Authors – 1. Ketaki Baravkar , Prisha Wahal , Sumant Ghantewar , Uditi Verma 

The relationship between environment, genetics, and behavior creates the foundation for many psychological and neurological studies. The most noteworthy genes promoting behavior are the MAOA (monoamine oxidase A) and CDH13 (Cadherin 13) genes. MAOA controls and manages Neurotransmitters like dopamine, serotonin, and norepinephrine. These are important mood regulators for emotional control and aggression.

MAOA and CDH13 mutations/variations and “serial killer genes” like forehand then always related to extreme behavior, such as impulsivity, aggression, and violent tendencies, However, it’s important to note that these predispositions are not working in isolation. Environmental factors like childhood neglect, childhood trauma, and stress all interact with the genes MAOA and CDH13 to affect behavioral outcomes. While CDH13 has been implicated in disorders such as Autism spectrum disorder and ADHD and perturbations in the pathways have been linked to impulsive and antisocial behavior, these results have catapulted these genes into conversations surrounding the biological basis of behavior and mental health. The negative experiences in early childhood expand variations in the MAOA and CDH13 gene which results in a greater risk of aggression, emotional imbalance and anti-social human behaviour.

However, genetic predispositions alone can’t determine the behavior. It cannot overemphasize the role of environmental factors such as neglect, childhood trauma, and chronic stress in determining the expression of these genetic tendencies. Research has shown that adverse experiences during sensitive developmental periods are thought to program the behavioral consequences of genetic variations. For example, children who are subjected to ill-treatment tend towards antisocial behavior when with the MAOA-L variant. Also, adverse conditions are significantly more likely to reduce the development of neural connectivity that is controlled by CDH13, making people more susceptible to emotional dysregulation and bad behavior. This interaction of gene and environment is complex and further illustrates the implication of this for research into mental health.

So this article will detail the far-reaching function of MAOA and CDH13 in neurotransmitter regulation, alongside the synergistic other environmental component (i.e., childhood trauma) linked with the heightened incidence of anxiety, PTSD, and other behavioral disorders. Also, we wish to analyze the research situation, draw attention to the literature gaps, and discuss the implications of the findings. Through the nature-genetics and nurture-environment interaction, this subject sheds insightful light on the viability of aggression, mental health disease, and the general effect on societal stability. To avoid the pitfalls of extreme outcomes, both positive and negative, this journey ends with the highlighting of the need to encompass both nature and nurture elements.

Background and literature 

Monoamine Oxidase A (MAOA), also known in the media as the “warrior gene,” has been widely discussed because of its association with aggressive and impulsive behaviors. This enzyme is crucial for the breakdown of major neurotransmitters like serotonin, dopamine, and norepinephrine, which control mood and behavior (Shih et al., 1999). The MAOA gene, with its low-activity variant MAOA-L, has been related to heightened aggression and antisocial behaviors in those who suffer early-life trauma or abuse (Caspi et al., 2002).

It has been suggested that the MAOA-L variant is responsible for vulnerability to extreme behavioral outcomes, typically presenting in individuals exposed to environmental stressors as violent tendencies. The interaction between the gene and the environment serves as the basis for its characterization as a “serial killer gene,” though the term grossly simplifies the interaction of biological and environmental elements.

Evidence of MAOA’s contribution to criminality has been reported from studies in populations with a higher frequency of the MAOA-L variant, which was characterized by increased impulsivity and reduced emotional control (Buckholtz & Meyer-Lindenberg, 2008). Such a biological susceptibility can predispose a person to more extreme forms of antisocial behaviors, but this is not in any way deterministic. It simply points out a possible avenue through which genetics contributes to aggression.

Cadherin 13 (CDH13)

CDH13 is a gene that encodes a non-classical cadherin molecule and is primarily associated with neural connectivity, synaptic plasticity, and neuronal migration (Takeuchi et al., 2000). Although not as widely known in public discourse as MAOA, CDH13 has also been associated with antisocial behaviors, including those found in individuals with psychopathic tendencies. Genome-wide association studies have implicated CDH13 in the regulation of impulsivity and aggression, thereby making it a candidate for studies on violent behavior (Franke et al., 2009).

The gene has been dubbed a “risk gene” in the context of Attention-Deficit/Hyperactivity Disorder (ADHD) and other neurodevelopmental disorders, often associated with impulsive and risk-seeking behavior. Importantly, these traits have been quite common in the profiles of serial offenders, which has further contributed to its reputation as a “serial killer gene.” Research indicates that CDH13’s neural connective function can compromise the brain’s ability to manage emotions or control executive functioning, both significantly important for prosocial behaviors (Langley et al., 2011).

Are MAOA and CDH13 “Serial Killer Genes”?

Designating MAOA and CDH13 as “serial killer genes” is, in essence, a creation of media sensationalism. Scientifically, these genes are related to behavioral characteristics that may enhance the risk for antisocial or violent behaviors when matched with certain environmental factors. For instance, those carrying the MAOA-L variant who were subjected to childhood abuse have a statistical propensity to commit violent acts than their counterparts who lack such genetic predisposition or environmental trigger (Caspi et al., 2002).

Similarly, CDH13’s involvement in regulating neural connectivity may predispose individuals to impulsive or aggressive behavior, particularly when combined with factors like poor social support, trauma, or neurodevelopmental disorders. However, neither gene alone is sufficient to “create” a serial killer. Instead, they highlight the intricate gene-environment interactions that contribute to the development of extreme behaviors.

