MAOA and CDH13: The “serial-killer genes”

Priasha Dutta, Amity University Kolkata

We all know how our genes are responsible for the transmission of characteristics like physical features, conditions, and diseases from one generation to the other. However, the discovery of a set of genes found in some individuals known as the “serial-killer genes” (or the “murder genes”) leads us to the question- Are serial killers really to blame? Or is it just an unavoidable instinct that runs in their blood? This article, without justifying the cold-blooded actions in any way, highlights the genetic and other possible factors that lead to such a deadly behavior. 

In the year 2010, an Italian judge made history by diminishing the sentence of a male convict who was accused of murder, after the convict was found to be a carrier of genetic variants that were presumed to be associated with a tendency for aggression. The defense, on conducting a ‘genetic susceptibility test’ showed that the convict carried certain variants for the MAOA, CDH13, SCL6A4, DRD4, and COMT genes, which have been linked with aggression modulation. MAOA and CDH13 genes are proven to be the two key players.

The first discovery:

A classic study in 1984 first showed the significant correlation between biological parents and adoptees for property crimes but not violent crimes. Much of the genes involved in serotonin pathways, such as SCL6A4, have been studied for their implication in impulsivity and substance abuse. Serotonin is a neurotransmitter that is involved in many functions like mood regulation, maintaining happiness and well-being. For instance, the HTR2B gene encodes one of the numerous receptors for serotonin. In 2010, a stop codon in the HTR2B mRNA was found that was associated with substance abuse and increased risk of committing impulsive crimes like homicide, arson, etc. But researchers were unable to prove whether the functional variant of HTR2B, a form of the gene that changes its function, was associated with substance abuse, or impulsivity. So, no conclusions were found about whether the gene made the person prone to substance abuse, which then resulted in impulsive, crime-causing behavior; or whether it just caused a tendency to act in an impulsive manner, leading to criminal behavior and substance abuse. This issue is known as the “direction of causality”.

The MAOA Gene:

 MAOA gene (also called the ‘warrior’ gene) is the most well-known among all of the ones mentioned above. This gene codes for the enzyme monoamine oxidase-A which is vital for the breakdown of neurotransmitters like serotonin. Individuals with defects in the MAOA gene, such as point mutations, are generally associated with a low dopamine turnover rate, thus developing a stronger tendency towards aggressive behavior than their counterparts. 

Scientists have carried out knockout studies of the MAOA vs MAOB (monoamine oxidase-B) enzymes in mice. This exhibited contrasting behaviour based on whether oxidase-A or -B is knocked out. The two enzymes oxidize different substrates and the resulting build-up of particular compounds when one enzyme is knocked out explains why MAOA knockout mice demonstrate aggressive behaviour. The MAOB ones, on the other hand, do not. As of 2014, several meta-analytical studies had shown interactions between the low-functioning variant (causing loss or reduced function) of the MAOA genotype and abusive childhood on antisocial outcomes. But the research on the MAOA gene was controversial because it still could not establish the exact relationship between antisocial behaviour and abusive childhood experiences. 

THE CDH13 GENE– 

To get more clarity on the causal direction, an interesting and insightful study was conducted in 2015. Jari Tiilhonen, a Professor in the Department of Clinical Neuroscience at the Karolinska Institute in Sweden, conducted a genome-wide association study (GWAS) with his group of colleagues on the genetic predispositions to repeat offenders and violent behaviors in a unit of Finnish prisoners. They formed two groups – violent, (which had at least one conviction of a violent crime like manslaughter or murder) and extremely violent, which had at least 10 violent crime convictions). 

The ‘extremely violent’ group was a subset of the ‘violent group’. It was found that the low-activity MAOA genotype was associated with violent offending and this did not differ between males and females. It was also seen that the risk was not influenced by childhood difficulties like in some previous studies. But the low-activity variant of the MAOA gene (i.e., the risk allele) was responsible for developing alcoholism in those who had faced some sort of childhood trauma. The association was stronger for the extremely violent group. In the individuals belonging to the latter, an additional strong association was found in a single nucleotide polymorphism (SNP) in the CDH13 gene. 

