La curieuse personnalité de l'allèle DRD4-7september 13, 2019
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Gyrification, risk taking, and greater attention to negativity
Posted Sep 13, 2019
In recent years, the DRD4 gene has remained the target of attention for its association with a number of the key staples of common behavioral disorders and illnesses – ADHD1, Schizophrenia2, and excessive gambling3 to name a few.
The use of dopamine within the brain typically facilitates executive functioning and decision making, reward and feel-good systems, and motor functioning, and for these reasons, dopamine-related dysfunction is often associated with problematic behavior.
DRD4 is the gene that codes for the building of the Dopamine 4 receptor, a G Protein usually found on the post synaptic membrane throughout the mesocorticolimbic projections. There are multiple alleles of this gene, all which build a slightly different version of the DRD4 receptor, but DRD4-7r is drawing the most attention.
DRD4-7r is famous in neuroscience circles for being a problematic member of chromosome 11. Palaniyappan et al. recently found that those with DRD4-7r and a diagnosis of ADHD had less prefrontal gyrification than those with a different DRD4 allele4. Gyrification analysis is a relatively novel approach at assessing neural development by exploring the extent of cortical folding in contrast to volume analysis, which has been done traditionally using voxel morphometry. Gyrification ceases and remains constant by around the second year after birth, but before this crucial milestone, gyrification can be disturbed by perinatal complications. As gyrification is influenced by both environmental and genetic factors, the reduced folding in patients with ADHD and who have the DRD4-7r allele, seems to suggest that the 7r allele could be involved in this hypogyrification4.
Studies of gyrification are now being explored to see if gyrification ratios can predict the onset of psychosis in susceptible individuals5, which is interesting because if the 7r allele plays a role in cortical gyrification, it could also be a part of the molecular orchestra that results in the experience of psychosis, expanding the growing risk factors associated with this allele. In addition, just as the the 7r allele produces a receptor with a lower affinity for dopamine than the shorter allelic variations, the DRD4-7r receptor also has a lower affinity for antipsychotics, such as Clozapine, which could minimize treatment options. This makes the 7r allele, of which 20% of the population has in their genome, cute to say the least.
The 7r allele has also been implicated in the onset of psychopathic behavior. Nikitopoulous et al. found that adolescents with the 7r allele and who received less maternal care and stimulation demonstrated more examples of Conduct Disorder and psychopathic behavior6. Indeed, the receptivity of children with the 7r allele to increased positive parental support is perhaps more crucial to these children than those without the allele. Children with the 7r allele demonstrate higher externalizing behaviors (aggression towards the external environment) when parents demonstrate less sensitive behavior towards their child7. The pathology behind the onset of violent disorders, such as psychopathy, Conduct Disorder, and Antisocial Personality Disorder, is still speculative and involves complex gene x environment interactions, but the presence of 7r could start to explain the depth and frequency of violence when a parent’s love is found wanting.
Interestingly, abnormal gyrification in the right mid cingulate cortex has also been found in adult male criminal psychopaths, and correlates strongly to Factor 1 scores (affective/interpersonal traits) on the Revised Psychopathy Checklist (PCL-R)8. For this reason, along with the greater frequency of externalization under low sensitivity parenting, DRD4-7 should become a gene of interest in future studies seeking to understand dangerous pathologies.
The 7r allele has also recently been implicated in what appears to be a strong introspective capacity. Those with the allele, when viewing negative imagery (negative facial expressions, injuries, insects), demonstrated greater brain activity than those without the allele9. These brain regions included the frontal, temporal, and parietal lobes, as well as limbic regions. This increased activation appears to indicate that when exposed to negative imagery, those with the 7r allele are experiencing greater meaning and association. The nature of this meaning and what it means for the individual is difficult to know, but it does indicate that the environment, when negative, causes significantly increased metabolism, which is likely to result in cognitive fatigue for the carrier faster than someone without the allele, all else being equal.
The 7r allele, therefore, could also be indicative of an introverted personality, in this case, someone who becomes easily fatigued when faced with the negativity of others. As negativity is also experienced as perceptual (versus actual), a negative view of other people could also result in avoidant behaviors and a perpetual quest for solitude for those with this allele.