This study contributes to understanding more complex biological factors that might support aggression and antisocial behavior, but so does CDH13. Their genetic factors themselves are non-deterministic rather than offering clear insight into whether genetics work with the environmental factors to exacerbate human behavior. Indeed, this does not lend the “serial killer gene” terminology much merit for the label and does not guarantee violent behavior upon expression.

Monoamine Oxidase A (MAOA)

Monoamine Oxidase A (MAOA), also known in the media as the “warrior gene,” has been widely discussed because of its association with aggressive and impulsive behaviors. This enzyme is crucial for the breakdown of major neurotransmitters like serotonin, dopamine, and norepinephrine, which control mood and behavior (Shih et al., 1999). The MAOA gene, with its low-activity variant MAOA-L, has been related to heightened aggression and antisocial behaviors in those who suffer early-life trauma or abuse (Caspi et al., 2002).

It has been suggested that the MAOA-L variant is responsible for vulnerability to extreme behavioral outcomes, typically presenting in individuals exposed to environmental stressors as violent tendencies. The interaction between the gene and the environment serves as the basis for its characterization as a “serial killer gene,” though the term grossly simplifies the interaction of biological and environmental elements.

Evidence of MAOA’s contribution to criminality has been reported from studies in populations with a higher frequency of the MAOA-L variant, which was characterized by increased impulsivity and reduced emotional control (Buckholtz & Meyer-Lindenberg, 2008). Such a biological susceptibility can predispose a person to more extreme forms of antisocial behaviors, but this is not in any way deterministic. It simply points out a possible avenue through which genetics contributes to aggression. 

Cadherin 13 (CDH13)

CDH13 is a gene that encodes a non-classical cadherin molecule and is primarily associated with neural connectivity, synaptic plasticity, and neuronal migration (Takeuchi et al., 2000). Although not as widely known in public discourse as MAOA, CDH13 has also been associated with antisocial behaviors, including those found in individuals with psychopathic tendencies. Genome-wide association studies have implicated CDH13 in the regulation of impulsivity and aggression, thereby making it a candidate for studies on violent behavior (Franke et al., 2009).

The gene has been dubbed a “risk gene” in the context of Attention-Deficit/Hyperactivity Disorder (ADHD) and other neurodevelopmental disorders, often associated with impulsive and risk-seeking behavior. Importantly, these traits have been quite common in the profiles of serial offenders, which has further contributed to its reputation as a “serial killer gene.” Research indicates that CDH13’s neural connective function can compromise the brain’s ability to manage emotions or control executive functioning, both significantly important for prosocial behaviors (Langley et al., 2011).

Are MAOA and CDH13 “Serial Killer Genes”?

Designating MAOA and CDH13 as “serial killer genes” is, in essence, a creation of media sensationalism. Scientifically, these genes are related to behavioral characteristics that may enhance the risk for antisocial or violent behaviors when matched with certain environmental factors. For instance, those carrying the MAOA-L variant who were subjected to childhood abuse have a statistical propensity to commit violent acts than their counterparts who lack such genetic predisposition or environmental trigger (Caspi et al., 2002).

Similarly, CDH13’s involvement in regulating neural connectivity may predispose individuals to impulsive or aggressive behavior, particularly when combined with factors like poor social support, trauma, or neurodevelopmental disorders. However, neither gene alone is sufficient to “create” a serial killer. Instead, they highlight the intricate gene-environment interactions that contribute to the development of extreme behaviors.

There is evidence in real-life cases of the potential link between criminal behavior and genetic markers, such as MAOA and CDH13 genes. The “MAOA gene,” popularly known as the “warrior gene,” has been associated with increased aggression in individuals carrying a particular low-activity variant. One case that is particularly worth mentioning is that of Bradley Waldroup, whose defense during his trial focused on his genetic predisposition. Waldroup, convicted of murder and attempted murder in Tennessee, carried the MAOA gene variant, and his legal team argued this predisposition, combined with childhood abuse, contributed to his violent actions (Raine, 2013). Similarly, the CDH13 gene has been linked to impulsivity and antisocial behavior. A Finnish study on more than 900 prisoners reported that the group of individuals carrying both MAOA and CDH13 gene variants was overrepresented in violent offender groups (Tiihonen et al., 2015). These findings are suggestive of a genetic influence, but one must not forget that genetic predispositions interact with environmental factors, such as upbringing and social context, to shape behavior. Critics argue that this overemphasis on genetics risks oversimplifying the complex interplay of biology and environment in criminal behavior. Therefore, although these genes may help explain tendencies, they cannot be said to determine criminality.

This study contributes to understanding more complex biological factors that might support aggression and antisocial behavior, but so does CDH13. Their genetic factors themselves are non-deterministic rather than offering clear insight into whether genetics work with the environmental factors to exacerbate human behavior. Indeed, this does not lend the “serial killer gene” terminology much merit for the label and does not guarantee violent behavior upon expression.

THEME: CDH 13 AND ADHD

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental condition characterized by persistent patterns of inattention, hyperactivity, and impulsivity. While the exact causes of ADHD remain complex, recent genetic research has shed light on the role of various genes in the development of the disorder. One such gene that has garnered increasing attention is CDH13, a cadherin gene involved in neural connectivity, synaptic development, and neuroplasticity. This article explores the potential mechanisms through which CDH13 may contribute to ADHD, with implications for diagnosis, treatment, and future research.