CDH13 gene codes for T-cadherin, a GPI-anchored protein, which is important in the migration, proliferation, and connectivity of neurons. Apart from being a major cell adhesion protein, it regulates several key signaling pathways- the P13K-AKT pathway and the signaling of small RhoGTPases. CDH13 is especially expressed in 5-HT neurons, and RNAi of CDH13 produces a decrease in the density of both glutamatergic and GABAergic synapses. CDH13 also contributes to maintaining excitatory and inhibitory synapses. It has been suggested that disturbed neural connectivity is the main pathophysiological mechanism underlying behavioral problems in attention-deficit/hyperactivity disorder (ADHD), a disorder whose core symptom is losing impulse control. Thus, it is strongly associated with violent criminality. 

To prove this, more than 20 studies have found associations between CDH13 and ADHD, schizophrenia, substance abuse, autism, or bipolar disorder. A genome-wide association analysis was performed to show that CDH13 variants are associated with working memory and cortical thickness in the dorsolateral prefrontal cortex of patients with ADHD. A meta-analysis concluded that about 25–30% of prisoners fulfill the criteria for ADHD symptoms. About 80% of the Finnish homicides were impulsive, unplanned crimes and it is plausible that an impulse control deficit is a link between the CDH13 genotype and impulsive violent behavior. On the basis of the replication cohort results, a considerably large percentage of violent crimes in Finland were attributable to the CDH13 genotype.

After many case studies and genetic analyses, the boundary between responsible scientific results and the bioethical application to the justice system starts to haze. Genetic susceptibility might lead to the mitigation of responsibility in convicts during trials, leading to decreased punishments. If we proceed to excuse people who are carriers of the “serial killer genes” we risk stigmatization at unparalleled levels. Labels can lead to widespread discrimination, genomic profiling, blurred social-equality norms, and resultant increased punishment without provocation. Although the presence of genes is not an excuse for any individual to go on a killing spree, it is unfortunate that some of them exhibit this kind of behavior unwillingly. 

Research on the CDH13 gene gave more substantial results, but studies on the MAOA gene are riddled with controversy. Males were mostly the subject of the genetic analysis as it is an X- linked recessive condition. Moreover, there is psychological and statistical evidence that supports the fact that males are prone to aggression, anger, and acting on impulse. This can be suggested as a reason why there is a higher percentage of male serial killers compared to females. Geneticists and biochemists however are still trying to decode the exact mechanisms of these genes and establish their link to antisocial behaviour. After all, who would know that inheriting these serial killer genes from their lineage would be an inevitable crime by itself?

Also read: 3D Bioprinting: A Technology for Prevention and Therapy of Infectious Diseases

References:

1. Evans, L., Engelman, M., Mikulas, A., & Malecki, K. (2021). How are social determinants of health integrated into epigenetic research? A systematic review. Social science & medicine (1982), 273, 113738. https://doi.org/10.1016/j.socscimed.2021.113738
2.  J. D. Davydova, S. S. Litvinov, R. F. Enikeeva, S. B.  Malykh, E. K. Khusnutdinova- “Recent advances in genetics of aggressive behavior” (2018). https://doi.org/10.18699/VJ18.415
3. Faizan Anwer – “The Heritable Component of Crime and the Genetics of Justice” (2019). https://journal.indianlegalsolution.com/2019/01/15/the-heritable-component-of-crime-andthe-genetics-of-justice-faizan-anwer/
4. Dominik Pascal Kiser – “Gene x Environment Interactions in Cdh13-deficient Mice: CDH13 as a Factor for Adaptation to the Environment” (2019)

DOI- https://doi.org/10.25972/OPUS-17959

5. Anusha Subramanian- “BORN TO KILL? THE STORY OF ‘SERIAL KILLER’ GENES” (2020)- https://bsj.berkeley.edu/born-to-kill-the-story-of-serial-killer-genes/

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