Impulsivity has been linked to various psychiatric disorders and forms of violent behaviour. A gene mutated in a population of violent Finnish criminal offenders provides clues to the neural basis of this trait. See article p.1061
An old adage admonishes us to look before we leap. This bit of common sense reflects a crucial and complex brain function that regulates behaviour. To act without thinking — impulsivity — is to risk leaping off a cliff. But to excessively delay an action may lead to inaction or missed opportunities. Now, using a powerful genomics approach, Bevilacqua and colleagues1 dissect elements of the neurotransmitter system in the brain that mediates impulsivity and show that the serotonin 2B receptor (HTR2B) has a role in severe impulsivity, at least in one human population (page 1061 of this issue).
Impulsivity is generally thought to be a failure of inhibitory function in the brain2. Clearly, fine-tuning of such inhibition is important for an organism to adapt to its environment. Impulsivity has been linked to a variety of behavioural and psychiatric syndromes, including attention deficit hyperactivity disorder, mania, drug addiction and borderline personality disorder (BPD)3,4. It has also been associated with violent behaviour, as seen in antisocial personality disorder (ASPD) and intermittent explosive disorder (IED), and with suicide. Several neurotransmitters — serotonin and dopamine in particular — have been implicated in mediating impulsivity, but unravelling the underlying mechanisms has proved challenging.
In their search for genes predisposing to impulsivity, Bevilacqua et al.1 used the well-studied 'founder' population of Finland. Because of the country's relative isolation, the current Finnish population is believed to be largely derived from two waves of immigration 4,000 and 2,000 years ago5. It has therefore been argued that, compared with other, more-outbred populations, there may be fewer mutations for genetic traits in this population, and studies of various genetic disorders support this assumption. To further enhance their odds of success, Bevilacqua and co-workers focused on Finnish subjects with the most extreme manifestation of impulsivity — violent offenders whom the authors evaluated in a forensic psychiatric unit and who had strong lifetime histories of aggressive acts.
Specifically, Bevilacqua et al. examined 96 individuals for 14 candidate genes, using next-generation sequencing technology to identify possible disorder-causing mutations. They focused on the protein-coding regions (exons) of the genes as the regions in which mutations would most probably affect gene function. They found a variation at a single nucleotide base — dubbed HTR2B Q20* — in the HTR2B gene, which results in an erroneous stop codon, a signal that ends further protein extension. The researchers show that this mutation triggers a process called nonsense-mediated RNA decay, such that no HTR2B-receptor protein is expressed.
The HTR2B Q20* mutation was present in the violent offenders at three times the rate of that in matched controls (psychiatrically normal Finnish individuals). It was also inherited, along with psychiatric illnesses such as ASPD, IED and BPD, by members of their families. The 17 violent offenders who carried HTR2B Q20* had all committed an average of five violent crimes, 94% of which were committed under the influence of alcohol. These crimes were largely aggressive reactions to minor events that lacked premeditation or financial gain as a goal.
The authors' results are consistent with many animal and human studies that implicate serotonin in impulsive behaviour6,7. Previous studies have in general supported the idea that low serotonin levels are associated with impulsive action. For instance, activation of the 5-HT1A receptor, which may inhibit serotonin release, has been linked to impulsivity in animal models8. Moreover, the levels of 5-hydroxyindoleacetic acid — a metabolite of serotonin — are reduced in the cerebrospinal fluid of people who are suicidal9. Furthermore, individuals whose serotonin levels have been experimentally lowered by diet are more likely to make impulsive choices10. Nonetheless, the role of serotonin is probably complex, not least because the serotonin system includes 14 different receptors with sometimes opposing actions.
The HTR2B receptor received little attention in earlier studies of impulsivity. So, to support their human data, Bevilacqua et al.1 examined mice that lack the Htr2b gene. They observed increased impulsive behaviour in these animals according to several measures. How exactly HTR2B deficiency leads to this effect remains unclear, although the authors find that both male mice lacking Htr2b and men carrying the HTR2B Q20* mutation have elevated levels of the hormone testosterone.
Previous work2 suggests that HTR2B may function by modulating both serotonin and dopamine in the nucleus accumbens — a brain region involved in impulsive behaviour (Fig. 1). For instance, the 'club drug' ecstasy has been shown11 to stimulate the release of both serotonin and dopamine in the nucleus accumbens by directly activating HTR2B. It could therefore be that depletion of the HTR2B receptor results in increased impulsive behaviour by reducing the release of both serotonin and dopamine in the nucleus accumbens. However, much more work is required to elucidate how HTR2B regulates impulsive behaviour through its modulation of the interaction between pathways involving serotonin and dopamine.
Bevilacqua and colleagues' observation1 that the HTR2B Q20* mutation is unique to Finns serves as yet another reminder of the high level of heterogeneity likely to be seen in complex genetic traits and the importance of population history. But although this specific mutation is absent in non-Finnish populations, different mutations in the HTR2B gene might operate in other populations.
Bevilacqua and colleagues' paper also illustrates the power of exon-based sequencing in founder populations, and suggests that exonic mutations of strong functional effect do play a part in complex behavioural traits.
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