CDH13 encodes a protein responsible for cell adhesion and the formation of neural connections. This gene plays a significant role in synaptic plasticity, the process by which synapses (the connections between neurons) are strengthened or weakened based on activity and experience. The importance of CDH13’s influence on neural circuits is particularly evident during critical periods of brain development, such as childhood and adolescence, when the brain undergoes extensive remodeling (O’Leary & Stein, 2016). Disruptions in synaptic plasticity can have lasting effects on cognitive function and behavior, especially in individuals with ADHD.

CDH13’s involvement in synaptic organization is central to the development of ADHD. The gene affects dendritic spine morphology, referring to the tiny protrusions on neurons where synapses are formed. Changes in dendritic spine shape and density can lead to weakened synaptic connections, particularly in brain areas responsible for attention and executive functions (Lee et al., 2019). In ADHD, alterations in synaptic plasticity might explain difficulties with sustained attention, impulse control, and working memory—core symptoms of the disorder.

Moreover, CDH13 affects neural network formation and integration, which refers to the communication between different brain regions. In ADHD, these networks may fail to synchronize properly, particularly in areas like the prefrontal cortex (Fornito et al., 2020). This lack of coordination may explain the difficulties individuals with ADHD have in organizing tasks, filtering distractions, and regulating emotions. Such disruptions in neural connectivity are thought to contribute to the severity of ADHD symptoms, particularly in complex tasks requiring sustained mental effort and focus.

Dysregulation of the dopamine system is a well-established neurobiological feature of ADHD. Dopamine is a neurotransmitter that plays a central role in attention regulation, reward processing, and motivation (Volkow et al., 2009). While genes like DAT1, which codes for the dopamine transporter, have been extensively studied in relation to ADHD, CDH13 is now believed to play an indirect but significant role in modulating dopamine pathways (Sallee, 2019).

CDH13 influences dopamine receptor expression in regions of the brain involved in the reward system, such as the ventral striatum and nucleus accumbens. These regions are critical for processing rewards and motivating goal-directed behavior (Meyer-Lindenberg et al., 2012). When CDH13 is disrupted, the brain’s ability to regulate reward-seeking behavior may be impaired, leading to decreased motivation and difficulties with sustained attention—both common challenges for individuals with ADHD.

The connection between CDH13 and dopamine highlights how the functioning of neural circuits and the regulation of neurotransmitters can have profound effects on behavior. Altered dopamine regulation due to variants in CDH13 could explain why individuals with ADHD often struggle with tasks that involve delayed or absent rewards or feedback (Nadeem et al., 2016), reinforcing the need for a better understanding of genetic contributions to ADHD.

The prefrontal cortex is a key brain region responsible for decision-making, impulse control, and attention regulation (Zarrouf et al., 2019). CDH13 has been shown to influence the function of this area, with alterations in its expression potentially impairing executive functions. In ADHD, executive dysfunction manifests as difficulties with planning, prioritizing tasks, and regulating attention over time. These cognitive impairments are likely linked to disruptions in synaptic plasticity and neural connectivity caused by variations in CDH13 (Fornito et al., 2020).

While genetic factors, including CDH13, play a key role in ADHD susceptibility, environmental factors also contribute significantly to the expression and severity of the disorder. Gene-environment interactions can modulate how CDH13 variants affect brain development and behavior, with environmental stressors, early life experiences, and social contexts potentially exacerbating or mitigating ADHD symptoms (Biederman et al., 2006; Nigg, 2013).

Stress during critical periods of brain development, such as early childhood, can influence gene expression and synaptic plasticity in ways that exacerbate ADHD symptoms. For example, children exposed to high levels of stress or trauma may experience alterations in how their brain circuits develop, particularly in areas related to attention, impulse control, and emotional regulation (McEwen, 2007). This is significant for ADHD because stress during these periods could worsen the dysfunctions in neural connectivity and dopamine regulation caused by CDH13 variations (Kendler et al., 2015). Early adversity may further disrupt synaptic plasticity and cognitive function, reinforcing the difficulties with attention and executive functioning seen in ADHD (Roth, 2017).

The expression of ADHD symptoms is also influenced by cultural and social factors. For instance, children growing up in supportive and structured environments may develop better coping mechanisms and social skills, which could buffer against the negative effects of ADHD (Miller & Tanguay, 2018). Conversely, stressful environments, such as those marked by socioeconomic hardship or familial instability, could amplify ADHD symptoms, making it harder for individuals to succeed academically and socially (Hammen, 2019). The role of environmental stress underscores the complex interaction between genetics and environmental influences in the expression of ADHD symptoms (Biederman et al., 2006; Hammen, 2019).

Thus, understanding the role of CDH13 in ADHD also involves recognizing the importance of the environment in shaping brain development and behavior. Environments that support cognitive and emotional growth can potentially mitigate the negative impact of genetic predispositions, while stressful environments may worsen outcomes.

The growing understanding of CDH13’s role in ADHD offers important implications for clinical practice, especially in the areas of diagnosis, treatment, and personalized care.

As research continues to reveal the genetic underpinnings of ADHD, genetic screening for CDH13 variants may become a valuable tool in diagnosing the disorder. Identifying specific CDH13 variants could help clinicians better understand the neurobiological mechanisms at play and tailor treatment approaches accordingly. For instance, patients with certain CDH13 variants may benefit from medications that target neurotransmitter systems, such as dopamine reuptake inhibitors, which are commonly used to treat ADHD symptoms (Muller et al., 2020).

