violent men.  Yet the possibility that MAOA deficiency might be associated with behavioral abnormalities was predicted as far back as the late seventies, on the basis of experiments with rats and mice. And some researchers who have studied the enzyme are impressed with Brunner’s results. Xandra Breakefield, a neurogeneticist at Massachusetts General Hospital who has cloned the MAOA gene, is now collaborating with Brunner to pinpoint the genetic defect in the Dutch family. Breakefield wants to find out whether the Dutch disorder is a rare, esoteric illness, as she puts it, or a relatively common deficiency. Rare or not, she says, MAOA deficiency may one day be treatable, either through dietary restrictions designed to limit the body’s synthesis of neurotransmitters, or through drugs that block their action.  Even if MAOA deficiency turns out to explain more than the strange history of one Dutch family, though, it is not likely to be anything remotely resembling a generalized biological root for aggressive behavior. Such behavior must have many causes. There is no such thing as an aggression gene, says Brunner. Rather there is a balanced system known as the brain. If it’s disturbed, you may have this type of behavior.  But Brunner and his colleagues are convinced they have found one particular form of disturbance that leads to aggression. When we started, Brunner points out, we were unaware of the huge literature linking MAOA deficiency and aggression in rats and mice. We weren’t looking for what we found, and I think that strengthens our credibility.