Genetics of aggression regulation

Started by Volunto, Feb 07, 2023, 06:55 PM

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Various studies show dozens of genes that affect certain aspects of offensive aggression. However, it is obvious that for effective regulation of aggression, the number of genes and neurotransmitters involved in this process must be limited (i.e., only some of them should play a key role). A range of evidence, ranging from evolutionary ancientry to pharmacological and clinical data, points to 5-HT1A and 5-HT1B receptors.

Since 5-HT1A and 5-HT1B receptors play a key role in the modulation of aggression, the genes corresponding to them are part of the genetic nature of the violence inhibitor (in humans, it is HTR1A gene, localized on chromosome 5, and HTR1B gene, localized on chromosome 6). Knockout of the 5-HT1B gene in mice resulted in increased aggressiveness in their behavior. Knockout of the 5-HT1A gene did not give such a result, however, this can be explained by the functional difference between the corresponding presynaptic and postsynaptic receptors, which we discussed earlier, as the gene knockout affects both types of receptors at once.

The fact that antisocial alcoholism (leading to impulsive and aggressive behavior) is associated with some alleles of the 5-HT1B gene is an example of clear evidence of the role of serotonin receptors in the modulation of aggression in humans. Compared with a control group of healthy individuals and non-aggressive alcoholics, antisocial alcoholism in Finns was significantly associated with the HTR1B H861C polymorphism and to some extent with the HTR1B D6S284 polymorphism. Both polymorphisms were also significantly associated with antisocial alcoholism in the studied American Indian tribe. In addition, the HTR1B rs11568817 genotypes were found to be very different between groups of children with high and low scores of CU-traits.

In addition to the 5-HT1A and 5-HT1B genes, it is also important to consider three more genes: TPH2, MAO-A (also known as the "warrior gene"), and SERT. Their respective enzymes are involved in 5-HT synthesis in the brain. In the case of the TPH2 gene, the C1473G allele may play an important role. 129X1/SvJ mice, homozygous for the 1473C (C/C) allele, were more aggressive than mice of the BALB/cJ strain, homozygous for the 1473G (G/G) allele. However, the difference in alleles did not affect penetrance – the percentage of mice that exhibited aggressive behavior when the corresponding allele was present. It was also found that the intensity of aggression is not related to its penetrance. However, in the case of rats and silver foxes, in which low aggressiveness was achieved by selection, increased activity of the TPH enzyme (as well as higher concentrations of serotonin and its metabolite, 5-HIAA) was observed. It should also be noted that the knockout of the TPH2 gene in rats led to aggressive behavior from a decrease in the sensitivity of 5-HT1A receptors.

Mice with MAO-A gene knockout showed increased aggressiveness and decreased 5-HIAA levels, which also indicates a decrease in the function of the 5-HT system. The same can be seen in humans as well. Males from one Dutch family with a point mutation in exon 8 of the MAO-A gene showed an increased level of impulsive aggression. Moreover, polymorphism in the promoter region of the MAO-A gene was associated with antisocial alcoholism in German subjects. Many other studies also demonstrate that mutations in the MAO-A gene are associated with abnormal male aggression.

Also, one study found that carriers of a low-active variant of the MAO-A gene, due to childhood abuse, were up to 4 times more likely to commit violent crimes in adulthood. At the same time, carriers of the high-active variant turned out to be "immune" to abuse and did not become more violent than the average individual.

Mice with a knockout of the serotonin transporter gene SERT (SLC6A4) showed reduced aggression in their behavior due to stopping serotonin reuptake and a corresponding increase in its level. However, it should be understood that the serotonin transporter is also involved in the modulation of other processes, so such elimination of its function can only have a non-selective effect (which we will see a little further). Still, it should be of note that the short variant (S) of the promoter region of the gene (5-HTTLPR) leads to a decrease in the expression of the 5-HTT protein. For the homozygous allele (S/S), it showed a significant relationship with aggressive behavior and a tendency for violence in people in various samples: children, adults, adopted children, cocaine addicts, and patients with conduct disorder. In addition, this allele is associated with decreased responsiveness of the amygdala.