CDH13’s role in synaptic plasticity suggests that therapies aimed at enhancing neural connectivity could be particularly effective for individuals with ADHD. Cognitive interventions, such as cognitive-behavioral therapy (CBT) or neurofeedback, could help strengthen the brain circuits that support attention and executive function (Hughes & Dawson, 2019). Additionally, pharmacological treatments that enhance synaptic plasticity, such as stimulant medications or new compounds aimed at regulating dopamine and serotonin systems, could be explored for individuals with CDH13-related ADHD (Muller et al., 2020).

Since gene-environment interactions play a significant role in ADHD, environmental interventions should also be part of the treatment approach. Strategies such as providing a structured routine, reducing stress, offering behavioral support, and fostering positive social interactions can help mitigate the effects of CDH13 variants and support better outcomes for individuals with ADHD (Brown et al., 2017). Environmental modifications can complement genetic treatments and improve daily functioning in individuals with ADHD.

Given the complex role of CDH13 in ADHD, further research is needed to deepen our understanding of how this gene influences brain development and behavior.

Future studies should focus on identifying specific CDH13 gene variants associated with ADHD and how they impact neural circuits and neurotransmitter systems. This research could help refine diagnostic criteria and lead to more targeted treatment options. For instance, a better understanding of how certain variants of CDH13 contribute to ADHD symptoms could allow for the development of genetic screening tools to predict susceptibility to ADHD and identify the most effective treatments (Biederman et al., 2006; Nigg, 2013).

More research is needed to explore how CDH13 influences synaptic plasticity and neuroplasticity in individuals with ADHD. Understanding the mechanisms through which CDH13 shapes neural networks could offer insights into novel therapeutic strategies aimed at improving attention and cognitive control. Specifically, research could examine how variations in CDH13 alter synaptic organization, affecting attention, executive function, and working memory in ADHD (Muller et al., 2020; Hughes & Dawson, 2019). This could lead to therapeutic strategies targeting synaptic plasticity to enhance cognitive function in individuals with ADHD.

Future studies should also focus on gene-environment interactions, examining how environmental factors, such as stress, nutrition, and social support, influence the expression of CDH13 and the development of ADHD. This line of research could lead to more personalized and effective interventions for individuals at risk for ADHD. For example, understanding how early life stressors or a lack of social support exacerbate CDH13-related neurodevelopmental disruptions could help tailor environmental interventions to mitigate ADHD symptoms (Biederman et al., 2006; Hammen, 2019). The goal would be to identify individuals at higher genetic risk for ADHD who could benefit from early environmental interventions, such as stress management or structured learning environments.

Gaps in the Literature : 

 Despite significant progress in understanding the genetic basis of ADHD, especially regarding the role of CDH13, there remain several key gaps in the literature. One major limitation is the lack of longitudinal studies that track individuals over time to examine how CDH13 variants influence ADHD from childhood through adulthood. This gap hampers our ability to pinpoint critical developmental periods when interventions may be most effective. Furthermore, while gene-environment interactions are recognized as important, there is insufficient research on how factors like stress, diet, and socio-economic conditions affect CDH13 expression and contribute to ADHD symptoms. Another gap is the limited exploration of specific CDH13 variants, with most studies grouping individuals broadly, without examining how particular genetic variations impact ADHD. Additionally, while CDH13 is known to affect synaptic plasticity, more research is needed to understand how these mechanisms specifically contribute to ADHD symptoms such as impaired attention and executive function. Studies focusing on sex differences in the expression of CDH13 and its impact on ADHD are also lacking, despite evidence suggesting varying ADHD presentations in males and females. Moreover, there is limited integration of neuroimaging studies to visualize how CDH13 variations affect brain structure and function, and a lack of research on whether CDH13 can serve as a therapeutic target. Finally, most genetic studies are based on Western populations, and there is a need for more research in diverse populations to ensure the findings are applicable across ethnic and cultural groups. Addressing these gaps will advance ADHD research and improve diagnosis and treatment strategies.

THEME: MAOA GENE AND AGGRESSIVE BEHAVIOUR

The MAOA gene regulates the breakdown of neurotransmitters like serotonin, dopamine, and norepinephrine, which are crucial for emotional regulation. Mutation of these genes is likely to disrupt the balance of neurotransmitters in the brain, potentially leading to heightened aggression, anxiety, and impulsive behavior. The debate surrounding the role of genetics influencing human behavior, particularly aggression, has long intrigued researchers. Such behavior has been dominated by investigations into the monoamine oxidase A (MAOA) gene. The interaction between genetic predispositions (Biochemical composition) and environmental influences (Nature) throws light on the roots of aggression and antisocial behaviors.  This theme is relevant to our overall study of MAOA and CDH13 genes influencing the human psyche and the traits as a product of the mutation of these genes have far-reaching consequences for individual mental health, potential criminal tendencies, and broader societal stability.

CURRENT INVESTIGATIONS–

The existing body of literature on the MAOA gene has consistently linked the MAOA-L variant to increased aggression and antisocial tendencies, particularly when coupled with adverse childhood experiences. Various studies including (Sohrabi, 2013), back the same. This study highlights the association of the MAOA-L variant with heightened aggression underscoring the importance of genes-environment interactions, and noting that childhood adversity amplifies the behavioral outcomes of MAOA-L carriers. It provides us with an example of a Dutch family whose male members have a history of violent behavior. It was discovered that they carried a harmful mutation in the MAOA gene, a mutation that was not present in the non-violent relatives.