Coincidentally, those with the 7r allele have also been found to have elevated daytime sleepiness when compared to those without the allele10, almost seeming to doom the carrier to a hermetic lifestyle out of necessity. However, more research is needed to know whether this is due to the DRD4 receptor being expressed in the retina, thus influencing the circadian rhythm, or heightened sensitivity to the environment simply results in more cognitive processing that results in fatigue, or perhaps because of currently unknown impacts of the troublesome allele.
DRD4-7r appears to have profound implications for the carrier, and seems to be involved in a number of fateful activities that could impact the carrier’s entire life. A propensity for greater risk-taking, a heightened sensitivity to the environment, being at greater risk of attention and behavior issues, and demanding more parental attention in the formative years all set one up for an exhausting life – all because of one version of a receptor that isn’t as receptive to stimulation as the other versions. In fact, the receptor, much like the carrier, does not seem to play well with others. The 7r allele almost seems like a mischievous imp, inspiring and pushing the carrier into antisocial and asocial behaviors.
In a world where we have greater access to genetic screening, through genetic counselors and private enterprise, such as 23 and Me, the 7r allele should perhaps be a point of interest for prospective parents. Even though there is nothing inherently terminal or catastrophic about the allele, it is associated with a multitude of behavioral concerns and seems even seems to impact how the carrier thinks and processes thoughts. This could be invaluable for parents when planning and forecasting parenting strategies, and perhaps even provide them with insight into their own lives.
© Jack Pemment, 2019
1. Myer, N., Boland, J., Faraone, S., & Krause, D. (2019). Pharmacogenetics predictors of methylphenidate efficacy response in childhood ADHD. European Neuropsychopharmacology, 29, S957-S958.
2. Rajagopal, V. M., Rajkumar, A. P., Jacob, K. S., & Jacob, M. (2018). Gene–gene interaction between DRD4 and COMT modulates clinical response to clozapine in treatment-resistant schizophrenia. Pharmacogenetics and genomics, 28(1), 31-35.
3. Slutske, W. S. (2019). Genetic and environmental contributions to risk for disordered gambling. In Gambling Disorder (pp. 73-100). Springer, Cham.
4. Palaniyappan, L., Batty, M. J., Liddle, P. F., Liddle, E. B., Groom, M. J., Hollis, C., & Scerif, G. (2019). Reduced Prefrontal Gyrification in Carriers of the Dopamine D4 Receptor 7-Repeat Allele With Attention Deficit/Hyperactivity Disorder: A Preliminary Report. Frontiers in psychiatry, 10.
5. Das, T., Borgwardt, S., Hauke, D. J., Harrisberger, F., Lang, U. E., Riecher-Rössler, A., Palaniyappan, L., Schmidt, A. (2018). Disorganized gyrification network properties during the transition to psychosis. JAMA psychiatry, 75(6), 613-622.
6. Nikitopoulos, J., Zohsel, K., Blomeyer, D., Buchmann, A. F., Schmid, B., Jennen-Steinmetz, C., et al. (2014). Are infants differentially sensitive to parenting? Early maternal care, DRD4 genotype and externalizing behavior during adolescence. Journal of Psychiatric Research, 59, 53-59.
7. King, A. P., Muzik, M., Hamilton, L., Taylor, A. B., Rosenblum, K. L., & Liberzon, I. (2016). Dopamine receptor gene DRD4 7-repeat allele X maternal sensitivity interaction on child externalizing behavior problems: independent replication of effects at 18 months. PloS one, 11(8), e0160473.
8. Miskovich, T. A., Anderson, N. E., Harenski, C. L., Harenski, K. A., Baskin-Sommers, A. R., Larson, C. L., et al. (2018). Abnormal cortical gyrification in criminal psychopathy. NeuroImage: Clinical, 19, 876-882.
9. Gehricke, J. G., Swanson, J. M., Duong, S., Nguyen, J., Wigal, T. L., Fallon, J., et al. (2015). Increased brain activity to unpleasant stimuli in individuals with the 7R allele of the DRD4 gene. Psychiatry Research: Neuroimaging, 231(1), 58-63.
10. Jawinski, P., Tegelkamp, S., Sander, C., Häntzsch, M., Huang, J., Mauche, N., et al. (2016). Time to wake up: No impact of COMT Val158Met gene variation on circadian preferences, arousal regulation and sleep. Chronobiology international, 33(7), 893-905.