Another research involving Syrian refugees (Christopher J. Clukay, Rana Dajani, 2019), highlights that resilience plays a pivotal role in reducing the impact of MAOA variants on stress outcomes. This study underscores the influence of social and environmental factors as protective buffers against genetic predispositions. The research collected data from urban centers in northern Jordan, including Irbid, Jarash, Mafraq,  and Zarqa, and stated that MAOA-L males with high resilience levels demonstrated lower perceived stress than their counterparts with low resilience. This reflects on the interplay between environmental buffers and genetic predispositions.

Additionally, studies utilizing functional MRI have provided deeper insights into the brain’s response to stress, revealing how MAOA variants can alter neural connectivity impacting human responses to stimuli around. This research (Sun, 2020), states that MAOA-H allele carriers showed exaggerated stress responses, with reduced hippocampal activity under stress. Functional MRI reports in the study revealed altered hippocampal connectivity in MAOA-H carriers during stress, suggesting a genetic basis for changes in stress resilience.

The above studies, as well as other relevant studies in the paper, provide us with insights to answer, can individuals be held accountable for actions influenced by their genetic makeup?

 GAPS IN EXISTING LITERATURE–

Despite advances in the study of the MAOA gene and its impact on the human psyche, significant gaps persist. A key issue in psychological and behavioral research is the overrepresentation of the Western populations. Most studies on genetics, like the MAOA-L (monoamine oxidase A low activity) gene’s association with aggression, have been conducted within these populations, leading to a limited understanding of how these genetic factors may interact with different cultural or societal factors. The manifestation of MAOA-L-associated aggression in non-Western contexts, where social structures and stressors differ, is poorly understood.

This theme plays a critical role in helping us better understand aggressive and antisocial behavior, both from the perspective of individual mental health and the broader impact on society.  By exploring genes like MAOA, often linked to aggressive tendencies in certain situations, researchers can explore some of the most pressing questions about where human aggression and impulsivity truly come from. It helps us delve deep into the Nature vs Nurture debate explaining the basis or influential factors of common human behaviours. 

THEME: ENVIRONMENTAL FACTORS SUCH AS CHILDHOOD TRAUMA IN THE CONTEXT OF MAOA AND CDH13

MAOA and CDH13 Genes also known as monoamine oxidase A and T-cadherin are genes that work together to shape human behavior.MAOA genes help regulate serotonin, dopamine, and norepinephrine in the body. Serotonin and Dopamine control emotions. While the CDH13 Genes play an important role in how brain cells connect and communicate. The interaction of environmental factors such as childhood trauma and Genetic predispositions such as CDH13 and MAOA mutations affects human behavior. Experiences of traumatic situations during important development periods can Exacerbate the behavior effect of MAOA and CDH13 gene. Which may lead to aggressive, impulsive behavior and emotional dysregulation. The collaboration between these genetic variations and environmental Difficulties contributes to a deeper understanding of societal challenges like violence and substance abuse.

This theme focuses on exploring how genetic and environmental interactions shape our minds, giving insights into the underlying mechanisms of aggression, resilience, and emotional instability. The impact of trauma on these genes not only affects individuals’ mental health but also has broader effects on societal well-being.

CURRENT INVESTIGATIONS-

The existing body of literature highlights the important interaction between environmental factors and Genetic predispositions in forming behavior. Various studies including Caspi et al. (2002) where scientists focused on the individuals with MAOA gene (MAOA-L)  a variant exposed to childhood trauma are more likely to show antisocial and aggressive behavior. This study highlights the importance of gene-environment interactions in understanding behavioral outcomes. Another study by Tiihonen et al.(2015) linked CDH13 variants to increased aggression and impulsivity mainly in individuals exposed to early adversity. This study indicates how trauma affects neural connectivity, compounding the behavioral effects of genetic susceptibility.

Other studies are by Christopher J. Clukay and Rana Dajani 2019 where they studied Syrian refugees and showed that resilience reduces the effects of genetic predispositions like MAOA variants on stress responses.MAOA variant MAOA-L transports with high resilience displayed reduced stress levels, featuring the protective role of environmental agents. There is a neuroimaging study on trauma and stress by Sun (2020) that used functional MRI to examine stress responses in MAOA-H carriers, revealing inflated neural responses and reduced hippocampal connectivity under stress. These findings showed how trauma-induced changes in brain functions complement genetic predispositions.

GAPS IN EXISTING LITERATURE–

Despite meaningful advancements, several gaps remain in understanding the interplay between Environmental factors, MAOA, and CDH13. Most studies have been administered in Western populations leading to a gap in understanding how genetic factors manifest in non-western cultures. Social structures and stressors differ over the world, and research should consider diverse cultural contexts. The studies also lack long-term studies tracking how environmental stressors and childhood trauma interact with MAOA and CDH13 over an individual’s lifespan. More studies are needed to specify epigenetic mechanisms through which trauma alters MAOA and CDH13 expressions, specifically in different developmental stages and different genders.

This theme sheds light on the intricate relationship between environment and genetics in shaping & forming behavior, featuring the importance of interdisciplinary research. It also asks particular discussions on ethical questions, such as accountability for genetically influenced behaviors, and emphasizes the need for preventive strategies to address childhood trauma as a modifiable risk factor for behavioral disorders. 

THEME: MAOA, CDH 13 AND NEUROTRANSMITTERS

The human brain is the most complex organ of the human body, controlled by a unique balance of genes, chemical signals, and the environment. Important among those genes and chemicals that affect behavior and mental health are the MAOA gene, the CDH13 gene, and neurotransmitters. This piece is about what they do and how they function together to impact brain activity and behavior.

Neurotransmitters are molecules that carry out communication between neurons. They are central to every aspect of brain function, from mood regulation to motor control. Some key neurotransmitters are serotonin, which modulates mood, sleep, appetite, and emotion. Low levels of serotonin are linked to depression and anxiety .; dopamine governs reward, motivation, and motor control. Its dysregulation is implicated in conditions like schizophrenia and Parkinson’s disease.; and norepinephrine regulates attention, arousal, and the fight-or-flight response.

The MAOA and CDH13 genes, along with neurotransmitters, form a dynamic trio that governs brain function and behavior. While the MAOA gene regulates the chemical environment of the brain, the CDH13 gene ensures the structural foundation for neural communication. Neurotransmitters act as messengers, translating these genetic influences into tangible effects on mood, cognition, and behavior.

Understanding the interplay between these components not only sheds light on the biological basis of behavior but also offers potential pathways for therapeutic interventions. Advances in genetic research and neuroscience hold promise for developing targeted treatments for mental health and neurodevelopmental disorders.

CURRENT INVESTIGATION – 

Various studies have explored the roles of the MAOA and CDH13 genes in neurotransmitter regulation and their implications for behavior and mental health.

The monoamine oxidase A gene codes for an enzyme involved in the catabolism of monoamines, including serotonin, dopamine, and norepinephrine. This helps maintain the equilibrium of neurotransmitter activity within the central nervous system. Altered MAOA function is associated with behavioral alterations characterized by impulsivity and aggression.

(Caspi et al. in 2002 )Demonstrated an early experiment indicating how low-activity variants of the MAOA gene interacted with environmental stressors to predict antisocial behavior. Their study, which targeted maltreated children, reported that such individuals with a low-activity variant of MAOA were more than twice as likely to show aggression. The researchers thus set down the hypothesis that MAOA exhibits a gene-environment interaction.

More recent studies have emphasized functional imaging studies. For instance, (Buckholtz and Meyer-Lindenberg 2008) employed fMRI to show that low-activity MAOA variants were associated with increased amygdala reactivity to emotional stimuli. This provides a possible pathway through which MAOA variants influence aggressive behavior: through the dysregulation of serotonin levels and the enhancement of emotional responses.

The cadherin 13 gene encodes T-cadherin, a protein that plays a role in cell adhesion and neuronal connectivity. Although CDH13’s direct role in neurotransmitter regulation is not as well-defined as MAOA’s, it has been implicated in neurodevelopmental processes that affect behavioral regulation.

Neale et al. (2010) identified CDH13 as one of the candidate genes associated with attention-deficit hyperactivity disorder (ADHD) through genome-wide association studies (GWAS). Since ADHD is characterized by dysregulation of dopamine and norepinephrine pathways, this finding may indicate a potential link between CDH13 and neurotransmitter systems.

Additional evidence arises from the studies of CDH13 variants in violent or impulsive populations. For example, (Tiihonen et al. 2015) studied Finnish individuals with serious criminal backgrounds and found that CDH13 variants were associated with violent offending. The exact neurobiological mechanisms are not clear, but the study suggested that CDH13 may contribute to aggression by altering synaptic transmission and connectivity within dopamine-regulated brain circuits.

The combined role of MAOA and CDH13 in neurotransmitter systems, thus potentially acting together to modify behavior, also underlines that dysfunction in MAOA can synergize with structural and connectivity abnormalities in CDH13, thus potentially exaggerating serotonin and dopamine levels responsible for impulsivity and aggression.

A crucial study by (Ferguson et al. 2020) examined the interaction between genetic variations of MAOA and CDH13 in youth. They determined that adolescents with a low-activity variant of MAOA and a risk allele of CDH13 had increased aggression and impulsivity compared to adolescents with only one genetic risk factor. This suggests that these genes may interact together in pathways related to emotional regulation.

Serotonin and dopamine disturbances have been consistently associated with aggression and impulsive behavior; both are influenced by MAOA and CDH13. In particular, the role of MAOA in degrading serotonin is critical because low levels of serotonin have been associated with impulsive aggression (Seo et al., 2008). CDH13 may influence the development and function of dopamine circuits, contributing to behavioral phenotypes such as ADHD or conduct disorders. 

Major avenues for continued research are likely to be therapeutic interventions into the pathways identified above. For example, studies into SSRIs on individuals carrying low-activity variants of MAOA seek to stabilize serotonin levels in mitigating aggression. In a like manner, understanding how CDH13 influences brain connectivity may inform novel treatments of neurodevelopmental disorders.

Both MAOA and CDH13 play important roles in the regulation of neurotransmitter systems, with implications for behavior. MAOA is involved mainly in the degradation of neurotransmitters, whereas CDH13 plays a role in neurodevelopmental processes that affect neurotransmitter dynamics. Together, these genes form part of a complex network underlying aggression, impulsivity, and related behaviors.

GAPS IN EXISTING LITERATURE – 

Although the role of MAOA is well established in breaking down neurotransmitter degradation (for example, serotonin, and dopamine), the mechanisms with which CDH13 exerts its influence in neurotransmitter regulation are not understood. CDH13 is extensively studied for its role in cell adhesion and neural connectivity. However, research on its more direct effects on dopamine or serotonin pathways is rather limited.

Speculative interactions of CDH13 with neurotransmitter systems, through synaptic plasticity or receptor regulation, are more speculative and subject to further empirical research.

Few studies have interrogated how the MAOA and CDH13 genetic variants might engage to modulate neurotransmitter functions and behavior. Although some such studies (eg, Ferguson et al., 2020), indicate synergism, there are no clear definitions of how their interaction might couple the regulation of brain circuits together or lead to phenotypic outcomes such as aggression or impulsivity.

It is sparse multi-omics approaches (involving integrating genomics, transcriptomics, and proteomics) research to study in detail their cross-talk.

Although the interaction between MAOA variants and environmental factors, such as childhood maltreatment, has been well established, such studies are missing for CDH13.              

The role of environmental or epigenetic modifications in modulating CDH13 expression and its downstream effects on neurotransmitter pathways is not known.

Epigenetic modifications of MAOA and CDH13, such as DNA methylation and histone modifications, and their impact on gene expression and behavior remain unexplored.

Most of the studies about MAOA have been on males because the gene is located on the X chromosome. The function of MAOA in females, who have two X chromosomes, has not been extensively studied. Likewise, studies about the sex-specific effects of CDH13 are scarce, though neurotransmitter systems are known to be sex-specific.

It might thus help elucidate sex-based disparities in aggression or related disorders’ prevalence to understand how these genes differentially impact males and females.

Previous research often targeted adults or specific behavioral outcomes, neglecting the differential role of MAOA and CDH13 at various developmental stages. For instance, it’s poorly understood how these genes affect neurotransmitter systems during critical periods of brain development, such as adolescence.

The longitudinal studies, therefore, follow up on individuals from early development into adulthood to map the dynamic influences of these genes over time.

Many studies have been conducted on MAOA and CDH13 within Western populations. This might limit the generalizability of the findings because genetic variation in these genes, as well as cultural differences in environmental stressors or behavioral norms, may influence the results.

Studies that are cross-cultural and ethnically diverse are necessary to establish whether findings are universal or population-specific.

The literature on MAOA and CDH13 is biased toward aggression, impulsivity, and antisocial behavior. However, these genes likely influence a much broader spectrum of behaviors and psychiatric conditions, such as depression, anxiety, and autism spectrum disorder. 

Future research should look into the roles of these genes in less-studied behavioral domains and comorbid conditions to fully capture their impact.

Insights into the MAOA and CDH13 Genes

Advances in single-cell RNA sequencing allow scientists to study the activity of MAOA and CDH13 genes in individual brain cells. This provides a clearer picture of how these genes function in specific types of brain cells, shedding light on their roles in brain development and behavior. For example, researchers can now identify which cells in the brain are most affected by these genes, leading to more precise insights into their effects.

Optogenetics is a technique that uses light to control genes and neural activity in living animals. This tool lets scientists switch certain brain circuits on or off to see how MAOA and CDH13 influence behavior. These experiments are helping to prove how these genes directly impact emotions, decision-making, and other mental processes.

Studies have shown that the frequency of certain versions of MAOA and CDH13 varies between populations. These differences may have evolved as adaptations to specific environments or lifestyles. For example, some gene variants might have provided benefits in certain climates or social settings, which is why they are more common in certain regions.

The influence of MAOA and CDH13 genes on behavior is complex, and culture plays a significant role in shaping their effects. Here’s how supportive environments versus stressful ones can impact the way these genes are expressed and influence behavior:

1. Supportive Environments and Buffering Effects

In societies with strong family and community networks, individuals are often surrounded by positive relationships, stability, and emotional resources. These conditions can help mitigate the potential negative effects of risky genetic variants. Here’s why:

• Reduced Stress Levels: Social support can lower stress hormones like cortisol, which are known to interact with genetic expression. Lower stress can prevent genes like MAOA and CDH13 from being over-activated or dysregulated in ways that lead to aggressive or antisocial behavior.
  
  

• Healthy Coping Mechanisms: People in supportive environments are more likely to learn and use positive coping strategies, which can counteract tendencies toward impulsivity or aggression that might be associated with these genetic variants.
  
  

• Epigenetic Changes: Positive social interactions and nurturing relationships can lead to beneficial epigenetic modifications, which means the environment influences how genes are “turned on” or “turned off” without changing the DNA sequence itself.
  
  

• Role Models and Community Values: Strong cultural or familial structures may promote behaviors like empathy, cooperation, and self-regulation, which can help offset the impulsive or aggressive tendencies linked to these genes.
  
  

2. Stressful Environments and Amplifying Effects

On the flip side, stressful environments can exacerbate the impact of risky genetic variants. This happens because stress interacts with genetic predispositions in several harmful ways:

• Increased Stress Hormones: Chronic stress, common in environments with poverty or violence, can amplify the activity of genes like MAOA, particularly those linked to neurotransmitter regulation. This can lead to imbalances in brain chemicals like serotonin and dopamine, which are associated with mood and aggression.
  
  

• Impulsive and Risky Behaviors: High-stress environments often create conditions where impulsive or aggressive behaviors may seem like adaptive responses, especially in settings where survival or protection is prioritized over long-term planning or cooperation.
  
  

• Limited Access to Resources: In environments with limited access to education, mental health services, or stable employment, individuals with risky genetic variants may not have the tools or support to manage their tendencies effectively.
  
  

• Trauma and Epigenetic( Changing Gene Activity Without Changing DNA) Changes: Adverse experiences, such as exposure to abuse or violence, can cause harmful epigenetic modifications. These changes may increase the expression of risky genetic traits, making individuals more vulnerable to negative behavioral outcomes.
  
  

MAOA and CDH13 affect the brain differently across life stages. In early childhood, MAOA helps regulate brain chemicals like serotonin, critical for mood and bonding, while CDH13 builds neural connections, influencing attention and learning. Disruptions here can lead to emotional or behavioral issues.During adolescence, the brain undergoes major changes, especially in areas controlling emotions and decision-making, making it a critical period for the effects of MAOA and CDH13. The MAOA gene, which regulates neurotransmitters like serotonin and dopamine, influences impulsivity and emotional control. Adolescents with certain MAOA variants may struggle with heightened aggression, risk-taking, or mood swings, especially in stressful environments. Meanwhile, the CDH13 gene, responsible for forming and refining neural connections, impacts focus, planning, and impulse regulation. Variants of CDH13 during this stage are linked to symptoms like inattention, hyperactivity, and poor decision-making. The rapid emotional and social changes of adolescence, combined with stress or negative peer influences, can amplify these effects, increasing risks for behavioral issues, anxiety, or depression. Recognizing these symptoms early could help target interventions like therapy or stress management to support healthy development. In adulthood, MAOA and CDH13 stabilize brain function, but early experiences shape stress responses, self-control, and mental health. Later in life, MAOA’s role in brain chemical balance and CDH13’s influence on neural connectivity affect aging-related challenges like cognitive decline.

Neural Circuit Dynamics

MAOA’s Role in Neural Circuitry

• Emotional Regulation:
  Variants of the MAOA gene impact the limbic system, especially the amygdala, which processes emotions. Low-activity MAOA variants can cause heightened amygdala reactivity to emotional stimuli, making it harder for the prefrontal cortex to regulate emotional responses. This imbalance often leads to impulsive or aggressive behaviors.
• Reward Sensitivity:
  MAOA’s regulation of dopamine affects the reward system centered in the nucleus accumbens. This alters motivation, reward-seeking behaviors, and decision-making, often leading to difficulty controlling impulsive actions in rewarding or high-risk scenarios.

CDH13’s Role in Neural Architecture

• Synaptic Development:
  CDH13 influences the formation and shape of dendritic spines, the structures where neurons communicate. Variations in this gene affect synaptic plasticity, crucial for learning and memory.
• Network Integration:
  CDH13 is vital for connecting local and long-range neural circuits. Disruptions can impair synchronization across brain networks, affecting attention, executive function, and emotional regulation.

Future Research Directions

Focus Areas

1. Circuit Mapping:
   Advanced techniques like optogenetics and calcium imaging can reveal how these genes influence specific neural circuits over time.
2. Gene-Environment Interactions:
   Research should explore how factors like stress, trauma, or enriched environments affect gene expression and neural plasticity.

CONCLUSION 

The relationship between the MAOA and CDH13 genes and their influence on the human psyche offers valuable insights into the intricate links between biology and behavior. The MAOA gene is often referred to as the “warrior gene” as it regulates emotional balance. Various studies present a notable interlink between environmental stressors and variants of the MAOA gene influencing levels of aggression and impulsivity. On the other hand, CDH13 is often seen as the “architect gene”. It plays a key role in building and maintaining neural connections. It impacts brain structure and functioning suggesting that it may shape pathways critical for self-control and impulse management. Research, including that by Ferguson et al. (2020), has shown that individuals carrying dangerous variants for both MAOA and CDH13 are more likely to exhibit impulsivity and aggression than those with just one genetic predisposition. These two genes together help us understand how behavior is shaped by the interplay of genetics and life experiences pointing towards the importance of examining the combined effects of these genes rather than studying them in isolation. This review helps us reflect upon crucial questions such as, “How epigenetic changes might affect both MAOA and CDH13, and how these changes could be shaped by life experiences or stress” or “ CDH13’s influence on neurotransmitter systems”. These genes do not determine violent behavior outright but their interaction with nature and one’s life experiences can increase the likelihood of aggression or impulsivity in certain individuals. Scientific research suggests that these genetic variants, the MAOA and CDH13 genes, do not independently determine violent behavior but their link to behavioral traits such as aggression and impulsivity combined with environmental factors like childhood abuse or social isolation, may increase the likelihood of such behaviors. The research referenced in this review analyzed the gene-environment interaction model of both the genes, showing how genetic predispositions when combined with negative experiences, can increase the chances of antisocial and criminal behavior. It also reflects upon the complexity of human behavior defined by psychological, biological, and environmental influences. Targeted approaches can be initiated using in-depth research of these gene combinations to cater to the specific needs of individuals at risk of extreme behaviors. Future research should focus on studying how epigenetic modifications may influence the expression of MAOA and CDH13 genes, particularly in response to life experiences or stress situations. Furthermore, it is crucial to design personalized interventions aimed at supporting individuals with genetic predispositions and environmental challenges that put them at higher risk of extreme behavioral outcomes. These interventions should focus on providing strategies to reduce risks and promote positive behavioral development. By addressing these aspects, future research can pave the way for a more ethically responsible and scientifically grounded approach to understanding and managing the complexities of behavioral genetics.

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